Sharon Worcester

A mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death, according to 5-year outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the ACCORD Study Group reported in the March 3 issue of The New England Journal of Medicine.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A1c below 6.0% or to standard therapy with a target HbA1c of 7.0%-7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. All participants were followed until the planned end of the trial; the current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90). The difference between the groups remained nonsignificant throughout the entire period of observation.

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

"These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) ... and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29)," they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy* group (1.42 vs. 1.16), and it remained higher – by 19% - at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA1c in a high-risk population does not result in a significantly lower number of major cardiovascular events after 5 years, compared with therapy that targets "levels that are more typically achieved in person in the United States and Canada (i.e., 7 to 7.9%)," and indeed, the intensive approach was associated with more deaths, they said.

Reasons for the higher mortality in the intensive therapy group prior to the transition to standard therapy are unclear, although findings from ACCORD and other studies rule out hypoglycemia and the degree of reduction in glycated hemoglobin levels as a cause, the investigators noted.

"Further analysis should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality," they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members’ disclosures are available with the full text of the article at http://www.nejm.com.

* CORRECTION, 3/7/2011: An earlier version of this article misstated which group had a 21% higher death rate from any cause. The intensive therapy group had this death rate at the time of transition. This version has been corrected.

A mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death, according to 5-year outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the ACCORD Study Group reported in the March 3 issue of The New England Journal of Medicine.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A1c below 6.0% or to standard therapy with a target HbA1c of 7.0%-7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. All participants were followed until the planned end of the trial; the current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90). The difference between the groups remained nonsignificant throughout the entire period of observation.

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

"These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) ... and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29)," they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy* group (1.42 vs. 1.16), and it remained higher – by 19% - at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA1c in a high-risk population does not result in a significantly lower number of major cardiovascular events after 5 years, compared with therapy that targets "levels that are more typically achieved in person in the United States and Canada (i.e., 7 to 7.9%)," and indeed, the intensive approach was associated with more deaths, they said.

Reasons for the higher mortality in the intensive therapy group prior to the transition to standard therapy are unclear, although findings from ACCORD and other studies rule out hypoglycemia and the degree of reduction in glycated hemoglobin levels as a cause, the investigators noted.

"Further analysis should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality," they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members’ disclosures are available with the full text of the article at http://www.nejm.com.

* CORRECTION, 3/7/2011: An earlier version of this article misstated which group had a 21% higher death rate from any cause. The intensive therapy group had this death rate at the time of transition. This version has been corrected.

A mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death, according to 5-year outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the ACCORD Study Group reported in the March 3 issue of The New England Journal of Medicine.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A1c below 6.0% or to standard therapy with a target HbA1c of 7.0%-7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. All participants were followed until the planned end of the trial; the current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90). The difference between the groups remained nonsignificant throughout the entire period of observation.

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

"These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) ... and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29)," they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy* group (1.42 vs. 1.16), and it remained higher – by 19% - at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA1c in a high-risk population does not result in a significantly lower number of major cardiovascular events after 5 years, compared with therapy that targets "levels that are more typically achieved in person in the United States and Canada (i.e., 7 to 7.9%)," and indeed, the intensive approach was associated with more deaths, they said.

Reasons for the higher mortality in the intensive therapy group prior to the transition to standard therapy are unclear, although findings from ACCORD and other studies rule out hypoglycemia and the degree of reduction in glycated hemoglobin levels as a cause, the investigators noted.

"Further analysis should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality," they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members’ disclosures are available with the full text of the article at http://www.nejm.com.

* CORRECTION, 3/7/2011: An earlier version of this article misstated which group had a 21% higher death rate from any cause. The intensive therapy group had this death rate at the time of transition. This version has been corrected.

A mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death, according to 5-year outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the ACCORD Study Group reported in the March 3 issue of The New England Journal of Medicine.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A1c below 6.0% or to standard therapy with a target HbA1c of 7.0%-7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. All participants were followed until the planned end of the trial; the current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90). The difference between the groups remained nonsignificant throughout the entire period of observation.

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

"These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) ... and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29)," they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy* group (1.42 vs. 1.16), and it remained higher – by 19% - at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA1c in a high-risk population does not result in a significantly lower number of major cardiovascular events after 5 years, compared with therapy that targets "levels that are more typically achieved in person in the United States and Canada (i.e., 7 to 7.9%)," and indeed, the intensive approach was associated with more deaths, they said.

Reasons for the higher mortality in the intensive therapy group prior to the transition to standard therapy are unclear, although findings from ACCORD and other studies rule out hypoglycemia and the degree of reduction in glycated hemoglobin levels as a cause, the investigators noted.

"Further analysis should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality," they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members’ disclosures are available with the full text of the article at http://www.nejm.com.

* CORRECTION, 3/7/2011: An earlier version of this article misstated which group had a 21% higher death rate from any cause. The intensive therapy group had this death rate at the time of transition. This version has been corrected.

A mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death, according to 5-year outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the ACCORD Study Group reported in the March 3 issue of The New England Journal of Medicine.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A1c below 6.0% or to standard therapy with a target HbA1c of 7.0%-7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. All participants were followed until the planned end of the trial; the current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90). The difference between the groups remained nonsignificant throughout the entire period of observation.

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

"These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) ... and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29)," they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy* group (1.42 vs. 1.16), and it remained higher – by 19% - at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA1c in a high-risk population does not result in a significantly lower number of major cardiovascular events after 5 years, compared with therapy that targets "levels that are more typically achieved in person in the United States and Canada (i.e., 7 to 7.9%)," and indeed, the intensive approach was associated with more deaths, they said.

Reasons for the higher mortality in the intensive therapy group prior to the transition to standard therapy are unclear, although findings from ACCORD and other studies rule out hypoglycemia and the degree of reduction in glycated hemoglobin levels as a cause, the investigators noted.

"Further analysis should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality," they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members’ disclosures are available with the full text of the article at http://www.nejm.com.

* CORRECTION, 3/7/2011: An earlier version of this article misstated which group had a 21% higher death rate from any cause. The intensive therapy group had this death rate at the time of transition. This version has been corrected.

A mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death, according to 5-year outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the ACCORD Study Group reported in the March 3 issue of The New England Journal of Medicine.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A1c below 6.0% or to standard therapy with a target HbA1c of 7.0%-7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. All participants were followed until the planned end of the trial; the current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90). The difference between the groups remained nonsignificant throughout the entire period of observation.

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

"These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) ... and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29)," they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy* group (1.42 vs. 1.16), and it remained higher – by 19% - at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA1c in a high-risk population does not result in a significantly lower number of major cardiovascular events after 5 years, compared with therapy that targets "levels that are more typically achieved in person in the United States and Canada (i.e., 7 to 7.9%)," and indeed, the intensive approach was associated with more deaths, they said.

Reasons for the higher mortality in the intensive therapy group prior to the transition to standard therapy are unclear, although findings from ACCORD and other studies rule out hypoglycemia and the degree of reduction in glycated hemoglobin levels as a cause, the investigators noted.

"Further analysis should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality," they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members’ disclosures are available with the full text of the article at http://www.nejm.com.

* CORRECTION, 3/7/2011: An earlier version of this article misstated which group had a 21% higher death rate from any cause. The intensive therapy group had this death rate at the time of transition. This version has been corrected.

Diabetes is independently associated with premature death from numerous causes, including several nonvascular causes, according to findings from an analysis of individual-participant data from 97 prospective studies.

The risk of death from any cause was increased in 40,116 patients with diabetes, compared with 674,945 without diabetes (hazard ratio, 1.80), after adjustment for age, sex, smoking status, and body mass index. Similarly, the patients with diabetes also had increased risks of death from cancer (HR, 1.25), vascular causes (HR, 2.32), "other" nonvascular causes not attributed to cancer (HR, 1.73), and deaths of unknown or ill-defined causes (HR, 1.88), investigators reported in the March 3 issue of the New England Journal of Medicine.

Specific cancers that were found in this study to be moderately associated with premature death in diabetes patients vs. nondiabetes patients were liver, pancreas, ovary, colorectum, bladder, lung, and breast cancer (HRs, 2.16, 1.51, 1.45, 1.40, 1.40, 1.27 and 1.25, respectively), reported Dr. Sreenivasa Rao Kondapally Seshasai of the University of Cambridge (England) and colleagues from the Emerging Risk Factors Collaboration (ERFC).

"Other" causes of death in diabetes patients vs. nondiabetes patients included renal disease; liver disease; pneumonia and other infectious diseases; mental disorders; nonhepatic digestive diseases; external causes; intentional self-harm; nervous-system disorders; and chronic obstructive pulmonary disease, the investigators found (N. Engl. J. Med. 2011;364:829-41).

"These hazard ratios were not appreciably reduced after additional adjustment for systolic blood pressure, lipid levels, C-reactive protein levels, fibrinogen levels, alcohol use, estimated glomerular filtration rate, or indicators of socioeconomic status," the investigators said.

The hazard ratios were, however, reduced considerably after adjustment for fasting glucose or glycated hemoglobin levels, they noted.

Fasting glucose levels exceeding 100 mg/dL – but not levels of 70-100 mg/dL – were associated with excess risk of mortality.

In this study, middle-aged adults with diabetes but without known vascular disease at the time of enrollment generally died earlier than did those without diabetes.

"At 40, 50, and 60 years of age, men with diabetes but without a history of vascular disease would incur about 6.3, 5.8, and 4.5 years of life lost, respectively. The corresponding years of life lost for women with diabetes in middle age were 6.8, 6.4, and 5.4 years, respectively," the investigators wrote. They noted that about 58%, 9%, and 30% of the survival difference at 50 years between those with and without diabetes was attributable to excess vascular, cancer, and noncancer nonvascular deaths, respectively. The number of years of life lost because of diabetes was close to the 7-year reduction in life expectancy among long-term cigarette smokers.

About 40% of the years of life lost as a result of diabetes were attributable to nonvascular conditions, including about 10% attributable to cancer-related death, they said.

The finding of "generally continuous associations" between fasting glucose levels above 100 mg/dL and death suggests that hyperglycemia or a similar factor has direct relevance to the association between diabetes and premature death from these various causes – a finding that is also supported by the "substantial attenuation observed in hazard ratios for death from diabetes after adjustment for markers of glycemia," they added.

In contrast, other risk factors (such as blood pressure, adiposity, inflammation, insulin, and renal function) do not appear to be major mediators of the excess risk of death.

The ERFC is a collaboration that has previously published reports on the associations between lipids, lipoproteins, and inflammatory markers and the risk of vascular disease and cause-specific death. In 2009, the group extended its focus to include analyses of diabetes and other metabolic markers as they relate to incident vascular disease outcomes and cause-specific death. For the current study, the collaboration analyzed individual-participant data from prospective studies with information on diabetes diagnosis or fasting baseline blood-glucose levels. Studies included in the analysis did not select participants on the basis of having previous chronic disease; they did, however, record cause-specific death classified according to clearly defined criteria, and accrued more than 1 year of follow-up data.

The current analysis included 820,900 participants from those studies, of whom 123,205 died. The average age of participants was 55 years, and 48% were women.

The findings of this study have several implications, the investigators said.

For example, the association that was observed between diabetes and deaths resulting from mental and neurologic disease requires further study, with investigation into the possible link between diabetes and onset of depression (especially in light of the association between diabetes and death resulting from intentional self-harm). The findings also reinforce the need for people with diabetes to seek appropriate cancer screenings.

"Future studies are warranted to investigate additional (and potentially more specific) risk factors that may link diabetes and chronic disease, to study non-Western populations, and to explain associations observed between very low glucose levels and vascular death in people without diabetes," they said, concluding that the findings of the study underscore the need for better understanding and prevention of the multisystem consequences of diabetes.

This study was supported by grants from the British Heart Foundation, the U.K. Medical Research Council, Pfizer, the Gates Cambridge Trust Scholarship, an Overseas Research Studentship Award, and an Addenbrooke’s Charitable Trust Clinical Research Fellowship to the EFRC and/or individual EFRC members. Members’ specific disclosures are available with the full text of the EFRC article at NEJM.com.

Diabetes is independently associated with premature death from numerous causes, including several nonvascular causes, according to findings from an analysis of individual-participant data from 97 prospective studies.

The risk of death from any cause was increased in 40,116 patients with diabetes, compared with 674,945 without diabetes (hazard ratio, 1.80), after adjustment for age, sex, smoking status, and body mass index. Similarly, the patients with diabetes also had increased risks of death from cancer (HR, 1.25), vascular causes (HR, 2.32), "other" nonvascular causes not attributed to cancer (HR, 1.73), and deaths of unknown or ill-defined causes (HR, 1.88), investigators reported in the March 3 issue of the New England Journal of Medicine.

Specific cancers that were found in this study to be moderately associated with premature death in diabetes patients vs. nondiabetes patients were liver, pancreas, ovary, colorectum, bladder, lung, and breast cancer (HRs, 2.16, 1.51, 1.45, 1.40, 1.40, 1.27 and 1.25, respectively), reported Dr. Sreenivasa Rao Kondapally Seshasai of the University of Cambridge (England) and colleagues from the Emerging Risk Factors Collaboration (ERFC).

"Other" causes of death in diabetes patients vs. nondiabetes patients included renal disease; liver disease; pneumonia and other infectious diseases; mental disorders; nonhepatic digestive diseases; external causes; intentional self-harm; nervous-system disorders; and chronic obstructive pulmonary disease, the investigators found (N. Engl. J. Med. 2011;364:829-41).

"These hazard ratios were not appreciably reduced after additional adjustment for systolic blood pressure, lipid levels, C-reactive protein levels, fibrinogen levels, alcohol use, estimated glomerular filtration rate, or indicators of socioeconomic status," the investigators said.

The hazard ratios were, however, reduced considerably after adjustment for fasting glucose or glycated hemoglobin levels, they noted.

Fasting glucose levels exceeding 100 mg/dL – but not levels of 70-100 mg/dL – were associated with excess risk of mortality.

In this study, middle-aged adults with diabetes but without known vascular disease at the time of enrollment generally died earlier than did those without diabetes.

"At 40, 50, and 60 years of age, men with diabetes but without a history of vascular disease would incur about 6.3, 5.8, and 4.5 years of life lost, respectively. The corresponding years of life lost for women with diabetes in middle age were 6.8, 6.4, and 5.4 years, respectively," the investigators wrote. They noted that about 58%, 9%, and 30% of the survival difference at 50 years between those with and without diabetes was attributable to excess vascular, cancer, and noncancer nonvascular deaths, respectively. The number of years of life lost because of diabetes was close to the 7-year reduction in life expectancy among long-term cigarette smokers.

About 40% of the years of life lost as a result of diabetes were attributable to nonvascular conditions, including about 10% attributable to cancer-related death, they said.

The finding of "generally continuous associations" between fasting glucose levels above 100 mg/dL and death suggests that hyperglycemia or a similar factor has direct relevance to the association between diabetes and premature death from these various causes – a finding that is also supported by the "substantial attenuation observed in hazard ratios for death from diabetes after adjustment for markers of glycemia," they added.

In contrast, other risk factors (such as blood pressure, adiposity, inflammation, insulin, and renal function) do not appear to be major mediators of the excess risk of death.

The ERFC is a collaboration that has previously published reports on the associations between lipids, lipoproteins, and inflammatory markers and the risk of vascular disease and cause-specific death. In 2009, the group extended its focus to include analyses of diabetes and other metabolic markers as they relate to incident vascular disease outcomes and cause-specific death. For the current study, the collaboration analyzed individual-participant data from prospective studies with information on diabetes diagnosis or fasting baseline blood-glucose levels. Studies included in the analysis did not select participants on the basis of having previous chronic disease; they did, however, record cause-specific death classified according to clearly defined criteria, and accrued more than 1 year of follow-up data.

The current analysis included 820,900 participants from those studies, of whom 123,205 died. The average age of participants was 55 years, and 48% were women.

The findings of this study have several implications, the investigators said.

For example, the association that was observed between diabetes and deaths resulting from mental and neurologic disease requires further study, with investigation into the possible link between diabetes and onset of depression (especially in light of the association between diabetes and death resulting from intentional self-harm). The findings also reinforce the need for people with diabetes to seek appropriate cancer screenings.

"Future studies are warranted to investigate additional (and potentially more specific) risk factors that may link diabetes and chronic disease, to study non-Western populations, and to explain associations observed between very low glucose levels and vascular death in people without diabetes," they said, concluding that the findings of the study underscore the need for better understanding and prevention of the multisystem consequences of diabetes.

This study was supported by grants from the British Heart Foundation, the U.K. Medical Research Council, Pfizer, the Gates Cambridge Trust Scholarship, an Overseas Research Studentship Award, and an Addenbrooke’s Charitable Trust Clinical Research Fellowship to the EFRC and/or individual EFRC members. Members’ specific disclosures are available with the full text of the EFRC article at NEJM.com.

Diabetes is independently associated with premature death from numerous causes, including several nonvascular causes, according to findings from an analysis of individual-participant data from 97 prospective studies.

The risk of death from any cause was increased in 40,116 patients with diabetes, compared with 674,945 without diabetes (hazard ratio, 1.80), after adjustment for age, sex, smoking status, and body mass index. Similarly, the patients with diabetes also had increased risks of death from cancer (HR, 1.25), vascular causes (HR, 2.32), "other" nonvascular causes not attributed to cancer (HR, 1.73), and deaths of unknown or ill-defined causes (HR, 1.88), investigators reported in the March 3 issue of the New England Journal of Medicine.

Specific cancers that were found in this study to be moderately associated with premature death in diabetes patients vs. nondiabetes patients were liver, pancreas, ovary, colorectum, bladder, lung, and breast cancer (HRs, 2.16, 1.51, 1.45, 1.40, 1.40, 1.27 and 1.25, respectively), reported Dr. Sreenivasa Rao Kondapally Seshasai of the University of Cambridge (England) and colleagues from the Emerging Risk Factors Collaboration (ERFC).

"Other" causes of death in diabetes patients vs. nondiabetes patients included renal disease; liver disease; pneumonia and other infectious diseases; mental disorders; nonhepatic digestive diseases; external causes; intentional self-harm; nervous-system disorders; and chronic obstructive pulmonary disease, the investigators found (N. Engl. J. Med. 2011;364:829-41).

"These hazard ratios were not appreciably reduced after additional adjustment for systolic blood pressure, lipid levels, C-reactive protein levels, fibrinogen levels, alcohol use, estimated glomerular filtration rate, or indicators of socioeconomic status," the investigators said.

The hazard ratios were, however, reduced considerably after adjustment for fasting glucose or glycated hemoglobin levels, they noted.

Fasting glucose levels exceeding 100 mg/dL – but not levels of 70-100 mg/dL – were associated with excess risk of mortality.

In this study, middle-aged adults with diabetes but without known vascular disease at the time of enrollment generally died earlier than did those without diabetes.

"At 40, 50, and 60 years of age, men with diabetes but without a history of vascular disease would incur about 6.3, 5.8, and 4.5 years of life lost, respectively. The corresponding years of life lost for women with diabetes in middle age were 6.8, 6.4, and 5.4 years, respectively," the investigators wrote. They noted that about 58%, 9%, and 30% of the survival difference at 50 years between those with and without diabetes was attributable to excess vascular, cancer, and noncancer nonvascular deaths, respectively. The number of years of life lost because of diabetes was close to the 7-year reduction in life expectancy among long-term cigarette smokers.

About 40% of the years of life lost as a result of diabetes were attributable to nonvascular conditions, including about 10% attributable to cancer-related death, they said.

The finding of "generally continuous associations" between fasting glucose levels above 100 mg/dL and death suggests that hyperglycemia or a similar factor has direct relevance to the association between diabetes and premature death from these various causes – a finding that is also supported by the "substantial attenuation observed in hazard ratios for death from diabetes after adjustment for markers of glycemia," they added.

In contrast, other risk factors (such as blood pressure, adiposity, inflammation, insulin, and renal function) do not appear to be major mediators of the excess risk of death.

The ERFC is a collaboration that has previously published reports on the associations between lipids, lipoproteins, and inflammatory markers and the risk of vascular disease and cause-specific death. In 2009, the group extended its focus to include analyses of diabetes and other metabolic markers as they relate to incident vascular disease outcomes and cause-specific death. For the current study, the collaboration analyzed individual-participant data from prospective studies with information on diabetes diagnosis or fasting baseline blood-glucose levels. Studies included in the analysis did not select participants on the basis of having previous chronic disease; they did, however, record cause-specific death classified according to clearly defined criteria, and accrued more than 1 year of follow-up data.

The current analysis included 820,900 participants from those studies, of whom 123,205 died. The average age of participants was 55 years, and 48% were women.

The findings of this study have several implications, the investigators said.

For example, the association that was observed between diabetes and deaths resulting from mental and neurologic disease requires further study, with investigation into the possible link between diabetes and onset of depression (especially in light of the association between diabetes and death resulting from intentional self-harm). The findings also reinforce the need for people with diabetes to seek appropriate cancer screenings.

"Future studies are warranted to investigate additional (and potentially more specific) risk factors that may link diabetes and chronic disease, to study non-Western populations, and to explain associations observed between very low glucose levels and vascular death in people without diabetes," they said, concluding that the findings of the study underscore the need for better understanding and prevention of the multisystem consequences of diabetes.

This study was supported by grants from the British Heart Foundation, the U.K. Medical Research Council, Pfizer, the Gates Cambridge Trust Scholarship, an Overseas Research Studentship Award, and an Addenbrooke’s Charitable Trust Clinical Research Fellowship to the EFRC and/or individual EFRC members. Members’ specific disclosures are available with the full text of the EFRC article at NEJM.com.

A mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death, according to 5-year outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the ACCORD Study Group reported in the March 3 issue of The New England Journal of Medicine.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A1c below 6.0% or to standard therapy with a target HbA1c of 7.0%-7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. All participants were followed until the planned end of the trial; the current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90). The difference between the groups remained nonsignificant throughout the entire period of observation.

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

"These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) ... and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29)," they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy* group (1.42 vs. 1.16), and it remained higher – by 19% - at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA1c in a high-risk population does not result in a significantly lower number of major cardiovascular events after 5 years, compared with therapy that targets "levels that are more typically achieved in person in the United States and Canada (i.e., 7 to 7.9%)," and indeed, the intensive approach was associated with more deaths, they said.

Reasons for the higher mortality in the intensive therapy group prior to the transition to standard therapy are unclear, although findings from ACCORD and other studies rule out hypoglycemia and the degree of reduction in glycated hemoglobin levels as a cause, the investigators noted.

"Further analysis should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality," they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members’ disclosures are available with the full text of the article at http://www.nejm.com.

* CORRECTION, 3/7/2011: An earlier version of this article misstated which group had a 21% higher death rate from any cause. The intensive therapy group had this death rate at the time of transition. This version has been corrected.

A mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death, according to 5-year outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the ACCORD Study Group reported in the March 3 issue of The New England Journal of Medicine.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A1c below 6.0% or to standard therapy with a target HbA1c of 7.0%-7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. All participants were followed until the planned end of the trial; the current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90). The difference between the groups remained nonsignificant throughout the entire period of observation.

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

"These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) ... and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29)," they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy* group (1.42 vs. 1.16), and it remained higher – by 19% - at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA1c in a high-risk population does not result in a significantly lower number of major cardiovascular events after 5 years, compared with therapy that targets "levels that are more typically achieved in person in the United States and Canada (i.e., 7 to 7.9%)," and indeed, the intensive approach was associated with more deaths, they said.

Reasons for the higher mortality in the intensive therapy group prior to the transition to standard therapy are unclear, although findings from ACCORD and other studies rule out hypoglycemia and the degree of reduction in glycated hemoglobin levels as a cause, the investigators noted.

"Further analysis should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality," they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members’ disclosures are available with the full text of the article at http://www.nejm.com.

* CORRECTION, 3/7/2011: An earlier version of this article misstated which group had a 21% higher death rate from any cause. The intensive therapy group had this death rate at the time of transition. This version has been corrected.

A mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death, according to 5-year outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the ACCORD Study Group reported in the March 3 issue of The New England Journal of Medicine.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A1c below 6.0% or to standard therapy with a target HbA1c of 7.0%-7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. All participants were followed until the planned end of the trial; the current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90). The difference between the groups remained nonsignificant throughout the entire period of observation.

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

"These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) ... and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29)," they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy* group (1.42 vs. 1.16), and it remained higher – by 19% - at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA1c in a high-risk population does not result in a significantly lower number of major cardiovascular events after 5 years, compared with therapy that targets "levels that are more typically achieved in person in the United States and Canada (i.e., 7 to 7.9%)," and indeed, the intensive approach was associated with more deaths, they said.

Reasons for the higher mortality in the intensive therapy group prior to the transition to standard therapy are unclear, although findings from ACCORD and other studies rule out hypoglycemia and the degree of reduction in glycated hemoglobin levels as a cause, the investigators noted.

"Further analysis should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood pressure and glycemia trials with respect to mortality," they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members’ disclosures are available with the full text of the article at http://www.nejm.com.

* CORRECTION, 3/7/2011: An earlier version of this article misstated which group had a 21% higher death rate from any cause. The intensive therapy group had this death rate at the time of transition. This version has been corrected.

Patients with type 2 diabetes were more likely to have genetic variations for a key protein regulating cells’ insulin receptors, according to a multinational case-control study.

The variants’ presence could serve as an early predictive marker of insulin resistance and type 2 diabetes, particularly in patients with a family history of the disease, the study’s authors noted.

The investigators examined variations in the high-mobility group A1 protein, or HMGA1, a key regulator of insulin receptor gene expression. The protein’s most frequent functional variant was found in 7.2% of the study’s 3,278 Italian patients with type 2 diabetes, compared with 0.4% and 3.3% of two Italian control groups (2,544 and 784 patients) without diabetes, significant differences resulting in adjusted odds ratios of 15.8 and 2.0, respectively.

In addition, the variant was found in 7.7% of 970 U.S. case patients, compared with 4.7% of 958 U.S. control patients (adjusted odds ratio, 1.6), a significant difference, and in 7.6% of 354 French case patients vs. 0% of 50 French controls, also a significant difference, reported Dr. Eusebio Chiefari of the University of Catanzaro (Italy) and colleagues (JAMA 2011;305:903-12).

Three other functional variants also were observed in the Italian population, although those variants were not studied in the U.S. and French populations because of the relatively small sample sizes.

Overall, when all four variants were analyzed, nearly 10% of Italian patients with type 2 diabetes were found to have HMGA1 defects, compared with less than 1% of controls.

The four functional variants of the HMGA1 gene were also shown to be associated with decreased insulin receptor (INSR) gene and insulin receptor protein expression.

"Because insulin downregulates its own receptor, we performed two different studies to rule out the possibility that the hyperinsulinemia we observed in our patients with HMGA1 gene variants was downregulating the INSR," the researchers said. Both tests ruled out a hyperinsulinemia effect, they added.

"We believe our observation that nearly 10% of individuals with type 2 diabetes have deleterious variations in the gene encoding HMGA1 has important clinical implications," the researchers wrote. In addition to potentially predicting insulin resistance, the variants might predict response to therapy. In addition, patients with HMGA1 variants and type 2 diabetes might have a different clinical course than do other patients with type 2 diabetes, the investigators said. The search for new type 2 diabetes therapies could include agents that upregulate the expression of HMGA1, they added.

More studies of the HMGA1 gene and its variants are needed, the investigators concluded, including studies in other racial types, to improve understanding of the role HMGA1 plays in insulin resistance and type 2 diabetes.

Dr. Chiefari and his colleagues reported no disclosures. Telethon-Italy, MIUR Italy, and the National Institutes of Health providing funding for the study.

Video: Gene Variations Associated With Risk of Type 2 Diabetes, from The JAMA Report

Patients with type 2 diabetes were more likely to have genetic variations for a key protein regulating cells’ insulin receptors, according to a multinational case-control study.

The variants’ presence could serve as an early predictive marker of insulin resistance and type 2 diabetes, particularly in patients with a family history of the disease, the study’s authors noted.

The investigators examined variations in the high-mobility group A1 protein, or HMGA1, a key regulator of insulin receptor gene expression. The protein’s most frequent functional variant was found in 7.2% of the study’s 3,278 Italian patients with type 2 diabetes, compared with 0.4% and 3.3% of two Italian control groups (2,544 and 784 patients) without diabetes, significant differences resulting in adjusted odds ratios of 15.8 and 2.0, respectively.

In addition, the variant was found in 7.7% of 970 U.S. case patients, compared with 4.7% of 958 U.S. control patients (adjusted odds ratio, 1.6), a significant difference, and in 7.6% of 354 French case patients vs. 0% of 50 French controls, also a significant difference, reported Dr. Eusebio Chiefari of the University of Catanzaro (Italy) and colleagues (JAMA 2011;305:903-12).

Three other functional variants also were observed in the Italian population, although those variants were not studied in the U.S. and French populations because of the relatively small sample sizes.

Overall, when all four variants were analyzed, nearly 10% of Italian patients with type 2 diabetes were found to have HMGA1 defects, compared with less than 1% of controls.

The four functional variants of the HMGA1 gene were also shown to be associated with decreased insulin receptor (INSR) gene and insulin receptor protein expression.

"Because insulin downregulates its own receptor, we performed two different studies to rule out the possibility that the hyperinsulinemia we observed in our patients with HMGA1 gene variants was downregulating the INSR," the researchers said. Both tests ruled out a hyperinsulinemia effect, they added.

"We believe our observation that nearly 10% of individuals with type 2 diabetes have deleterious variations in the gene encoding HMGA1 has important clinical implications," the researchers wrote. In addition to potentially predicting insulin resistance, the variants might predict response to therapy. In addition, patients with HMGA1 variants and type 2 diabetes might have a different clinical course than do other patients with type 2 diabetes, the investigators said. The search for new type 2 diabetes therapies could include agents that upregulate the expression of HMGA1, they added.

More studies of the HMGA1 gene and its variants are needed, the investigators concluded, including studies in other racial types, to improve understanding of the role HMGA1 plays in insulin resistance and type 2 diabetes.

Dr. Chiefari and his colleagues reported no disclosures. Telethon-Italy, MIUR Italy, and the National Institutes of Health providing funding for the study.

Video: Gene Variations Associated With Risk of Type 2 Diabetes, from The JAMA Report

Patients with type 2 diabetes were more likely to have genetic variations for a key protein regulating cells’ insulin receptors, according to a multinational case-control study.

The variants’ presence could serve as an early predictive marker of insulin resistance and type 2 diabetes, particularly in patients with a family history of the disease, the study’s authors noted.

The investigators examined variations in the high-mobility group A1 protein, or HMGA1, a key regulator of insulin receptor gene expression. The protein’s most frequent functional variant was found in 7.2% of the study’s 3,278 Italian patients with type 2 diabetes, compared with 0.4% and 3.3% of two Italian control groups (2,544 and 784 patients) without diabetes, significant differences resulting in adjusted odds ratios of 15.8 and 2.0, respectively.

In addition, the variant was found in 7.7% of 970 U.S. case patients, compared with 4.7% of 958 U.S. control patients (adjusted odds ratio, 1.6), a significant difference, and in 7.6% of 354 French case patients vs. 0% of 50 French controls, also a significant difference, reported Dr. Eusebio Chiefari of the University of Catanzaro (Italy) and colleagues (JAMA 2011;305:903-12).

Three other functional variants also were observed in the Italian population, although those variants were not studied in the U.S. and French populations because of the relatively small sample sizes.

Overall, when all four variants were analyzed, nearly 10% of Italian patients with type 2 diabetes were found to have HMGA1 defects, compared with less than 1% of controls.

The four functional variants of the HMGA1 gene were also shown to be associated with decreased insulin receptor (INSR) gene and insulin receptor protein expression.

"Because insulin downregulates its own receptor, we performed two different studies to rule out the possibility that the hyperinsulinemia we observed in our patients with HMGA1 gene variants was downregulating the INSR," the researchers said. Both tests ruled out a hyperinsulinemia effect, they added.

"We believe our observation that nearly 10% of individuals with type 2 diabetes have deleterious variations in the gene encoding HMGA1 has important clinical implications," the researchers wrote. In addition to potentially predicting insulin resistance, the variants might predict response to therapy. In addition, patients with HMGA1 variants and type 2 diabetes might have a different clinical course than do other patients with type 2 diabetes, the investigators said. The search for new type 2 diabetes therapies could include agents that upregulate the expression of HMGA1, they added.

More studies of the HMGA1 gene and its variants are needed, the investigators concluded, including studies in other racial types, to improve understanding of the role HMGA1 plays in insulin resistance and type 2 diabetes.

Dr. Chiefari and his colleagues reported no disclosures. Telethon-Italy, MIUR Italy, and the National Institutes of Health providing funding for the study.

Video: Gene Variations Associated With Risk of Type 2 Diabetes, from The JAMA Report

Patients with type 2 diabetes were more likely to have genetic variations for a key protein regulating cells’ insulin receptors, according to a multinational case-control study.

The variants’ presence could serve as an early predictive marker of insulin resistance and type 2 diabetes, particularly in patients with a family history of the disease, the study’s authors noted.

The investigators examined variations in the high-mobility group A1 protein, or HMGA1, a key regulator of insulin receptor gene expression. The protein’s most frequent functional variant was found in 7.2% of the study’s 3,278 Italian patients with type 2 diabetes, compared with 0.4% and 3.3% of two Italian control groups (2,544 and 784 patients) without diabetes, significant differences resulting in adjusted odds ratios of 15.8 and 2.0, respectively.

In addition, the variant was found in 7.7% of 970 U.S. case patients, compared with 4.7% of 958 U.S. control patients (adjusted odds ratio, 1.6), a significant difference, and in 7.6% of 354 French case patients vs. 0% of 50 French controls, also a significant difference, reported Dr. Eusebio Chiefari of the University of Catanzaro (Italy) and colleagues (JAMA 2011;305:903-12).

Three other functional variants also were observed in the Italian population, although those variants were not studied in the U.S. and French populations because of the relatively small sample sizes.

Overall, when all four variants were analyzed, nearly 10% of Italian patients with type 2 diabetes were found to have HMGA1 defects, compared with less than 1% of controls.

The four functional variants of the HMGA1 gene were also shown to be associated with decreased insulin receptor (INSR) gene and insulin receptor protein expression.

"Because insulin downregulates its own receptor, we performed two different studies to rule out the possibility that the hyperinsulinemia we observed in our patients with HMGA1 gene variants was downregulating the INSR," the researchers said. Both tests ruled out a hyperinsulinemia effect, they added.

"We believe our observation that nearly 10% of individuals with type 2 diabetes have deleterious variations in the gene encoding HMGA1 has important clinical implications," the researchers wrote. In addition to potentially predicting insulin resistance, the variants might predict response to therapy. In addition, patients with HMGA1 variants and type 2 diabetes might have a different clinical course than do other patients with type 2 diabetes, the investigators said. The search for new type 2 diabetes therapies could include agents that upregulate the expression of HMGA1, they added.

More studies of the HMGA1 gene and its variants are needed, the investigators concluded, including studies in other racial types, to improve understanding of the role HMGA1 plays in insulin resistance and type 2 diabetes.

Dr. Chiefari and his colleagues reported no disclosures. Telethon-Italy, MIUR Italy, and the National Institutes of Health providing funding for the study.

Video: Gene Variations Associated With Risk of Type 2 Diabetes, from The JAMA Report

Patients with type 2 diabetes were more likely to have genetic variations for a key protein regulating cells’ insulin receptors, according to a multinational case-control study.

The variants’ presence could serve as an early predictive marker of insulin resistance and type 2 diabetes, particularly in patients with a family history of the disease, the study’s authors noted.

The investigators examined variations in the high-mobility group A1 protein, or HMGA1, a key regulator of insulin receptor gene expression. The protein’s most frequent functional variant was found in 7.2% of the study’s 3,278 Italian patients with type 2 diabetes, compared with 0.4% and 3.3% of two Italian control groups (2,544 and 784 patients) without diabetes, significant differences resulting in adjusted odds ratios of 15.8 and 2.0, respectively.

In addition, the variant was found in 7.7% of 970 U.S. case patients, compared with 4.7% of 958 U.S. control patients (adjusted odds ratio, 1.6), a significant difference, and in 7.6% of 354 French case patients vs. 0% of 50 French controls, also a significant difference, reported Dr. Eusebio Chiefari of the University of Catanzaro (Italy) and colleagues (JAMA 2011;305:903-12).

Three other functional variants also were observed in the Italian population, although those variants were not studied in the U.S. and French populations because of the relatively small sample sizes.

Overall, when all four variants were analyzed, nearly 10% of Italian patients with type 2 diabetes were found to have HMGA1 defects, compared with less than 1% of controls.

The four functional variants of the HMGA1 gene were also shown to be associated with decreased insulin receptor (INSR) gene and insulin receptor protein expression.

"Because insulin downregulates its own receptor, we performed two different studies to rule out the possibility that the hyperinsulinemia we observed in our patients with HMGA1 gene variants was downregulating the INSR," the researchers said. Both tests ruled out a hyperinsulinemia effect, they added.

"We believe our observation that nearly 10% of individuals with type 2 diabetes have deleterious variations in the gene encoding HMGA1 has important clinical implications," the researchers wrote. In addition to potentially predicting insulin resistance, the variants might predict response to therapy. In addition, patients with HMGA1 variants and type 2 diabetes might have a different clinical course than do other patients with type 2 diabetes, the investigators said. The search for new type 2 diabetes therapies could include agents that upregulate the expression of HMGA1, they added.

More studies of the HMGA1 gene and its variants are needed, the investigators concluded, including studies in other racial types, to improve understanding of the role HMGA1 plays in insulin resistance and type 2 diabetes.

Dr. Chiefari and his colleagues reported no disclosures. Telethon-Italy, MIUR Italy, and the National Institutes of Health providing funding for the study.

Video: Gene Variations Associated With Risk of Type 2 Diabetes, from The JAMA Report

Patients with type 2 diabetes were more likely to have genetic variations for a key protein regulating cells’ insulin receptors, according to a multinational case-control study.

The variants’ presence could serve as an early predictive marker of insulin resistance and type 2 diabetes, particularly in patients with a family history of the disease, the study’s authors noted.

The investigators examined variations in the high-mobility group A1 protein, or HMGA1, a key regulator of insulin receptor gene expression. The protein’s most frequent functional variant was found in 7.2% of the study’s 3,278 Italian patients with type 2 diabetes, compared with 0.4% and 3.3% of two Italian control groups (2,544 and 784 patients) without diabetes, significant differences resulting in adjusted odds ratios of 15.8 and 2.0, respectively.

In addition, the variant was found in 7.7% of 970 U.S. case patients, compared with 4.7% of 958 U.S. control patients (adjusted odds ratio, 1.6), a significant difference, and in 7.6% of 354 French case patients vs. 0% of 50 French controls, also a significant difference, reported Dr. Eusebio Chiefari of the University of Catanzaro (Italy) and colleagues (JAMA 2011;305:903-12).

Three other functional variants also were observed in the Italian population, although those variants were not studied in the U.S. and French populations because of the relatively small sample sizes.

Overall, when all four variants were analyzed, nearly 10% of Italian patients with type 2 diabetes were found to have HMGA1 defects, compared with less than 1% of controls.

The four functional variants of the HMGA1 gene were also shown to be associated with decreased insulin receptor (INSR) gene and insulin receptor protein expression.

"Because insulin downregulates its own receptor, we performed two different studies to rule out the possibility that the hyperinsulinemia we observed in our patients with HMGA1 gene variants was downregulating the INSR," the researchers said. Both tests ruled out a hyperinsulinemia effect, they added.

"We believe our observation that nearly 10% of individuals with type 2 diabetes have deleterious variations in the gene encoding HMGA1 has important clinical implications," the researchers wrote. In addition to potentially predicting insulin resistance, the variants might predict response to therapy. In addition, patients with HMGA1 variants and type 2 diabetes might have a different clinical course than do other patients with type 2 diabetes, the investigators said. The search for new type 2 diabetes therapies could include agents that upregulate the expression of HMGA1, they added.

More studies of the HMGA1 gene and its variants are needed, the investigators concluded, including studies in other racial types, to improve understanding of the role HMGA1 plays in insulin resistance and type 2 diabetes.

Dr. Chiefari and his colleagues reported no disclosures. Telethon-Italy, MIUR Italy, and the National Institutes of Health providing funding for the study.

Video: Gene Variations Associated With Risk of Type 2 Diabetes, from The JAMA Report

Antihypertensive therapy appears to benefit patients who have a clinical history of cardiovascular disease, but who have blood pressures in the normal or prehypertensive range, according to a meta-analysis of data from 25 randomized controlled trials involving more than 64,000 such patients.

Compared with control patients who received placebo, study participants without clinically defined hypertension who received antihypertensive treatment for the secondary prevention of cardiovascular disease events had a 23% reduction in risk of stroke, a 20% reduction in risk of myocardial infarction, a 29% reduction in risk of congestive heart failure, a 15% reduction in risk for composite cardiovascular disease (CVD) events, a 17% reduction in risk for cardiovascular disease mortality, and a 13% reduction in risk for all-cause mortality, Angela M. Thompson of Tulane School of Public Health and Tropical Medicine, New Orleans, and colleagues reported in the March 2 issue of JAMA.

The absolute risk reduction per 1,000 persons was -7.7 for stroke, -13.3 for MI, -43.6 for congestive heart failure events, -27.1 for composite CVD events, -15.4 for CVD mortality, and -13.7 for all-cause mortality, the investigators said (JAMA. 2011;305: 913-22).

All pooled relative risk reductions were statistically significant, but the pooled absolute risk reductions did not achieve statistical significance for myocardial infarction and CVD mortality – a discrepancy that reflects "the increased variance of the absolute measures compared with the variance of the relative measures," they explained.

The investigators conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials, as well as a manual examination of references. The 25 trials included represent those that fulfilled all predetermined inclusion and exclusion criteria, and incorporated data from 64,162 participants at least 19 years of age and with blood pressure less than 140 mm Hg systolic or less than 90 mm Hg diastolic. The mean age across the studies ranged from 55 to 68 years; 76% of participants were men, and study duration varied from a mean of 1.5 months to 63 months.

The class and dose of antihypertensive treatments varied, but in most studies it progressively increased to a defined target dose, the investigators noted.

All studies required that participants have a history of cardiovascular disease; clinical evidence of recent MI, congestive heart failure, coronary artery disease, or stroke; or a CVD equivalent such as type 2 diabetes.

No statistically significant benefit of treatment was seen in regard to CVD outcomes and all-cause mortality in trials conducted exclusively in patients with diabetes, but the investigators cautioned that these findings were based on a small number of trials in the analysis.

Previous clinical trials have demonstrated that lowering blood pressure is associated with reduced risk of mortality among patients with hypertension, yet studies in individuals with prehypertension or normal blood pressures have yielded conflicting results, they noted.

The current findings suggest antihypertensive treatment might confer significant benefit.

Existing algorithms for treating hypertension in those with "compelling indications" – those with congestive heart failure, who are post MI, or at high coronary disease risk – call for pharmacologic treatment when blood pressure is not controlled to less than 140/90 mm Hg with lifestyle interventions alone.

"The results of this meta-analysis suggest that persons with these compelling indications, but without hypertension, may also benefit from reduced morbidity and mortality attributable to CVD events when treated with antihypertensive medications," the investigators said.

Since 90% of those aged 40 years and older at have least one above-optimal risk factor, and more than 68% have at least one clinically high-risk factor for heart disease or stroke, it would be economically infeasible to treat everyone at risk. A more reasonable strategy might be to identify groups within the prehypertensive population who would obtain the greatest benefit from early pharmacologic intervention, they suggested.

Additional studies are needed to determine the benefit of treating prehypertension at levels less than 140/90 mm Hg in patients with specific risk factors (elevated lipid levels, smoking history, kidney disease, and minority race or ethnicity), and also to examine the baseline blood pressure level at which treatment should begin in those with CVD or CVD equivalents (such as diabetes), they said.

None of the researchers reported having conflicts of interest. Funding was provided by Tulane University; the National Heart, Lung, and Blood Institute; and the National Institutes of Health.

Antihypertensive therapy appears to benefit patients who have a clinical history of cardiovascular disease, but who have blood pressures in the normal or prehypertensive range, according to a meta-analysis of data from 25 randomized controlled trials involving more than 64,000 such patients.

Compared with control patients who received placebo, study participants without clinically defined hypertension who received antihypertensive treatment for the secondary prevention of cardiovascular disease events had a 23% reduction in risk of stroke, a 20% reduction in risk of myocardial infarction, a 29% reduction in risk of congestive heart failure, a 15% reduction in risk for composite cardiovascular disease (CVD) events, a 17% reduction in risk for cardiovascular disease mortality, and a 13% reduction in risk for all-cause mortality, Angela M. Thompson of Tulane School of Public Health and Tropical Medicine, New Orleans, and colleagues reported in the March 2 issue of JAMA.

The absolute risk reduction per 1,000 persons was -7.7 for stroke, -13.3 for MI, -43.6 for congestive heart failure events, -27.1 for composite CVD events, -15.4 for CVD mortality, and -13.7 for all-cause mortality, the investigators said (JAMA. 2011;305: 913-22).

All pooled relative risk reductions were statistically significant, but the pooled absolute risk reductions did not achieve statistical significance for myocardial infarction and CVD mortality – a discrepancy that reflects "the increased variance of the absolute measures compared with the variance of the relative measures," they explained.

The investigators conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials, as well as a manual examination of references. The 25 trials included represent those that fulfilled all predetermined inclusion and exclusion criteria, and incorporated data from 64,162 participants at least 19 years of age and with blood pressure less than 140 mm Hg systolic or less than 90 mm Hg diastolic. The mean age across the studies ranged from 55 to 68 years; 76% of participants were men, and study duration varied from a mean of 1.5 months to 63 months.

The class and dose of antihypertensive treatments varied, but in most studies it progressively increased to a defined target dose, the investigators noted.

All studies required that participants have a history of cardiovascular disease; clinical evidence of recent MI, congestive heart failure, coronary artery disease, or stroke; or a CVD equivalent such as type 2 diabetes.

No statistically significant benefit of treatment was seen in regard to CVD outcomes and all-cause mortality in trials conducted exclusively in patients with diabetes, but the investigators cautioned that these findings were based on a small number of trials in the analysis.

Previous clinical trials have demonstrated that lowering blood pressure is associated with reduced risk of mortality among patients with hypertension, yet studies in individuals with prehypertension or normal blood pressures have yielded conflicting results, they noted.

The current findings suggest antihypertensive treatment might confer significant benefit.

Existing algorithms for treating hypertension in those with "compelling indications" – those with congestive heart failure, who are post MI, or at high coronary disease risk – call for pharmacologic treatment when blood pressure is not controlled to less than 140/90 mm Hg with lifestyle interventions alone.

"The results of this meta-analysis suggest that persons with these compelling indications, but without hypertension, may also benefit from reduced morbidity and mortality attributable to CVD events when treated with antihypertensive medications," the investigators said.

Since 90% of those aged 40 years and older at have least one above-optimal risk factor, and more than 68% have at least one clinically high-risk factor for heart disease or stroke, it would be economically infeasible to treat everyone at risk. A more reasonable strategy might be to identify groups within the prehypertensive population who would obtain the greatest benefit from early pharmacologic intervention, they suggested.

Additional studies are needed to determine the benefit of treating prehypertension at levels less than 140/90 mm Hg in patients with specific risk factors (elevated lipid levels, smoking history, kidney disease, and minority race or ethnicity), and also to examine the baseline blood pressure level at which treatment should begin in those with CVD or CVD equivalents (such as diabetes), they said.

None of the researchers reported having conflicts of interest. Funding was provided by Tulane University; the National Heart, Lung, and Blood Institute; and the National Institutes of Health.

Antihypertensive therapy appears to benefit patients who have a clinical history of cardiovascular disease, but who have blood pressures in the normal or prehypertensive range, according to a meta-analysis of data from 25 randomized controlled trials involving more than 64,000 such patients.

Compared with control patients who received placebo, study participants without clinically defined hypertension who received antihypertensive treatment for the secondary prevention of cardiovascular disease events had a 23% reduction in risk of stroke, a 20% reduction in risk of myocardial infarction, a 29% reduction in risk of congestive heart failure, a 15% reduction in risk for composite cardiovascular disease (CVD) events, a 17% reduction in risk for cardiovascular disease mortality, and a 13% reduction in risk for all-cause mortality, Angela M. Thompson of Tulane School of Public Health and Tropical Medicine, New Orleans, and colleagues reported in the March 2 issue of JAMA.

The absolute risk reduction per 1,000 persons was -7.7 for stroke, -13.3 for MI, -43.6 for congestive heart failure events, -27.1 for composite CVD events, -15.4 for CVD mortality, and -13.7 for all-cause mortality, the investigators said (JAMA. 2011;305: 913-22).

All pooled relative risk reductions were statistically significant, but the pooled absolute risk reductions did not achieve statistical significance for myocardial infarction and CVD mortality – a discrepancy that reflects "the increased variance of the absolute measures compared with the variance of the relative measures," they explained.

The investigators conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials, as well as a manual examination of references. The 25 trials included represent those that fulfilled all predetermined inclusion and exclusion criteria, and incorporated data from 64,162 participants at least 19 years of age and with blood pressure less than 140 mm Hg systolic or less than 90 mm Hg diastolic. The mean age across the studies ranged from 55 to 68 years; 76% of participants were men, and study duration varied from a mean of 1.5 months to 63 months.

The class and dose of antihypertensive treatments varied, but in most studies it progressively increased to a defined target dose, the investigators noted.

All studies required that participants have a history of cardiovascular disease; clinical evidence of recent MI, congestive heart failure, coronary artery disease, or stroke; or a CVD equivalent such as type 2 diabetes.

No statistically significant benefit of treatment was seen in regard to CVD outcomes and all-cause mortality in trials conducted exclusively in patients with diabetes, but the investigators cautioned that these findings were based on a small number of trials in the analysis.

Previous clinical trials have demonstrated that lowering blood pressure is associated with reduced risk of mortality among patients with hypertension, yet studies in individuals with prehypertension or normal blood pressures have yielded conflicting results, they noted.

The current findings suggest antihypertensive treatment might confer significant benefit.

Existing algorithms for treating hypertension in those with "compelling indications" – those with congestive heart failure, who are post MI, or at high coronary disease risk – call for pharmacologic treatment when blood pressure is not controlled to less than 140/90 mm Hg with lifestyle interventions alone.

"The results of this meta-analysis suggest that persons with these compelling indications, but without hypertension, may also benefit from reduced morbidity and mortality attributable to CVD events when treated with antihypertensive medications," the investigators said.

Since 90% of those aged 40 years and older at have least one above-optimal risk factor, and more than 68% have at least one clinically high-risk factor for heart disease or stroke, it would be economically infeasible to treat everyone at risk. A more reasonable strategy might be to identify groups within the prehypertensive population who would obtain the greatest benefit from early pharmacologic intervention, they suggested.

Additional studies are needed to determine the benefit of treating prehypertension at levels less than 140/90 mm Hg in patients with specific risk factors (elevated lipid levels, smoking history, kidney disease, and minority race or ethnicity), and also to examine the baseline blood pressure level at which treatment should begin in those with CVD or CVD equivalents (such as diabetes), they said.

None of the researchers reported having conflicts of interest. Funding was provided by Tulane University; the National Heart, Lung, and Blood Institute; and the National Institutes of Health.

Antihypertensive therapy appears to benefit patients who have a clinical history of cardiovascular disease, but who have blood pressures in the normal or prehypertensive range, according to a meta-analysis of data from 25 randomized controlled trials involving more than 64,000 such patients.

Compared with control patients who received placebo, study participants without clinically defined hypertension who received antihypertensive treatment for the secondary prevention of cardiovascular disease events had a 23% reduction in risk of stroke, a 20% reduction in risk of myocardial infarction, a 29% reduction in risk of congestive heart failure, a 15% reduction in risk for composite cardiovascular disease (CVD) events, a 17% reduction in risk for cardiovascular disease mortality, and a 13% reduction in risk for all-cause mortality, Angela M. Thompson of Tulane School of Public Health and Tropical Medicine, New Orleans, and colleagues reported in the March 2 issue of JAMA.

The absolute risk reduction per 1,000 persons was -7.7 for stroke, -13.3 for MI, -43.6 for congestive heart failure events, -27.1 for composite CVD events, -15.4 for CVD mortality, and -13.7 for all-cause mortality, the investigators said (JAMA. 2011;305: 913-22).

All pooled relative risk reductions were statistically significant, but the pooled absolute risk reductions did not achieve statistical significance for myocardial infarction and CVD mortality – a discrepancy that reflects "the increased variance of the absolute measures compared with the variance of the relative measures," they explained.

The investigators conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials, as well as a manual examination of references. The 25 trials included represent those that fulfilled all predetermined inclusion and exclusion criteria, and incorporated data from 64,162 participants at least 19 years of age and with blood pressure less than 140 mm Hg systolic or less than 90 mm Hg diastolic. The mean age across the studies ranged from 55 to 68 years; 76% of participants were men, and study duration varied from a mean of 1.5 months to 63 months.

The class and dose of antihypertensive treatments varied, but in most studies it progressively increased to a defined target dose, the investigators noted.

All studies required that participants have a history of cardiovascular disease; clinical evidence of recent MI, congestive heart failure, coronary artery disease, or stroke; or a CVD equivalent such as type 2 diabetes.

No statistically significant benefit of treatment was seen in regard to CVD outcomes and all-cause mortality in trials conducted exclusively in patients with diabetes, but the investigators cautioned that these findings were based on a small number of trials in the analysis.

Previous clinical trials have demonstrated that lowering blood pressure is associated with reduced risk of mortality among patients with hypertension, yet studies in individuals with prehypertension or normal blood pressures have yielded conflicting results, they noted.

The current findings suggest antihypertensive treatment might confer significant benefit.

Existing algorithms for treating hypertension in those with "compelling indications" – those with congestive heart failure, who are post MI, or at high coronary disease risk – call for pharmacologic treatment when blood pressure is not controlled to less than 140/90 mm Hg with lifestyle interventions alone.

"The results of this meta-analysis suggest that persons with these compelling indications, but without hypertension, may also benefit from reduced morbidity and mortality attributable to CVD events when treated with antihypertensive medications," the investigators said.

Since 90% of those aged 40 years and older at have least one above-optimal risk factor, and more than 68% have at least one clinically high-risk factor for heart disease or stroke, it would be economically infeasible to treat everyone at risk. A more reasonable strategy might be to identify groups within the prehypertensive population who would obtain the greatest benefit from early pharmacologic intervention, they suggested.

Additional studies are needed to determine the benefit of treating prehypertension at levels less than 140/90 mm Hg in patients with specific risk factors (elevated lipid levels, smoking history, kidney disease, and minority race or ethnicity), and also to examine the baseline blood pressure level at which treatment should begin in those with CVD or CVD equivalents (such as diabetes), they said.

None of the researchers reported having conflicts of interest. Funding was provided by Tulane University; the National Heart, Lung, and Blood Institute; and the National Institutes of Health.

Antihypertensive therapy appears to benefit patients who have a clinical history of cardiovascular disease, but who have blood pressures in the normal or prehypertensive range, according to a meta-analysis of data from 25 randomized controlled trials involving more than 64,000 such patients.

Compared with control patients who received placebo, study participants without clinically defined hypertension who received antihypertensive treatment for the secondary prevention of cardiovascular disease events had a 23% reduction in risk of stroke, a 20% reduction in risk of myocardial infarction, a 29% reduction in risk of congestive heart failure, a 15% reduction in risk for composite cardiovascular disease (CVD) events, a 17% reduction in risk for cardiovascular disease mortality, and a 13% reduction in risk for all-cause mortality, Angela M. Thompson of Tulane School of Public Health and Tropical Medicine, New Orleans, and colleagues reported in the March 2 issue of JAMA.

The absolute risk reduction per 1,000 persons was -7.7 for stroke, -13.3 for MI, -43.6 for congestive heart failure events, -27.1 for composite CVD events, -15.4 for CVD mortality, and -13.7 for all-cause mortality, the investigators said (JAMA. 2011;305: 913-22).

All pooled relative risk reductions were statistically significant, but the pooled absolute risk reductions did not achieve statistical significance for myocardial infarction and CVD mortality – a discrepancy that reflects "the increased variance of the absolute measures compared with the variance of the relative measures," they explained.

The investigators conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials, as well as a manual examination of references. The 25 trials included represent those that fulfilled all predetermined inclusion and exclusion criteria, and incorporated data from 64,162 participants at least 19 years of age and with blood pressure less than 140 mm Hg systolic or less than 90 mm Hg diastolic. The mean age across the studies ranged from 55 to 68 years; 76% of participants were men, and study duration varied from a mean of 1.5 months to 63 months.

The class and dose of antihypertensive treatments varied, but in most studies it progressively increased to a defined target dose, the investigators noted.

All studies required that participants have a history of cardiovascular disease; clinical evidence of recent MI, congestive heart failure, coronary artery disease, or stroke; or a CVD equivalent such as type 2 diabetes.

No statistically significant benefit of treatment was seen in regard to CVD outcomes and all-cause mortality in trials conducted exclusively in patients with diabetes, but the investigators cautioned that these findings were based on a small number of trials in the analysis.

Previous clinical trials have demonstrated that lowering blood pressure is associated with reduced risk of mortality among patients with hypertension, yet studies in individuals with prehypertension or normal blood pressures have yielded conflicting results, they noted.

The current findings suggest antihypertensive treatment might confer significant benefit.

Existing algorithms for treating hypertension in those with "compelling indications" – those with congestive heart failure, who are post MI, or at high coronary disease risk – call for pharmacologic treatment when blood pressure is not controlled to less than 140/90 mm Hg with lifestyle interventions alone.

"The results of this meta-analysis suggest that persons with these compelling indications, but without hypertension, may also benefit from reduced morbidity and mortality attributable to CVD events when treated with antihypertensive medications," the investigators said.

Since 90% of those aged 40 years and older at have least one above-optimal risk factor, and more than 68% have at least one clinically high-risk factor for heart disease or stroke, it would be economically infeasible to treat everyone at risk. A more reasonable strategy might be to identify groups within the prehypertensive population who would obtain the greatest benefit from early pharmacologic intervention, they suggested.

Additional studies are needed to determine the benefit of treating prehypertension at levels less than 140/90 mm Hg in patients with specific risk factors (elevated lipid levels, smoking history, kidney disease, and minority race or ethnicity), and also to examine the baseline blood pressure level at which treatment should begin in those with CVD or CVD equivalents (such as diabetes), they said.

None of the researchers reported having conflicts of interest. Funding was provided by Tulane University; the National Heart, Lung, and Blood Institute; and the National Institutes of Health.

Antihypertensive therapy appears to benefit patients who have a clinical history of cardiovascular disease, but who have blood pressures in the normal or prehypertensive range, according to a meta-analysis of data from 25 randomized controlled trials involving more than 64,000 such patients.

Compared with control patients who received placebo, study participants without clinically defined hypertension who received antihypertensive treatment for the secondary prevention of cardiovascular disease events had a 23% reduction in risk of stroke, a 20% reduction in risk of myocardial infarction, a 29% reduction in risk of congestive heart failure, a 15% reduction in risk for composite cardiovascular disease (CVD) events, a 17% reduction in risk for cardiovascular disease mortality, and a 13% reduction in risk for all-cause mortality, Angela M. Thompson of Tulane School of Public Health and Tropical Medicine, New Orleans, and colleagues reported in the March 2 issue of JAMA.

The absolute risk reduction per 1,000 persons was -7.7 for stroke, -13.3 for MI, -43.6 for congestive heart failure events, -27.1 for composite CVD events, -15.4 for CVD mortality, and -13.7 for all-cause mortality, the investigators said (JAMA. 2011;305: 913-22).

All pooled relative risk reductions were statistically significant, but the pooled absolute risk reductions did not achieve statistical significance for myocardial infarction and CVD mortality – a discrepancy that reflects "the increased variance of the absolute measures compared with the variance of the relative measures," they explained.

The investigators conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials, as well as a manual examination of references. The 25 trials included represent those that fulfilled all predetermined inclusion and exclusion criteria, and incorporated data from 64,162 participants at least 19 years of age and with blood pressure less than 140 mm Hg systolic or less than 90 mm Hg diastolic. The mean age across the studies ranged from 55 to 68 years; 76% of participants were men, and study duration varied from a mean of 1.5 months to 63 months.

The class and dose of antihypertensive treatments varied, but in most studies it progressively increased to a defined target dose, the investigators noted.

All studies required that participants have a history of cardiovascular disease; clinical evidence of recent MI, congestive heart failure, coronary artery disease, or stroke; or a CVD equivalent such as type 2 diabetes.

No statistically significant benefit of treatment was seen in regard to CVD outcomes and all-cause mortality in trials conducted exclusively in patients with diabetes, but the investigators cautioned that these findings were based on a small number of trials in the analysis.

Previous clinical trials have demonstrated that lowering blood pressure is associated with reduced risk of mortality among patients with hypertension, yet studies in individuals with prehypertension or normal blood pressures have yielded conflicting results, they noted.

The current findings suggest antihypertensive treatment might confer significant benefit.

Existing algorithms for treating hypertension in those with "compelling indications" – those with congestive heart failure, who are post MI, or at high coronary disease risk – call for pharmacologic treatment when blood pressure is not controlled to less than 140/90 mm Hg with lifestyle interventions alone.

"The results of this meta-analysis suggest that persons with these compelling indications, but without hypertension, may also benefit from reduced morbidity and mortality attributable to CVD events when treated with antihypertensive medications," the investigators said.

Since 90% of those aged 40 years and older at have least one above-optimal risk factor, and more than 68% have at least one clinically high-risk factor for heart disease or stroke, it would be economically infeasible to treat everyone at risk. A more reasonable strategy might be to identify groups within the prehypertensive population who would obtain the greatest benefit from early pharmacologic intervention, they suggested.

Additional studies are needed to determine the benefit of treating prehypertension at levels less than 140/90 mm Hg in patients with specific risk factors (elevated lipid levels, smoking history, kidney disease, and minority race or ethnicity), and also to examine the baseline blood pressure level at which treatment should begin in those with CVD or CVD equivalents (such as diabetes), they said.

None of the researchers reported having conflicts of interest. Funding was provided by Tulane University; the National Heart, Lung, and Blood Institute; and the National Institutes of Health.

Antihypertensive therapy appears to benefit patients who have a clinical history of cardiovascular disease, but who have blood pressures in the normal or prehypertensive range, according to a meta-analysis of data from 25 randomized controlled trials involving more than 64,000 such patients.

Compared with control patients who received placebo, study participants without clinically defined hypertension who received antihypertensive treatment for the secondary prevention of cardiovascular disease events had a 23% reduction in risk of stroke, a 20% reduction in risk of myocardial infarction, a 29% reduction in risk of congestive heart failure, a 15% reduction in risk for composite cardiovascular disease (CVD) events, a 17% reduction in risk for cardiovascular disease mortality, and a 13% reduction in risk for all-cause mortality, Angela M. Thompson of Tulane School of Public Health and Tropical Medicine, New Orleans, and colleagues reported in the March 2 issue of JAMA.

The absolute risk reduction per 1,000 persons was -7.7 for stroke, -13.3 for MI, -43.6 for congestive heart failure events, -27.1 for composite CVD events, -15.4 for CVD mortality, and -13.7 for all-cause mortality, the investigators said (JAMA. 2011;305: 913-22).

All pooled relative risk reductions were statistically significant, but the pooled absolute risk reductions did not achieve statistical significance for myocardial infarction and CVD mortality – a discrepancy that reflects "the increased variance of the absolute measures compared with the variance of the relative measures," they explained.

The investigators conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials, as well as a manual examination of references. The 25 trials included represent those that fulfilled all predetermined inclusion and exclusion criteria, and incorporated data from 64,162 participants at least 19 years of age and with blood pressure less than 140 mm Hg systolic or less than 90 mm Hg diastolic. The mean age across the studies ranged from 55 to 68 years; 76% of participants were men, and study duration varied from a mean of 1.5 months to 63 months.

The class and dose of antihypertensive treatments varied, but in most studies it progressively increased to a defined target dose, the investigators noted.

All studies required that participants have a history of cardiovascular disease; clinical evidence of recent MI, congestive heart failure, coronary artery disease, or stroke; or a CVD equivalent such as type 2 diabetes.

No statistically significant benefit of treatment was seen in regard to CVD outcomes and all-cause mortality in trials conducted exclusively in patients with diabetes, but the investigators cautioned that these findings were based on a small number of trials in the analysis.

Previous clinical trials have demonstrated that lowering blood pressure is associated with reduced risk of mortality among patients with hypertension, yet studies in individuals with prehypertension or normal blood pressures have yielded conflicting results, they noted.

The current findings suggest antihypertensive treatment might confer significant benefit.

Existing algorithms for treating hypertension in those with "compelling indications" – those with congestive heart failure, who are post MI, or at high coronary disease risk – call for pharmacologic treatment when blood pressure is not controlled to less than 140/90 mm Hg with lifestyle interventions alone.

"The results of this meta-analysis suggest that persons with these compelling indications, but without hypertension, may also benefit from reduced morbidity and mortality attributable to CVD events when treated with antihypertensive medications," the investigators said.

Since 90% of those aged 40 years and older at have least one above-optimal risk factor, and more than 68% have at least one clinically high-risk factor for heart disease or stroke, it would be economically infeasible to treat everyone at risk. A more reasonable strategy might be to identify groups within the prehypertensive population who would obtain the greatest benefit from early pharmacologic intervention, they suggested.

Additional studies are needed to determine the benefit of treating prehypertension at levels less than 140/90 mm Hg in patients with specific risk factors (elevated lipid levels, smoking history, kidney disease, and minority race or ethnicity), and also to examine the baseline blood pressure level at which treatment should begin in those with CVD or CVD equivalents (such as diabetes), they said.

None of the researchers reported having conflicts of interest. Funding was provided by Tulane University; the National Heart, Lung, and Blood Institute; and the National Institutes of Health.

Antihypertensive therapy appears to benefit patients who have a clinical history of cardiovascular disease, but who have blood pressures in the normal or prehypertensive range, according to a meta-analysis of data from 25 randomized controlled trials involving more than 64,000 such patients.

Compared with control patients who received placebo, study participants without clinically defined hypertension who received antihypertensive treatment for the secondary prevention of cardiovascular disease events had a 23% reduction in risk of stroke, a 20% reduction in risk of myocardial infarction, a 29% reduction in risk of congestive heart failure, a 15% reduction in risk for composite cardiovascular disease (CVD) events, a 17% reduction in risk for cardiovascular disease mortality, and a 13% reduction in risk for all-cause mortality, Angela M. Thompson of Tulane School of Public Health and Tropical Medicine, New Orleans, and colleagues reported in the March 2 issue of JAMA.

The absolute risk reduction per 1,000 persons was -7.7 for stroke, -13.3 for MI, -43.6 for congestive heart failure events, -27.1 for composite CVD events, -15.4 for CVD mortality, and -13.7 for all-cause mortality, the investigators said (JAMA. 2011;305: 913-22).

All pooled relative risk reductions were statistically significant, but the pooled absolute risk reductions did not achieve statistical significance for myocardial infarction and CVD mortality – a discrepancy that reflects "the increased variance of the absolute measures compared with the variance of the relative measures," they explained.

The investigators conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials, as well as a manual examination of references. The 25 trials included represent those that fulfilled all predetermined inclusion and exclusion criteria, and incorporated data from 64,162 participants at least 19 years of age and with blood pressure less than 140 mm Hg systolic or less than 90 mm Hg diastolic. The mean age across the studies ranged from 55 to 68 years; 76% of participants were men, and study duration varied from a mean of 1.5 months to 63 months.

The class and dose of antihypertensive treatments varied, but in most studies it progressively increased to a defined target dose, the investigators noted.

All studies required that participants have a history of cardiovascular disease; clinical evidence of recent MI, congestive heart failure, coronary artery disease, or stroke; or a CVD equivalent such as type 2 diabetes.

No statistically significant benefit of treatment was seen in regard to CVD outcomes and all-cause mortality in trials conducted exclusively in patients with diabetes, but the investigators cautioned that these findings were based on a small number of trials in the analysis.

Previous clinical trials have demonstrated that lowering blood pressure is associated with reduced risk of mortality among patients with hypertension, yet studies in individuals with prehypertension or normal blood pressures have yielded conflicting results, they noted.

The current findings suggest antihypertensive treatment might confer significant benefit.

Existing algorithms for treating hypertension in those with "compelling indications" – those with congestive heart failure, who are post MI, or at high coronary disease risk – call for pharmacologic treatment when blood pressure is not controlled to less than 140/90 mm Hg with lifestyle interventions alone.

"The results of this meta-analysis suggest that persons with these compelling indications, but without hypertension, may also benefit from reduced morbidity and mortality attributable to CVD events when treated with antihypertensive medications," the investigators said.

Since 90% of those aged 40 years and older at have least one above-optimal risk factor, and more than 68% have at least one clinically high-risk factor for heart disease or stroke, it would be economically infeasible to treat everyone at risk. A more reasonable strategy might be to identify groups within the prehypertensive population who would obtain the greatest benefit from early pharmacologic intervention, they suggested.

Additional studies are needed to determine the benefit of treating prehypertension at levels less than 140/90 mm Hg in patients with specific risk factors (elevated lipid levels, smoking history, kidney disease, and minority race or ethnicity), and also to examine the baseline blood pressure level at which treatment should begin in those with CVD or CVD equivalents (such as diabetes), they said.

None of the researchers reported having conflicts of interest. Funding was provided by Tulane University; the National Heart, Lung, and Blood Institute; and the National Institutes of Health.

Antihypertensive therapy appears to benefit patients who have a clinical history of cardiovascular disease, but who have blood pressures in the normal or prehypertensive range, according to a meta-analysis of data from 25 randomized controlled trials involving more than 64,000 such patients.

Compared with control patients who received placebo, study participants without clinically defined hypertension who received antihypertensive treatment for the secondary prevention of cardiovascular disease events had a 23% reduction in risk of stroke, a 20% reduction in risk of myocardial infarction, a 29% reduction in risk of congestive heart failure, a 15% reduction in risk for composite cardiovascular disease (CVD) events, a 17% reduction in risk for cardiovascular disease mortality, and a 13% reduction in risk for all-cause mortality, Angela M. Thompson of Tulane School of Public Health and Tropical Medicine, New Orleans, and colleagues reported in the March 2 issue of JAMA.

The absolute risk reduction per 1,000 persons was -7.7 for stroke, -13.3 for MI, -43.6 for congestive heart failure events, -27.1 for composite CVD events, -15.4 for CVD mortality, and -13.7 for all-cause mortality, the investigators said (JAMA. 2011;305: 913-22).

All pooled relative risk reductions were statistically significant, but the pooled absolute risk reductions did not achieve statistical significance for myocardial infarction and CVD mortality – a discrepancy that reflects "the increased variance of the absolute measures compared with the variance of the relative measures," they explained.

The investigators conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials, as well as a manual examination of references. The 25 trials included represent those that fulfilled all predetermined inclusion and exclusion criteria, and incorporated data from 64,162 participants at least 19 years of age and with blood pressure less than 140 mm Hg systolic or less than 90 mm Hg diastolic. The mean age across the studies ranged from 55 to 68 years; 76% of participants were men, and study duration varied from a mean of 1.5 months to 63 months.

The class and dose of antihypertensive treatments varied, but in most studies it progressively increased to a defined target dose, the investigators noted.

All studies required that participants have a history of cardiovascular disease; clinical evidence of recent MI, congestive heart failure, coronary artery disease, or stroke; or a CVD equivalent such as type 2 diabetes.

No statistically significant benefit of treatment was seen in regard to CVD outcomes and all-cause mortality in trials conducted exclusively in patients with diabetes, but the investigators cautioned that these findings were based on a small number of trials in the analysis.

Previous clinical trials have demonstrated that lowering blood pressure is associated with reduced risk of mortality among patients with hypertension, yet studies in individuals with prehypertension or normal blood pressures have yielded conflicting results, they noted.

The current findings suggest antihypertensive treatment might confer significant benefit.

Existing algorithms for treating hypertension in those with "compelling indications" – those with congestive heart failure, who are post MI, or at high coronary disease risk – call for pharmacologic treatment when blood pressure is not controlled to less than 140/90 mm Hg with lifestyle interventions alone.

"The results of this meta-analysis suggest that persons with these compelling indications, but without hypertension, may also benefit from reduced morbidity and mortality attributable to CVD events when treated with antihypertensive medications," the investigators said.

Since 90% of those aged 40 years and older at have least one above-optimal risk factor, and more than 68% have at least one clinically high-risk factor for heart disease or stroke, it would be economically infeasible to treat everyone at risk. A more reasonable strategy might be to identify groups within the prehypertensive population who would obtain the greatest benefit from early pharmacologic intervention, they suggested.

Additional studies are needed to determine the benefit of treating prehypertension at levels less than 140/90 mm Hg in patients with specific risk factors (elevated lipid levels, smoking history, kidney disease, and minority race or ethnicity), and also to examine the baseline blood pressure level at which treatment should begin in those with CVD or CVD equivalents (such as diabetes), they said.

None of the researchers reported having conflicts of interest. Funding was provided by Tulane University; the National Heart, Lung, and Blood Institute; and the National Institutes of Health.

ATLANTA – Nonbiologic disease-modifying anti-rheumatic drugs – particularly methotrexate – and treat-to-target strategies are at least as responsible as are biologic agents for improvements in the control of rheumatoid arthritis over the last 2 decades.

Data from 1989 to 2008 for 992 patients from the Nijmegen Inception Cohort of patients with newly diagnosed RA showed that the use of biologics increased from 0% around 2000 to 22%, Dr. Wietske Kievit reported at the annual meeting of the American College of Rheumatology.

During the same time period, the use of sulfasalazine decreased from 60% to 16%, with the greatest decline beginning around 2000. Also, the use of methotrexate increased from about 5% to 62%, with the sharpest increases occurring before the biologic era.

"We also saw an increase in the mean dose of methotrexate in the population; in 1989, the mean dose was almost 7 [mg/week] with a maximum of 7.5, and in 2008, the mean dose was 16 with a maximum dose of 30," said Dr. Kievit of Radboud University Nijmegen Medical Centre, the Netherlands.

Estimated mean Disease Activity Scores in 28 joints (DAS28) decreased from 4.3 to 3.2 from 1989 to 2008. The decline in estimated scores was fairly steady over time, and began before the start of the biologic era. A similar trend was seen with functional disability scores, which started at 0.65, and ended at 0.5, with the decreases beginning before the start of the biologic era.

Mean joint damage (Ratingen) scores decreased from 90% in 1989 to 50% in 2005, the last year that data were available for this measure, Dr. Kievit noted. Mean joint damage scores were much lower in the more recent years of follow-up.

She and her colleagues also looked at the number of orthopedic surgeries in the cohort over time. There were 13 surgeries in 197 patients in 1991 (incidence rate 0.07) and 14 in 728 patients in 2008 (incidence rate 0.02).

Patients in the cohort were from two centers in the Netherlands. Patients with newly diagnosed RA were entered into the cohort each year, for a total of 992 patients representing 8419 patient years of follow-up.

Rheumatoid factor and gender did not differ by year, and mean age increased from 56 years in 1989 to 61 years in 2008. Mean disease duration increased from 1.9 to 8.1 years across the study period.

Outcomes were compared by cohort year, and data were adjusted for differences in patient characteristics.

While secular trends, improvements in lifestyle (such as quitting tobacco use), or earlier referrals for specialty care later in the study period could provide an explanation for the improvements in RA control over time, the "most straightforward explanation is the introduction of biologics and tight control strategies, but also enhanced use of methotrexate and other DMARDs already available since the 1980s," Dr. Kievit said.

Neither Dr. Kievit nor any of her coauthors had any financial disclosures related to the presentation of these findings.

ATLANTA – Nonbiologic disease-modifying anti-rheumatic drugs – particularly methotrexate – and treat-to-target strategies are at least as responsible as are biologic agents for improvements in the control of rheumatoid arthritis over the last 2 decades.

Data from 1989 to 2008 for 992 patients from the Nijmegen Inception Cohort of patients with newly diagnosed RA showed that the use of biologics increased from 0% around 2000 to 22%, Dr. Wietske Kievit reported at the annual meeting of the American College of Rheumatology.

During the same time period, the use of sulfasalazine decreased from 60% to 16%, with the greatest decline beginning around 2000. Also, the use of methotrexate increased from about 5% to 62%, with the sharpest increases occurring before the biologic era.

"We also saw an increase in the mean dose of methotrexate in the population; in 1989, the mean dose was almost 7 [mg/week] with a maximum of 7.5, and in 2008, the mean dose was 16 with a maximum dose of 30," said Dr. Kievit of Radboud University Nijmegen Medical Centre, the Netherlands.

Estimated mean Disease Activity Scores in 28 joints (DAS28) decreased from 4.3 to 3.2 from 1989 to 2008. The decline in estimated scores was fairly steady over time, and began before the start of the biologic era. A similar trend was seen with functional disability scores, which started at 0.65, and ended at 0.5, with the decreases beginning before the start of the biologic era.

Mean joint damage (Ratingen) scores decreased from 90% in 1989 to 50% in 2005, the last year that data were available for this measure, Dr. Kievit noted. Mean joint damage scores were much lower in the more recent years of follow-up.

She and her colleagues also looked at the number of orthopedic surgeries in the cohort over time. There were 13 surgeries in 197 patients in 1991 (incidence rate 0.07) and 14 in 728 patients in 2008 (incidence rate 0.02).

Patients in the cohort were from two centers in the Netherlands. Patients with newly diagnosed RA were entered into the cohort each year, for a total of 992 patients representing 8419 patient years of follow-up.

Rheumatoid factor and gender did not differ by year, and mean age increased from 56 years in 1989 to 61 years in 2008. Mean disease duration increased from 1.9 to 8.1 years across the study period.

Outcomes were compared by cohort year, and data were adjusted for differences in patient characteristics.

While secular trends, improvements in lifestyle (such as quitting tobacco use), or earlier referrals for specialty care later in the study period could provide an explanation for the improvements in RA control over time, the "most straightforward explanation is the introduction of biologics and tight control strategies, but also enhanced use of methotrexate and other DMARDs already available since the 1980s," Dr. Kievit said.

Neither Dr. Kievit nor any of her coauthors had any financial disclosures related to the presentation of these findings.

ATLANTA – Nonbiologic disease-modifying anti-rheumatic drugs – particularly methotrexate – and treat-to-target strategies are at least as responsible as are biologic agents for improvements in the control of rheumatoid arthritis over the last 2 decades.

Data from 1989 to 2008 for 992 patients from the Nijmegen Inception Cohort of patients with newly diagnosed RA showed that the use of biologics increased from 0% around 2000 to 22%, Dr. Wietske Kievit reported at the annual meeting of the American College of Rheumatology.

During the same time period, the use of sulfasalazine decreased from 60% to 16%, with the greatest decline beginning around 2000. Also, the use of methotrexate increased from about 5% to 62%, with the sharpest increases occurring before the biologic era.

"We also saw an increase in the mean dose of methotrexate in the population; in 1989, the mean dose was almost 7 [mg/week] with a maximum of 7.5, and in 2008, the mean dose was 16 with a maximum dose of 30," said Dr. Kievit of Radboud University Nijmegen Medical Centre, the Netherlands.

Estimated mean Disease Activity Scores in 28 joints (DAS28) decreased from 4.3 to 3.2 from 1989 to 2008. The decline in estimated scores was fairly steady over time, and began before the start of the biologic era. A similar trend was seen with functional disability scores, which started at 0.65, and ended at 0.5, with the decreases beginning before the start of the biologic era.

Mean joint damage (Ratingen) scores decreased from 90% in 1989 to 50% in 2005, the last year that data were available for this measure, Dr. Kievit noted. Mean joint damage scores were much lower in the more recent years of follow-up.

She and her colleagues also looked at the number of orthopedic surgeries in the cohort over time. There were 13 surgeries in 197 patients in 1991 (incidence rate 0.07) and 14 in 728 patients in 2008 (incidence rate 0.02).

Patients in the cohort were from two centers in the Netherlands. Patients with newly diagnosed RA were entered into the cohort each year, for a total of 992 patients representing 8419 patient years of follow-up.

Rheumatoid factor and gender did not differ by year, and mean age increased from 56 years in 1989 to 61 years in 2008. Mean disease duration increased from 1.9 to 8.1 years across the study period.

Outcomes were compared by cohort year, and data were adjusted for differences in patient characteristics.

While secular trends, improvements in lifestyle (such as quitting tobacco use), or earlier referrals for specialty care later in the study period could provide an explanation for the improvements in RA control over time, the "most straightforward explanation is the introduction of biologics and tight control strategies, but also enhanced use of methotrexate and other DMARDs already available since the 1980s," Dr. Kievit said.

Neither Dr. Kievit nor any of her coauthors had any financial disclosures related to the presentation of these findings.