Miriam E. Tucker

PHILADELPHIA — Be alert for potential interactions and side effects when prescribing statins, Dr. Douglas S. Paauw advised at the annual meeting of the American College of Physicians.

Hepatotoxicity and rhabdomyolysis are relatively rare, but myalgias are quite common and often prompt patients to discontinue the drugs, said Dr. Paauw, professor of medicine at the University of Washington, Seattle.

And, although the overall risk of rhabdomyolysis is low, the chance is greater with the addition of other drugs.

In one frequently cited study, rates of toxicity were very low (2% myalgias, 0.4% myositis, and 0.4% hepatotoxicity) among 252 atherosclerotic patients receiving a statin plus gemfibrozil, leading the authors to conclude that the combination could be used safely in high-risk patients (Am. Heart J. 1999;138:151–5).

But those results may not reflect current clinical experience. Pravastatin, which is used less often today, was the statin most commonly used in the study. Simvastatin and lovastatin, both used more often today, are metabolized by a subunit of the cytochrome P450 system that is affected to a greater degree by gemfibrozil than are pravastatin or fluvastatin. Thus, the investigators were using “safer statins” in terms of drug interactions, Dr. Paauw noted.

If it is necessary to use both gemfibrozil and a statin—a common scenario—it's important to document the reason. Also, educate the patient about myalgias and rhabdomyolysis, including the importance of stopping the drug right away when muscle pain starts and then calling the physician afterward—especially if the symptoms occur during weekends or holidays. “I tell patients to stop the drug if there's any question. It's not going to be a problem if they're off the statin for 24 hours.”

Always ask patients about muscle pain, and monitor signs and symptoms at every office visit. There is no set policy about blood monitoring, but it's a good idea to measure creatinine phosphokinase (CPK) levels periodically and any time that symptoms develop, he advised.

Fibrates top a long list of other drugs that can increase statin toxicity, including azole antifungals, niacin, erythromycin/clarithromycin, protease inhibitors, verapamil/diltiazem, and cyclosporine. About half of all severe cases of rhabdomyolysis occur when three or more of these agents are taken together, such as in a patient who is already taking a fibrate plus a statin who is then prescribed erythromycin for 2 weeks.

“It's that third drug that markedly increases the risk,” Dr. Paauw said.

Less attention has been paid to simple muscle pain and weakness. Published data suggest that this side effect occurs in only 1%–5% of patients on statins. “I really believe that that number is higher. In my practice, it's probably 20% at least,” he said.

Indeed, patients will often take themselves off the drug and report that the pain goes away. The problem appears to be both dose- and drug-related.

In one study, muscle cell abnormalities were found on biopsy in patients who had normal CPK levels but who complained of muscle pain (Ann. Intern. Med. 2002;137:581–5). “If a CPK comes back normal, it doesn't tell us that the pain isn't from the statin. It simply tells us that the magnitude of the muscle problem doesn't put them at risk for rhabdomyolysis right now, but they could still be severely debilitated by the pain,” Dr. Paauw said.

Further complicating the picture, statin-induced muscle pain isn't necessarily uniform throughout the body. For example, a patient may complain of severe pain only in the left thigh. Quite often, the pain goes away if you take the patient off the drug. “Take very seriously any pain syndrome in a patient on statins. If you can't find an alternative diagnosis, consider a short drug holiday and see what happens,” he recommended.

Once the pain resolves—typically in 1–2 weeks—you can restart the same statin at a low dose, or try switching to a different one. If the patient still experiences muscle pain after trying two different statins, it may be necessary to consider a different category of lipid-lowering drug.

In contrast to muscle problems, hepatotoxicity appears to be less of an issue with statins than was originally thought. In a retrospective cohort study of 23,000 adult HMO patients who received statins over a 5-year period, just 0.3% had severe transaminitis, defined as an alanine aminotransferase (ALT) level 10 times greater than normal. Of those 62 patients, only 17 had ALT elevation due to the statin, and the problem resolved after stopping the statin in 16 of those 17. Most patients were symptomatic at the time of the elevation, which usually occurred within 4 weeks of starting or changing therapy (Am. J. Med. 2005;118:618–24).

Another study, which included 1,014 primary care patients taking statins who had at least one transaminase measurement, only 1% (10) had a significant elevation and another 5 had moderate elevations, but none of those cases appeared to be related to statin use (Arch. Intern. Med. 2003;163:688–92).

Based on the data, it's reasonable to monitor liver function within the first 12 weeks of therapy and perhaps annually thereafter for the first 3–4 years. After that, if the patient has been on a stable dose and has not had an ALT elevation, it's not necessary to keep going. “I don't continue to monitor for years and years,” Dr. Paauw said.

And finally, there's the grapefruit juice problem. Grapefruit juice increases the bioavailability of drugs known to be metabolized by the CYP3A4 subunit of the P450 system, including simvastatin, lovastatin, and to a lesser degree, atorvastatin. Pravastatin, fluvastatin, and rosuvastatin do not rely on CYP3A4 and therefore do not interact with grapefruit juice.

Small amounts—a half of a grapefruit every 2 weeks, for example—are not likely to be clinically significant, but a daily glass of juice at breakfast may increase statin bioavailability.

PHILADELPHIA — Be alert for potential interactions and side effects when prescribing statins, Dr. Douglas S. Paauw advised at the annual meeting of the American College of Physicians.

Hepatotoxicity and rhabdomyolysis are relatively rare, but myalgias are quite common and often prompt patients to discontinue the drugs, said Dr. Paauw, professor of medicine at the University of Washington, Seattle.

And, although the overall risk of rhabdomyolysis is low, the chance is greater with the addition of other drugs.

In one frequently cited study, rates of toxicity were very low (2% myalgias, 0.4% myositis, and 0.4% hepatotoxicity) among 252 atherosclerotic patients receiving a statin plus gemfibrozil, leading the authors to conclude that the combination could be used safely in high-risk patients (Am. Heart J. 1999;138:151–5).

But those results may not reflect current clinical experience. Pravastatin, which is used less often today, was the statin most commonly used in the study. Simvastatin and lovastatin, both used more often today, are metabolized by a subunit of the cytochrome P450 system that is affected to a greater degree by gemfibrozil than are pravastatin or fluvastatin. Thus, the investigators were using “safer statins” in terms of drug interactions, Dr. Paauw noted.

If it is necessary to use both gemfibrozil and a statin—a common scenario—it's important to document the reason. Also, educate the patient about myalgias and rhabdomyolysis, including the importance of stopping the drug right away when muscle pain starts and then calling the physician afterward—especially if the symptoms occur during weekends or holidays. “I tell patients to stop the drug if there's any question. It's not going to be a problem if they're off the statin for 24 hours.”

Always ask patients about muscle pain, and monitor signs and symptoms at every office visit. There is no set policy about blood monitoring, but it's a good idea to measure creatinine phosphokinase (CPK) levels periodically and any time that symptoms develop, he advised.

Fibrates top a long list of other drugs that can increase statin toxicity, including azole antifungals, niacin, erythromycin/clarithromycin, protease inhibitors, verapamil/diltiazem, and cyclosporine. About half of all severe cases of rhabdomyolysis occur when three or more of these agents are taken together, such as in a patient who is already taking a fibrate plus a statin who is then prescribed erythromycin for 2 weeks.

“It's that third drug that markedly increases the risk,” Dr. Paauw said.

Less attention has been paid to simple muscle pain and weakness. Published data suggest that this side effect occurs in only 1%–5% of patients on statins. “I really believe that that number is higher. In my practice, it's probably 20% at least,” he said.

Indeed, patients will often take themselves off the drug and report that the pain goes away. The problem appears to be both dose- and drug-related.

In one study, muscle cell abnormalities were found on biopsy in patients who had normal CPK levels but who complained of muscle pain (Ann. Intern. Med. 2002;137:581–5). “If a CPK comes back normal, it doesn't tell us that the pain isn't from the statin. It simply tells us that the magnitude of the muscle problem doesn't put them at risk for rhabdomyolysis right now, but they could still be severely debilitated by the pain,” Dr. Paauw said.

Further complicating the picture, statin-induced muscle pain isn't necessarily uniform throughout the body. For example, a patient may complain of severe pain only in the left thigh. Quite often, the pain goes away if you take the patient off the drug. “Take very seriously any pain syndrome in a patient on statins. If you can't find an alternative diagnosis, consider a short drug holiday and see what happens,” he recommended.

Once the pain resolves—typically in 1–2 weeks—you can restart the same statin at a low dose, or try switching to a different one. If the patient still experiences muscle pain after trying two different statins, it may be necessary to consider a different category of lipid-lowering drug.

In contrast to muscle problems, hepatotoxicity appears to be less of an issue with statins than was originally thought. In a retrospective cohort study of 23,000 adult HMO patients who received statins over a 5-year period, just 0.3% had severe transaminitis, defined as an alanine aminotransferase (ALT) level 10 times greater than normal. Of those 62 patients, only 17 had ALT elevation due to the statin, and the problem resolved after stopping the statin in 16 of those 17. Most patients were symptomatic at the time of the elevation, which usually occurred within 4 weeks of starting or changing therapy (Am. J. Med. 2005;118:618–24).

Another study, which included 1,014 primary care patients taking statins who had at least one transaminase measurement, only 1% (10) had a significant elevation and another 5 had moderate elevations, but none of those cases appeared to be related to statin use (Arch. Intern. Med. 2003;163:688–92).

Based on the data, it's reasonable to monitor liver function within the first 12 weeks of therapy and perhaps annually thereafter for the first 3–4 years. After that, if the patient has been on a stable dose and has not had an ALT elevation, it's not necessary to keep going. “I don't continue to monitor for years and years,” Dr. Paauw said.

And finally, there's the grapefruit juice problem. Grapefruit juice increases the bioavailability of drugs known to be metabolized by the CYP3A4 subunit of the P450 system, including simvastatin, lovastatin, and to a lesser degree, atorvastatin. Pravastatin, fluvastatin, and rosuvastatin do not rely on CYP3A4 and therefore do not interact with grapefruit juice.

Small amounts—a half of a grapefruit every 2 weeks, for example—are not likely to be clinically significant, but a daily glass of juice at breakfast may increase statin bioavailability.

PHILADELPHIA — Be alert for potential interactions and side effects when prescribing statins, Dr. Douglas S. Paauw advised at the annual meeting of the American College of Physicians.

Hepatotoxicity and rhabdomyolysis are relatively rare, but myalgias are quite common and often prompt patients to discontinue the drugs, said Dr. Paauw, professor of medicine at the University of Washington, Seattle.

And, although the overall risk of rhabdomyolysis is low, the chance is greater with the addition of other drugs.

In one frequently cited study, rates of toxicity were very low (2% myalgias, 0.4% myositis, and 0.4% hepatotoxicity) among 252 atherosclerotic patients receiving a statin plus gemfibrozil, leading the authors to conclude that the combination could be used safely in high-risk patients (Am. Heart J. 1999;138:151–5).

But those results may not reflect current clinical experience. Pravastatin, which is used less often today, was the statin most commonly used in the study. Simvastatin and lovastatin, both used more often today, are metabolized by a subunit of the cytochrome P450 system that is affected to a greater degree by gemfibrozil than are pravastatin or fluvastatin. Thus, the investigators were using “safer statins” in terms of drug interactions, Dr. Paauw noted.

If it is necessary to use both gemfibrozil and a statin—a common scenario—it's important to document the reason. Also, educate the patient about myalgias and rhabdomyolysis, including the importance of stopping the drug right away when muscle pain starts and then calling the physician afterward—especially if the symptoms occur during weekends or holidays. “I tell patients to stop the drug if there's any question. It's not going to be a problem if they're off the statin for 24 hours.”

Always ask patients about muscle pain, and monitor signs and symptoms at every office visit. There is no set policy about blood monitoring, but it's a good idea to measure creatinine phosphokinase (CPK) levels periodically and any time that symptoms develop, he advised.

Fibrates top a long list of other drugs that can increase statin toxicity, including azole antifungals, niacin, erythromycin/clarithromycin, protease inhibitors, verapamil/diltiazem, and cyclosporine. About half of all severe cases of rhabdomyolysis occur when three or more of these agents are taken together, such as in a patient who is already taking a fibrate plus a statin who is then prescribed erythromycin for 2 weeks.

“It's that third drug that markedly increases the risk,” Dr. Paauw said.

Less attention has been paid to simple muscle pain and weakness. Published data suggest that this side effect occurs in only 1%–5% of patients on statins. “I really believe that that number is higher. In my practice, it's probably 20% at least,” he said.

Indeed, patients will often take themselves off the drug and report that the pain goes away. The problem appears to be both dose- and drug-related.

In one study, muscle cell abnormalities were found on biopsy in patients who had normal CPK levels but who complained of muscle pain (Ann. Intern. Med. 2002;137:581–5). “If a CPK comes back normal, it doesn't tell us that the pain isn't from the statin. It simply tells us that the magnitude of the muscle problem doesn't put them at risk for rhabdomyolysis right now, but they could still be severely debilitated by the pain,” Dr. Paauw said.

Further complicating the picture, statin-induced muscle pain isn't necessarily uniform throughout the body. For example, a patient may complain of severe pain only in the left thigh. Quite often, the pain goes away if you take the patient off the drug. “Take very seriously any pain syndrome in a patient on statins. If you can't find an alternative diagnosis, consider a short drug holiday and see what happens,” he recommended.

Once the pain resolves—typically in 1–2 weeks—you can restart the same statin at a low dose, or try switching to a different one. If the patient still experiences muscle pain after trying two different statins, it may be necessary to consider a different category of lipid-lowering drug.

In contrast to muscle problems, hepatotoxicity appears to be less of an issue with statins than was originally thought. In a retrospective cohort study of 23,000 adult HMO patients who received statins over a 5-year period, just 0.3% had severe transaminitis, defined as an alanine aminotransferase (ALT) level 10 times greater than normal. Of those 62 patients, only 17 had ALT elevation due to the statin, and the problem resolved after stopping the statin in 16 of those 17. Most patients were symptomatic at the time of the elevation, which usually occurred within 4 weeks of starting or changing therapy (Am. J. Med. 2005;118:618–24).

Another study, which included 1,014 primary care patients taking statins who had at least one transaminase measurement, only 1% (10) had a significant elevation and another 5 had moderate elevations, but none of those cases appeared to be related to statin use (Arch. Intern. Med. 2003;163:688–92).

Based on the data, it's reasonable to monitor liver function within the first 12 weeks of therapy and perhaps annually thereafter for the first 3–4 years. After that, if the patient has been on a stable dose and has not had an ALT elevation, it's not necessary to keep going. “I don't continue to monitor for years and years,” Dr. Paauw said.

And finally, there's the grapefruit juice problem. Grapefruit juice increases the bioavailability of drugs known to be metabolized by the CYP3A4 subunit of the P450 system, including simvastatin, lovastatin, and to a lesser degree, atorvastatin. Pravastatin, fluvastatin, and rosuvastatin do not rely on CYP3A4 and therefore do not interact with grapefruit juice.

Small amounts—a half of a grapefruit every 2 weeks, for example—are not likely to be clinically significant, but a daily glass of juice at breakfast may increase statin bioavailability.

WASHINGTON — Statin-induced myopathy and myalgia may be higher than reported previously in patients with diabetes, but myositis and rhabdomyolysis are rare, Gregory A. Nichols, Ph.D., and Carol E. Koro, Ph.D., reported in a poster at the annual scientific sessions of the American Diabetes Association.

Clinical trial results suggest that statin-induced myopathy occurs in less than 1% of patients, but no previously published reports of muscle syndromes following statin initiation have come from real-world settings, said Dr. Nichols and Dr. Koro, both of Kaiser Permanente Northwest, Portland, Ore.

They compared electronic pharmacy records for 10,247 Kaiser enrollees who have type 2 diabetes and initiated statins between 1997 and 2004. Their results were compared with those of the same number of diabetic patients who did not take statins during that time period. Study subjects were followed until they experienced a myopathic event or until the end of 2005.

Kaiser Permanente recommends that any patient who presents with muscle complaints while taking statins undergo a creatine kinase (CK) test and suspend statin use pending the results.

Therefore, myopathy was defined as the presence of any creatine kinase test during a break in statin dispense records, any CK test greater than three times the upper limit of normal (ULN), or any diagnosis of myopathy. Myalgia was defined as the presence of a normal CK test during a break in the statin dispense records or a diagnosis of myalgia.

During the study period, myopathy developed in 7.1% of the statin initiators and 5.5% of the controls, a statistically significant difference. The unadjusted incidence of myopathy/1,000 person-years was also significantly greater for the statin users, 21.9, than for the nonusers, 18.1. In addition, the rates of CK levels between 1 and 3 times the ULN were significantly different, seen in 1.7% of the statin users and 0.6% of the controls, translating to unadjusted incidence rates of 5.5/1,000 vs. 2.0/1,000 person-years.

Similarly, the proportion developing myalgia was also significantly greater with statins (5.8%), compared with controls (4.7%), as was the incidence rate of myalgia (18.3/1,000 vs. 15.4/1,000), Dr. Nichols and Dr. Koro reported.

On the other hand, myositis—defined as a CK test with a result 3–10 times the ULN or a diagnosis—was not significantly more common among statin users, occurring in 0.21% of statin users and 0.14% of controls, with rates of 0.70/1,000 vs. 0.46/1,000. Similarly, comparable rates of rhabdomyolysis, defined as a CK test result more than 10 times above the ULN (0.13% vs. 0.12%) or a diagnosis (0.41/1,000 vs. 0.17/1,000), were seen.

Concurrent use of fibrates and corticosteroids were the strongest predictors of myopathy (hazard ratios 2.11 and 1.80, respectively). Older age, presence of cardiovascular disease, and higher body-mass index also contributed to the myopathy risk. After adjustment for those factors, the incidence rates were not significantly different between statin users and controls (21.1/1,000 vs. 19.4/1,000).

Older age, higher BMI, concurrent fibrate use, concurrent corticosteroid use, and the presence of cardiovascular disease also increased the risk for myalgia; male sex and metformin use appeared to be protective. As with myopathy, adjusting for those factors eliminated the difference between statin users and nonusers (17.3/1,000 vs. 16.4/1,000).

But the rates of elevated CK test results of 1–3 times the ULN remained significantly higher for statin users even after adjusting for predictors such as younger age, longer duration of diabetes, male sex, concurrent fibrate use, higher BMI, and poor kidney function (4.1/1,000 vs. 1.3/1,000). Differences between statin users and controls in rates of myositis and rhabdomyolysis remained insignificant after adjusting for male sex (a predictor of both) and for concurrent use of diuretics (a predictor of rhabdomyolysis).

WASHINGTON — Statin-induced myopathy and myalgia may be higher than reported previously in patients with diabetes, but myositis and rhabdomyolysis are rare, Gregory A. Nichols, Ph.D., and Carol E. Koro, Ph.D., reported in a poster at the annual scientific sessions of the American Diabetes Association.

Clinical trial results suggest that statin-induced myopathy occurs in less than 1% of patients, but no previously published reports of muscle syndromes following statin initiation have come from real-world settings, said Dr. Nichols and Dr. Koro, both of Kaiser Permanente Northwest, Portland, Ore.

They compared electronic pharmacy records for 10,247 Kaiser enrollees who have type 2 diabetes and initiated statins between 1997 and 2004. Their results were compared with those of the same number of diabetic patients who did not take statins during that time period. Study subjects were followed until they experienced a myopathic event or until the end of 2005.

Kaiser Permanente recommends that any patient who presents with muscle complaints while taking statins undergo a creatine kinase (CK) test and suspend statin use pending the results.

Therefore, myopathy was defined as the presence of any creatine kinase test during a break in statin dispense records, any CK test greater than three times the upper limit of normal (ULN), or any diagnosis of myopathy. Myalgia was defined as the presence of a normal CK test during a break in the statin dispense records or a diagnosis of myalgia.

During the study period, myopathy developed in 7.1% of the statin initiators and 5.5% of the controls, a statistically significant difference. The unadjusted incidence of myopathy/1,000 person-years was also significantly greater for the statin users, 21.9, than for the nonusers, 18.1. In addition, the rates of CK levels between 1 and 3 times the ULN were significantly different, seen in 1.7% of the statin users and 0.6% of the controls, translating to unadjusted incidence rates of 5.5/1,000 vs. 2.0/1,000 person-years.

Similarly, the proportion developing myalgia was also significantly greater with statins (5.8%), compared with controls (4.7%), as was the incidence rate of myalgia (18.3/1,000 vs. 15.4/1,000), Dr. Nichols and Dr. Koro reported.

On the other hand, myositis—defined as a CK test with a result 3–10 times the ULN or a diagnosis—was not significantly more common among statin users, occurring in 0.21% of statin users and 0.14% of controls, with rates of 0.70/1,000 vs. 0.46/1,000. Similarly, comparable rates of rhabdomyolysis, defined as a CK test result more than 10 times above the ULN (0.13% vs. 0.12%) or a diagnosis (0.41/1,000 vs. 0.17/1,000), were seen.

Concurrent use of fibrates and corticosteroids were the strongest predictors of myopathy (hazard ratios 2.11 and 1.80, respectively). Older age, presence of cardiovascular disease, and higher body-mass index also contributed to the myopathy risk. After adjustment for those factors, the incidence rates were not significantly different between statin users and controls (21.1/1,000 vs. 19.4/1,000).

Older age, higher BMI, concurrent fibrate use, concurrent corticosteroid use, and the presence of cardiovascular disease also increased the risk for myalgia; male sex and metformin use appeared to be protective. As with myopathy, adjusting for those factors eliminated the difference between statin users and nonusers (17.3/1,000 vs. 16.4/1,000).

But the rates of elevated CK test results of 1–3 times the ULN remained significantly higher for statin users even after adjusting for predictors such as younger age, longer duration of diabetes, male sex, concurrent fibrate use, higher BMI, and poor kidney function (4.1/1,000 vs. 1.3/1,000). Differences between statin users and controls in rates of myositis and rhabdomyolysis remained insignificant after adjusting for male sex (a predictor of both) and for concurrent use of diuretics (a predictor of rhabdomyolysis).

WASHINGTON — Statin-induced myopathy and myalgia may be higher than reported previously in patients with diabetes, but myositis and rhabdomyolysis are rare, Gregory A. Nichols, Ph.D., and Carol E. Koro, Ph.D., reported in a poster at the annual scientific sessions of the American Diabetes Association.

Clinical trial results suggest that statin-induced myopathy occurs in less than 1% of patients, but no previously published reports of muscle syndromes following statin initiation have come from real-world settings, said Dr. Nichols and Dr. Koro, both of Kaiser Permanente Northwest, Portland, Ore.

They compared electronic pharmacy records for 10,247 Kaiser enrollees who have type 2 diabetes and initiated statins between 1997 and 2004. Their results were compared with those of the same number of diabetic patients who did not take statins during that time period. Study subjects were followed until they experienced a myopathic event or until the end of 2005.

Kaiser Permanente recommends that any patient who presents with muscle complaints while taking statins undergo a creatine kinase (CK) test and suspend statin use pending the results.

Therefore, myopathy was defined as the presence of any creatine kinase test during a break in statin dispense records, any CK test greater than three times the upper limit of normal (ULN), or any diagnosis of myopathy. Myalgia was defined as the presence of a normal CK test during a break in the statin dispense records or a diagnosis of myalgia.

During the study period, myopathy developed in 7.1% of the statin initiators and 5.5% of the controls, a statistically significant difference. The unadjusted incidence of myopathy/1,000 person-years was also significantly greater for the statin users, 21.9, than for the nonusers, 18.1. In addition, the rates of CK levels between 1 and 3 times the ULN were significantly different, seen in 1.7% of the statin users and 0.6% of the controls, translating to unadjusted incidence rates of 5.5/1,000 vs. 2.0/1,000 person-years.

Similarly, the proportion developing myalgia was also significantly greater with statins (5.8%), compared with controls (4.7%), as was the incidence rate of myalgia (18.3/1,000 vs. 15.4/1,000), Dr. Nichols and Dr. Koro reported.

On the other hand, myositis—defined as a CK test with a result 3–10 times the ULN or a diagnosis—was not significantly more common among statin users, occurring in 0.21% of statin users and 0.14% of controls, with rates of 0.70/1,000 vs. 0.46/1,000. Similarly, comparable rates of rhabdomyolysis, defined as a CK test result more than 10 times above the ULN (0.13% vs. 0.12%) or a diagnosis (0.41/1,000 vs. 0.17/1,000), were seen.

Concurrent use of fibrates and corticosteroids were the strongest predictors of myopathy (hazard ratios 2.11 and 1.80, respectively). Older age, presence of cardiovascular disease, and higher body-mass index also contributed to the myopathy risk. After adjustment for those factors, the incidence rates were not significantly different between statin users and controls (21.1/1,000 vs. 19.4/1,000).

Older age, higher BMI, concurrent fibrate use, concurrent corticosteroid use, and the presence of cardiovascular disease also increased the risk for myalgia; male sex and metformin use appeared to be protective. As with myopathy, adjusting for those factors eliminated the difference between statin users and nonusers (17.3/1,000 vs. 16.4/1,000).

But the rates of elevated CK test results of 1–3 times the ULN remained significantly higher for statin users even after adjusting for predictors such as younger age, longer duration of diabetes, male sex, concurrent fibrate use, higher BMI, and poor kidney function (4.1/1,000 vs. 1.3/1,000). Differences between statin users and controls in rates of myositis and rhabdomyolysis remained insignificant after adjusting for male sex (a predictor of both) and for concurrent use of diuretics (a predictor of rhabdomyolysis).

WASHINGTON — Statin-induced myopathy and myalgia may be higher than reported previously in patients with diabetes, but myositis and rhabdomyolysis are rare, Gregory A. Nichols, Ph.D., and Carol E. Koro, Ph.D., reported in a poster at the annual scientific sessions of the American Diabetes Association.

Clinical trial results suggest that statin-induced myopathy occurs in less than 1% of patients, but no previously published reports of muscle syndromes following statin initiation have come from real-world settings, said Dr. Nichols and Dr. Koro, both of Kaiser Permanente Northwest, Portland, Ore.

They compared electronic pharmacy records for 10,247 Kaiser enrollees who have type 2 diabetes and initiated statins between 1997 and 2004. Their results were compared with those of the same number of diabetic patients who did not take statins during that time period. Study subjects were followed until they experienced a myopathic event or until the end of 2005.

Kaiser Permanente recommends that any patient who presents with muscle complaints while taking statins undergo a creatine kinase (CK) test and suspend statin use pending the results. Therefore, myopathy was defined as the presence of any creatine kinase test during a break in statin dispense records, any CK test greater than three times the upper limit of normal (ULN), or any diagnosis of myopathy. Myalgia was defined as the presence of a normal CK test during a break in the statin dispense records or a diagnosis of myalgia.

During the study period, myopathy developed in 7.1% of the statin initiators and 5.5% of the controls, a statistically significant difference. The unadjusted incidence of myopathy/1,000 person-years was also significantly greater for the statin users, 21.9, than for the nonusers, 18.1. Also, the rates of CK levels between 1 and 3 times the ULN were significantly different, seen in 1.7% of the statin users and 0.6% of the controls, translating to unadjusted incidence rates of 5.5/1,000 vs. 2.0/1,000 person-years.

Similarly, the proportion developing myalgia was also significantly greater with statins (5.8%), compared with controls (4.7%), as was the incidence rate of myalgia (18.3/1,000 vs. 15.4/1,000), Dr. Nichols and Dr. Koro reported.

On the other hand, myositis—defined as a CK test with a result 3–10 times the ULN or a diagnosis—was not significantly more common among statin users, occurring in 0.21% of statin users and 0.14% of controls, with rates of 0.70/1,000 vs. 0.46/1,000. Similarly, comparable rates of rhabdomyolysis, defined as a CK test result more than 10 times above the ULN (0.13% vs. 0.12%) or a diagnosis (0.41/1,000 vs. 0.17/1,000), were seen.

Concurrent use of fibrates and corticosteroids were the strongest predictors of myopathy (hazard ratios 2.11 and 1.80, respectively). Older age, presence of cardiovascular disease, and higher body-mass index also contributed to the myopathy risk. After adjustment for those factors, the incidence rates were not significantly different between statin users and controls (21.1/1,000 vs. 19.4/1,000).

Older age, higher BMI, concurrent fibrate use, concurrent corticosteroid use, and the presence of cardiovascular disease also increased the risk for myalgia; male sex and metformin use appeared to be protective. As with myopathy, adjusting for those factors eliminated the difference between statin users and nonusers (17.3/1,000 vs. 16.4/1,000).

However, the rates of elevated CK test results of 1–3 times the ULN remained significantly higher for statin users even after adjusting for predictors such as younger age, longer duration of diabetes, male sex, concurrent fibrate use, higher BMI, and poor kidney function (4.1/1,000 vs. 1.3/1,000).

Differences between statin users and controls in rates of myositis and rhabdomyolysis remained insignificant after adjusting for male sex (a predictor of both) and for concurrent use of diuretics (a predictor of rhabdomyolysis).

WASHINGTON — Statin-induced myopathy and myalgia may be higher than reported previously in patients with diabetes, but myositis and rhabdomyolysis are rare, Gregory A. Nichols, Ph.D., and Carol E. Koro, Ph.D., reported in a poster at the annual scientific sessions of the American Diabetes Association.

Clinical trial results suggest that statin-induced myopathy occurs in less than 1% of patients, but no previously published reports of muscle syndromes following statin initiation have come from real-world settings, said Dr. Nichols and Dr. Koro, both of Kaiser Permanente Northwest, Portland, Ore.

They compared electronic pharmacy records for 10,247 Kaiser enrollees who have type 2 diabetes and initiated statins between 1997 and 2004. Their results were compared with those of the same number of diabetic patients who did not take statins during that time period. Study subjects were followed until they experienced a myopathic event or until the end of 2005.

Kaiser Permanente recommends that any patient who presents with muscle complaints while taking statins undergo a creatine kinase (CK) test and suspend statin use pending the results. Therefore, myopathy was defined as the presence of any creatine kinase test during a break in statin dispense records, any CK test greater than three times the upper limit of normal (ULN), or any diagnosis of myopathy. Myalgia was defined as the presence of a normal CK test during a break in the statin dispense records or a diagnosis of myalgia.

During the study period, myopathy developed in 7.1% of the statin initiators and 5.5% of the controls, a statistically significant difference. The unadjusted incidence of myopathy/1,000 person-years was also significantly greater for the statin users, 21.9, than for the nonusers, 18.1. Also, the rates of CK levels between 1 and 3 times the ULN were significantly different, seen in 1.7% of the statin users and 0.6% of the controls, translating to unadjusted incidence rates of 5.5/1,000 vs. 2.0/1,000 person-years.

Similarly, the proportion developing myalgia was also significantly greater with statins (5.8%), compared with controls (4.7%), as was the incidence rate of myalgia (18.3/1,000 vs. 15.4/1,000), Dr. Nichols and Dr. Koro reported.

On the other hand, myositis—defined as a CK test with a result 3–10 times the ULN or a diagnosis—was not significantly more common among statin users, occurring in 0.21% of statin users and 0.14% of controls, with rates of 0.70/1,000 vs. 0.46/1,000. Similarly, comparable rates of rhabdomyolysis, defined as a CK test result more than 10 times above the ULN (0.13% vs. 0.12%) or a diagnosis (0.41/1,000 vs. 0.17/1,000), were seen.

Concurrent use of fibrates and corticosteroids were the strongest predictors of myopathy (hazard ratios 2.11 and 1.80, respectively). Older age, presence of cardiovascular disease, and higher body-mass index also contributed to the myopathy risk. After adjustment for those factors, the incidence rates were not significantly different between statin users and controls (21.1/1,000 vs. 19.4/1,000).

Older age, higher BMI, concurrent fibrate use, concurrent corticosteroid use, and the presence of cardiovascular disease also increased the risk for myalgia; male sex and metformin use appeared to be protective. As with myopathy, adjusting for those factors eliminated the difference between statin users and nonusers (17.3/1,000 vs. 16.4/1,000).

However, the rates of elevated CK test results of 1–3 times the ULN remained significantly higher for statin users even after adjusting for predictors such as younger age, longer duration of diabetes, male sex, concurrent fibrate use, higher BMI, and poor kidney function (4.1/1,000 vs. 1.3/1,000).

Differences between statin users and controls in rates of myositis and rhabdomyolysis remained insignificant after adjusting for male sex (a predictor of both) and for concurrent use of diuretics (a predictor of rhabdomyolysis).

WASHINGTON — Statin-induced myopathy and myalgia may be higher than reported previously in patients with diabetes, but myositis and rhabdomyolysis are rare, Gregory A. Nichols, Ph.D., and Carol E. Koro, Ph.D., reported in a poster at the annual scientific sessions of the American Diabetes Association.

Clinical trial results suggest that statin-induced myopathy occurs in less than 1% of patients, but no previously published reports of muscle syndromes following statin initiation have come from real-world settings, said Dr. Nichols and Dr. Koro, both of Kaiser Permanente Northwest, Portland, Ore.

They compared electronic pharmacy records for 10,247 Kaiser enrollees who have type 2 diabetes and initiated statins between 1997 and 2004. Their results were compared with those of the same number of diabetic patients who did not take statins during that time period. Study subjects were followed until they experienced a myopathic event or until the end of 2005.

Kaiser Permanente recommends that any patient who presents with muscle complaints while taking statins undergo a creatine kinase (CK) test and suspend statin use pending the results. Therefore, myopathy was defined as the presence of any creatine kinase test during a break in statin dispense records, any CK test greater than three times the upper limit of normal (ULN), or any diagnosis of myopathy. Myalgia was defined as the presence of a normal CK test during a break in the statin dispense records or a diagnosis of myalgia.

During the study period, myopathy developed in 7.1% of the statin initiators and 5.5% of the controls, a statistically significant difference. The unadjusted incidence of myopathy/1,000 person-years was also significantly greater for the statin users, 21.9, than for the nonusers, 18.1. Also, the rates of CK levels between 1 and 3 times the ULN were significantly different, seen in 1.7% of the statin users and 0.6% of the controls, translating to unadjusted incidence rates of 5.5/1,000 vs. 2.0/1,000 person-years.

Similarly, the proportion developing myalgia was also significantly greater with statins (5.8%), compared with controls (4.7%), as was the incidence rate of myalgia (18.3/1,000 vs. 15.4/1,000), Dr. Nichols and Dr. Koro reported.

On the other hand, myositis—defined as a CK test with a result 3–10 times the ULN or a diagnosis—was not significantly more common among statin users, occurring in 0.21% of statin users and 0.14% of controls, with rates of 0.70/1,000 vs. 0.46/1,000. Similarly, comparable rates of rhabdomyolysis, defined as a CK test result more than 10 times above the ULN (0.13% vs. 0.12%) or a diagnosis (0.41/1,000 vs. 0.17/1,000), were seen.

Concurrent use of fibrates and corticosteroids were the strongest predictors of myopathy (hazard ratios 2.11 and 1.80, respectively). Older age, presence of cardiovascular disease, and higher body-mass index also contributed to the myopathy risk. After adjustment for those factors, the incidence rates were not significantly different between statin users and controls (21.1/1,000 vs. 19.4/1,000).

Older age, higher BMI, concurrent fibrate use, concurrent corticosteroid use, and the presence of cardiovascular disease also increased the risk for myalgia; male sex and metformin use appeared to be protective. As with myopathy, adjusting for those factors eliminated the difference between statin users and nonusers (17.3/1,000 vs. 16.4/1,000).

However, the rates of elevated CK test results of 1–3 times the ULN remained significantly higher for statin users even after adjusting for predictors such as younger age, longer duration of diabetes, male sex, concurrent fibrate use, higher BMI, and poor kidney function (4.1/1,000 vs. 1.3/1,000).

Differences between statin users and controls in rates of myositis and rhabdomyolysis remained insignificant after adjusting for male sex (a predictor of both) and for concurrent use of diuretics (a predictor of rhabdomyolysis).

WASHINGTON — If 80% of Americans with type 2 diabetes met treatment goals, over $150 billion in medical costs would be saved over the next 30 years, Dr. Robert A. Rizza said in his presidential address at the annual scientific sessions of the American Diabetes Association.

If 80% of patients achieved just five goals—a hemoglobin A_1c less than 7%, blood pressure less than 130/80 mm Hg, LDL cholesterol below 100 mg/dL, HDL greater than 40 mg/dL for men and greater than 50 mg/dL for women, and use of a daily baby aspirin—there would be 5 million fewer heart attacks, 600,000 fewer strokes, 1.2 million fewer cases of renal failure, 1.8 million fewer cases of blindness/eye surgery, and 1.8 million fewer premature deaths. The increased costs of achieving the goals would be offset by the savings that result from prevention of the complications, explained Dr. Rizza, of the Mayo Clinic, Rochester, Minn., who just completed his term as ADA's president, medicine & science.

Investigators used a large-scale mathematical model with equations that simulate metabolic pathway and processes leading to complications, called Archimedes (www.archimedesmodel.com

Archimedes also predicted that if 80% of type 2 diabetics took a daily generic “polypill” consisting of 1,000 mg metformin, 75 mg aspirin, 40 mg statin, and 10 mg of an ACE inhibitor, the number of heart attacks over the next 30 years would drop by 50%, renal failure by 4%, and blindness and eye surgery by 33%. Such a pill—with an all-generic formulation—would cost $100 per year while saving about $400 per year. And even if the treatments cost $500, the health care system would still see a savings within 5 years.

“It costs less to properly treat diabetes than it does to treat the complications that you get if you don't properly treat diabetes. It's a wise investment no matter how you look at it,” he said.

A cure for diabetes would go much farther, saving 8.4 million lives and preventing 41 million serious diabetes-related complications over 30 years. In the absence of a cure, the U.S. health care system will spend $6.6 trillion on diabetes complications over the next 30 years. A cure would save over $700 billion, suggesting there is a powerful financial incentive for a cure.

Dr. Rizza outlined a four-point proposal that the ADA plans to issue:

▸ America must invest heavily in diabetes research aimed at finding a cure.

▸ The size of the investment must be commensurate with the risk that diabetes represents to the country.

▸ Financial support must be established to sustain systems that ensure every person with diabetes the best possible care.

▸ And a message for physicians: “We must all renew our commitment to our patients, acknowledge that the current level of care for people with diabetes is simply not acceptable, and do everything in our power to make it better.”

WASHINGTON — If 80% of Americans with type 2 diabetes met treatment goals, over $150 billion in medical costs would be saved over the next 30 years, Dr. Robert A. Rizza said in his presidential address at the annual scientific sessions of the American Diabetes Association.

If 80% of patients achieved just five goals—a hemoglobin A_1c less than 7%, blood pressure less than 130/80 mm Hg, LDL cholesterol below 100 mg/dL, HDL greater than 40 mg/dL for men and greater than 50 mg/dL for women, and use of a daily baby aspirin—there would be 5 million fewer heart attacks, 600,000 fewer strokes, 1.2 million fewer cases of renal failure, 1.8 million fewer cases of blindness/eye surgery, and 1.8 million fewer premature deaths. The increased costs of achieving the goals would be offset by the savings that result from prevention of the complications, explained Dr. Rizza, of the Mayo Clinic, Rochester, Minn., who just completed his term as ADA's president, medicine & science.

Investigators used a large-scale mathematical model with equations that simulate metabolic pathway and processes leading to complications, called Archimedes (www.archimedesmodel.com

Archimedes also predicted that if 80% of type 2 diabetics took a daily generic “polypill” consisting of 1,000 mg metformin, 75 mg aspirin, 40 mg statin, and 10 mg of an ACE inhibitor, the number of heart attacks over the next 30 years would drop by 50%, renal failure by 4%, and blindness and eye surgery by 33%. Such a pill—with an all-generic formulation—would cost $100 per year while saving about $400 per year. And even if the treatments cost $500, the health care system would still see a savings within 5 years.

“It costs less to properly treat diabetes than it does to treat the complications that you get if you don't properly treat diabetes. It's a wise investment no matter how you look at it,” he said.

A cure for diabetes would go much farther, saving 8.4 million lives and preventing 41 million serious diabetes-related complications over 30 years. In the absence of a cure, the U.S. health care system will spend $6.6 trillion on diabetes complications over the next 30 years. A cure would save over $700 billion, suggesting there is a powerful financial incentive for a cure.

Dr. Rizza outlined a four-point proposal that the ADA plans to issue:

▸ America must invest heavily in diabetes research aimed at finding a cure.

▸ The size of the investment must be commensurate with the risk that diabetes represents to the country.

▸ Financial support must be established to sustain systems that ensure every person with diabetes the best possible care.

▸ And a message for physicians: “We must all renew our commitment to our patients, acknowledge that the current level of care for people with diabetes is simply not acceptable, and do everything in our power to make it better.”

WASHINGTON — If 80% of Americans with type 2 diabetes met treatment goals, over $150 billion in medical costs would be saved over the next 30 years, Dr. Robert A. Rizza said in his presidential address at the annual scientific sessions of the American Diabetes Association.

If 80% of patients achieved just five goals—a hemoglobin A_1c less than 7%, blood pressure less than 130/80 mm Hg, LDL cholesterol below 100 mg/dL, HDL greater than 40 mg/dL for men and greater than 50 mg/dL for women, and use of a daily baby aspirin—there would be 5 million fewer heart attacks, 600,000 fewer strokes, 1.2 million fewer cases of renal failure, 1.8 million fewer cases of blindness/eye surgery, and 1.8 million fewer premature deaths. The increased costs of achieving the goals would be offset by the savings that result from prevention of the complications, explained Dr. Rizza, of the Mayo Clinic, Rochester, Minn., who just completed his term as ADA's president, medicine & science.

Investigators used a large-scale mathematical model with equations that simulate metabolic pathway and processes leading to complications, called Archimedes (www.archimedesmodel.com

Archimedes also predicted that if 80% of type 2 diabetics took a daily generic “polypill” consisting of 1,000 mg metformin, 75 mg aspirin, 40 mg statin, and 10 mg of an ACE inhibitor, the number of heart attacks over the next 30 years would drop by 50%, renal failure by 4%, and blindness and eye surgery by 33%. Such a pill—with an all-generic formulation—would cost $100 per year while saving about $400 per year. And even if the treatments cost $500, the health care system would still see a savings within 5 years.

“It costs less to properly treat diabetes than it does to treat the complications that you get if you don't properly treat diabetes. It's a wise investment no matter how you look at it,” he said.

A cure for diabetes would go much farther, saving 8.4 million lives and preventing 41 million serious diabetes-related complications over 30 years. In the absence of a cure, the U.S. health care system will spend $6.6 trillion on diabetes complications over the next 30 years. A cure would save over $700 billion, suggesting there is a powerful financial incentive for a cure.

Dr. Rizza outlined a four-point proposal that the ADA plans to issue:

▸ America must invest heavily in diabetes research aimed at finding a cure.

▸ The size of the investment must be commensurate with the risk that diabetes represents to the country.

▸ Financial support must be established to sustain systems that ensure every person with diabetes the best possible care.

▸ And a message for physicians: “We must all renew our commitment to our patients, acknowledge that the current level of care for people with diabetes is simply not acceptable, and do everything in our power to make it better.”

The future of dual α-/γ-peroxisome proliferator-activated receptor agonists may be in question now that development has been halted on two such agents after the completion of phase III trials.

In early May, AstraZeneca announced the discontinuation of tesaglitazar (Galida), its dual α-/γ-peroxisome proliferator-activated receptor (PPAR) agonist. Phase III data suggested elevations in serum creatinine and a decrease in glomerular filtration rate, effects previously associated with the PPAR-α agonist (fibrate) portion of the molecule. Two weeks later, Bristol-Myers Squibb said it was halting development of muraglitazar (Pargluva).

The action followed the Food and Drug Administration's request for additional long-term data to clarify the agent's cardiovascular risk profile.

The specific reasons for the decisions differed, but both reflect the difficulty associated with developing agents that maximize the glucose-lowering effect without increasing the risk for side effects, according to Dr. John B. Buse, the American Diabetes Association's vice president for medicine and science and director of the Diabetes Care Center at the University of North Carolina, Chapel Hill.

“I think the FDA got it right. What the world needs is not a stronger diabetes drug, but a safer one,” he said.

Indeed, for lowering glucose levels, tesaglitazar and muraglitazar were at least as good as the currently marketed agents pioglitazone (Takeda's Actos) and rosiglitazone (GlaxoSmithKline's Avandia).

However, increased doses of pioglitazone and rosiglitazone are often associated with significant weight gain and edema without much further improvement in lowering glucose, compared with the more moderate doses, Dr. Buse pointed out.

Given that pioglitazone, which also has a lipid-lowering effect, may become generic in 2011, Dr. Buse commented that new PPAR-agonist drugs face substantial challenges for successful development unless their efficacy rivals that of the current glitazones and their safety and tolerance are superior.

Such a drug could particularly benefit the 25% of insulin-requiring type 2 diabetic patients with contraindications or inability to tolerate rosiglitazone or pioglitazone.

“We have good drugs. What we need are better tolerated drugs,” he said.

Dr. Buse has no current financial ties to AstraZeneca, Bristol-Myers Squibb, Glaxo-SmithKline, or Takeda.

The future of dual α-/γ-peroxisome proliferator-activated receptor agonists may be in question now that development has been halted on two such agents after the completion of phase III trials.

In early May, AstraZeneca announced the discontinuation of tesaglitazar (Galida), its dual α-/γ-peroxisome proliferator-activated receptor (PPAR) agonist. Phase III data suggested elevations in serum creatinine and a decrease in glomerular filtration rate, effects previously associated with the PPAR-α agonist (fibrate) portion of the molecule. Two weeks later, Bristol-Myers Squibb said it was halting development of muraglitazar (Pargluva).

The action followed the Food and Drug Administration's request for additional long-term data to clarify the agent's cardiovascular risk profile.

The specific reasons for the decisions differed, but both reflect the difficulty associated with developing agents that maximize the glucose-lowering effect without increasing the risk for side effects, according to Dr. John B. Buse, the American Diabetes Association's vice president for medicine and science and director of the Diabetes Care Center at the University of North Carolina, Chapel Hill.

“I think the FDA got it right. What the world needs is not a stronger diabetes drug, but a safer one,” he said.

Indeed, for lowering glucose levels, tesaglitazar and muraglitazar were at least as good as the currently marketed agents pioglitazone (Takeda's Actos) and rosiglitazone (GlaxoSmithKline's Avandia).

However, increased doses of pioglitazone and rosiglitazone are often associated with significant weight gain and edema without much further improvement in lowering glucose, compared with the more moderate doses, Dr. Buse pointed out.

Given that pioglitazone, which also has a lipid-lowering effect, may become generic in 2011, Dr. Buse commented that new PPAR-agonist drugs face substantial challenges for successful development unless their efficacy rivals that of the current glitazones and their safety and tolerance are superior.

Such a drug could particularly benefit the 25% of insulin-requiring type 2 diabetic patients with contraindications or inability to tolerate rosiglitazone or pioglitazone.

“We have good drugs. What we need are better tolerated drugs,” he said.

Dr. Buse has no current financial ties to AstraZeneca, Bristol-Myers Squibb, Glaxo-SmithKline, or Takeda.

The future of dual α-/γ-peroxisome proliferator-activated receptor agonists may be in question now that development has been halted on two such agents after the completion of phase III trials.

In early May, AstraZeneca announced the discontinuation of tesaglitazar (Galida), its dual α-/γ-peroxisome proliferator-activated receptor (PPAR) agonist. Phase III data suggested elevations in serum creatinine and a decrease in glomerular filtration rate, effects previously associated with the PPAR-α agonist (fibrate) portion of the molecule. Two weeks later, Bristol-Myers Squibb said it was halting development of muraglitazar (Pargluva).

The action followed the Food and Drug Administration's request for additional long-term data to clarify the agent's cardiovascular risk profile.

The specific reasons for the decisions differed, but both reflect the difficulty associated with developing agents that maximize the glucose-lowering effect without increasing the risk for side effects, according to Dr. John B. Buse, the American Diabetes Association's vice president for medicine and science and director of the Diabetes Care Center at the University of North Carolina, Chapel Hill.

“I think the FDA got it right. What the world needs is not a stronger diabetes drug, but a safer one,” he said.

Indeed, for lowering glucose levels, tesaglitazar and muraglitazar were at least as good as the currently marketed agents pioglitazone (Takeda's Actos) and rosiglitazone (GlaxoSmithKline's Avandia).

However, increased doses of pioglitazone and rosiglitazone are often associated with significant weight gain and edema without much further improvement in lowering glucose, compared with the more moderate doses, Dr. Buse pointed out.

Given that pioglitazone, which also has a lipid-lowering effect, may become generic in 2011, Dr. Buse commented that new PPAR-agonist drugs face substantial challenges for successful development unless their efficacy rivals that of the current glitazones and their safety and tolerance are superior.

Such a drug could particularly benefit the 25% of insulin-requiring type 2 diabetic patients with contraindications or inability to tolerate rosiglitazone or pioglitazone.

“We have good drugs. What we need are better tolerated drugs,” he said.

Dr. Buse has no current financial ties to AstraZeneca, Bristol-Myers Squibb, Glaxo-SmithKline, or Takeda.

PHILADELPHIA — Be alert for potential interactions and side effects when prescribing statins, Dr. Douglas S. Paauw advised at the annual meeting of the American College of Physicians.

While hepatotoxicity and rhabdomyolysis are relatively rare, myalgias are quite common and often prompt patients to discontinue the drugs, said Dr. Paauw, professor of medicine at the University of Washington, Seattle.

And, although the overall risk of rhabdomyolysis is low, the chance is greater with the addition of other drugs.

In one frequently cited study, rates of toxicity were very low (2% myalgias, 0.4% myositis, and 0.4% hepatotoxicity) among 252 atherosclerotic patients receiving a statin plus gemfibrozil, leading the authors to conclude that the combination could be used safely in high-risk patients (Am. Heart J. 1999;138:151–5).

But those results may not reflect current clinical experience. Pravastatin, which is used less often today, was the statin most commonly used in the study (325.7 patient-years), followed by simvastatin (178.1), fluvastatin (54.0), lovastatin (20.3), and atorvastatin (15.5).

Simvastatin and lovastatin, both used more often today, are metabolized by a subunit of the cytochrome P450 system that is affected to a greater degree by gemfibrozil than are pravastatin or fluvastatin. Thus, in the study, the investigators were using “safer statins” in terms of drug interactions, Dr. Paauw noted.

If it is necessary to use both gemfibrozil and a statin—a very common scenario—it's important to document the reason for using the combination. Also, educate the patient about myalgias and rhabdomyolysis, including the importance of stopping the drug right away when muscle pain starts and then calling the physician afterward—especially if the symptoms occur during weekends or holidays.

Always ask patients about muscle pain, and monitor signs and symptoms at every office visit. There is no set policy about blood monitoring, but it's a good idea to measure creatinine phosphokinase (CPK) levels periodically and any time that symptoms develop, he advised.

Fibrates top a long list of other drugs that can increase statin toxicity, including azole antifungals, niacin, erythromycin/clarithromycin, protease inhibitors, verapamil/diltiazem, and cyclosporine. About half of all severe cases of rhabdomyolysis occur when three or more of these agents are taken together, such as in a patient who is already taking a fibrate plus a statin who is then prescribed erythromycin for 2 weeks. “It's that third drug that markedly increases the risk,” Dr. Paauw said.

Less attention has been paid to simple muscle pain and weakness. Published data suggest that this side effect occurs in only 1%–5% of patients on statins. “I really believe that that number is higher. In my practice, it's probably 20% at least,” he said.

Indeed, patients will often take themselves off the drug and report that the pain goes away. The problem appears to be both dose- and drug-related, with certain statins causing more problems than other drugs for some individuals.

In one study, muscle cell abnormalities were found on biopsy in patients who had normal CPK levels but who complained of muscle pain (Ann. Intern. Med. 2002;137:581–5). “If a CPK comes back normal, it doesn't tell us that the pain isn't from the statin. It simply tells us that the magnitude of the muscle problem doesn't put them at risk for rhabdomyolysis right now, but they could still be severely debilitated by the pain.”

Further complicating the picture, statin-induced muscle pain isn't necessarily uniform throughout the body. For example, a patient may complain of severe pain only in the left thigh. It may seem highly improbable that the statin is the problem, but quite often the pain goes away if you take the patient off the drug. “Take very seriously any pain syndrome in a patient on statins. If you can't find an alternative diagnosis, consider a short drug holiday and see what happens,” Dr. Paauw recommended.

Once the pain resolves—typically in 1–2 weeks—you can restart the same statin at a low dose, or try switching to a different one. If the patient still experiences muscle pain after trying two different statins, it may be necessary to consider a different category of lipid-lowering drug.

Hepatotoxicity appears to be less of an issue with statins than was originally thought. In a retrospective cohort study of 23,000 adult HMO patients who received statins over a 5-year period, just 0.3% had severe transaminitis, defined as an alanine aminotransferase (ALT) level 10 times greater than normal. Of those 62 patients, only 17 had ALT elevation due to the statin, and the problem resolved after stopping the statin in 16 of those 17. Most patients were symptomatic at the time of the elevation, which usually occurred within 4 weeks of starting or changing therapy (Am. J. Med. 2005;118:618–24).

Another study, which included 1,014 primary care patients taking statins who had at least one transaminase measurement, only 1% (10) had a significant elevation and another 5 had moderate elevations, but none of those cases appeared to be related to statin use (Arch. Intern. Med. 2003;163:688–92).

Based on the data, it's reasonable to monitor liver function within the first 12 weeks of therapy and perhaps annually thereafter for the first 3–4 years. After that, if the patient has been on a stable dose and has not had an ALT elevation, it's not necessary to keep going. “I don't continue to monitor for years and years,” Dr. Paauw said.

Finally, grapefruit juice increases the bioavailability of drugs known to be metabolized by the CYP3A4 subunit of the P450 system, including simvastatin, lovastatin, and to a lesser degree, atorvastatin. Pravastatin, fluvastatin, and rosuvastatin do not rely on CYP3A4 and therefore do not interact with grapefruit juice.

While small amounts—a half of a grapefruit every 2 weeks, for example—are not likely to be clinically significant, a daily glass of juice at breakfast may cause a significant rise in statin bioavailability. Indeed, one study documented a 15-fold increase in mean peak serum lovastatin in 10 healthy volunteers who drank 200 mL of grapefruit juice, compared with subjects who drank water, three times a day for 3 days; subjects took one 80-mg dose of lovastatin on day 3 (Clin. Pharmacol. Ther. 1998;63:397–402). This highly significant effect may work to the advantage of some patients who have not achieved lipid control on statins, Dr. Paauw noted.

PHILADELPHIA — Be alert for potential interactions and side effects when prescribing statins, Dr. Douglas S. Paauw advised at the annual meeting of the American College of Physicians.

While hepatotoxicity and rhabdomyolysis are relatively rare, myalgias are quite common and often prompt patients to discontinue the drugs, said Dr. Paauw, professor of medicine at the University of Washington, Seattle.

And, although the overall risk of rhabdomyolysis is low, the chance is greater with the addition of other drugs.

In one frequently cited study, rates of toxicity were very low (2% myalgias, 0.4% myositis, and 0.4% hepatotoxicity) among 252 atherosclerotic patients receiving a statin plus gemfibrozil, leading the authors to conclude that the combination could be used safely in high-risk patients (Am. Heart J. 1999;138:151–5).

But those results may not reflect current clinical experience. Pravastatin, which is used less often today, was the statin most commonly used in the study (325.7 patient-years), followed by simvastatin (178.1), fluvastatin (54.0), lovastatin (20.3), and atorvastatin (15.5).

Simvastatin and lovastatin, both used more often today, are metabolized by a subunit of the cytochrome P450 system that is affected to a greater degree by gemfibrozil than are pravastatin or fluvastatin. Thus, in the study, the investigators were using “safer statins” in terms of drug interactions, Dr. Paauw noted.

If it is necessary to use both gemfibrozil and a statin—a very common scenario—it's important to document the reason for using the combination. Also, educate the patient about myalgias and rhabdomyolysis, including the importance of stopping the drug right away when muscle pain starts and then calling the physician afterward—especially if the symptoms occur during weekends or holidays.

Always ask patients about muscle pain, and monitor signs and symptoms at every office visit. There is no set policy about blood monitoring, but it's a good idea to measure creatinine phosphokinase (CPK) levels periodically and any time that symptoms develop, he advised.

Fibrates top a long list of other drugs that can increase statin toxicity, including azole antifungals, niacin, erythromycin/clarithromycin, protease inhibitors, verapamil/diltiazem, and cyclosporine. About half of all severe cases of rhabdomyolysis occur when three or more of these agents are taken together, such as in a patient who is already taking a fibrate plus a statin who is then prescribed erythromycin for 2 weeks. “It's that third drug that markedly increases the risk,” Dr. Paauw said.

Less attention has been paid to simple muscle pain and weakness. Published data suggest that this side effect occurs in only 1%–5% of patients on statins. “I really believe that that number is higher. In my practice, it's probably 20% at least,” he said.

Indeed, patients will often take themselves off the drug and report that the pain goes away. The problem appears to be both dose- and drug-related, with certain statins causing more problems than other drugs for some individuals.

In one study, muscle cell abnormalities were found on biopsy in patients who had normal CPK levels but who complained of muscle pain (Ann. Intern. Med. 2002;137:581–5). “If a CPK comes back normal, it doesn't tell us that the pain isn't from the statin. It simply tells us that the magnitude of the muscle problem doesn't put them at risk for rhabdomyolysis right now, but they could still be severely debilitated by the pain.”

Further complicating the picture, statin-induced muscle pain isn't necessarily uniform throughout the body. For example, a patient may complain of severe pain only in the left thigh. It may seem highly improbable that the statin is the problem, but quite often the pain goes away if you take the patient off the drug. “Take very seriously any pain syndrome in a patient on statins. If you can't find an alternative diagnosis, consider a short drug holiday and see what happens,” Dr. Paauw recommended.

Once the pain resolves—typically in 1–2 weeks—you can restart the same statin at a low dose, or try switching to a different one. If the patient still experiences muscle pain after trying two different statins, it may be necessary to consider a different category of lipid-lowering drug.

Hepatotoxicity appears to be less of an issue with statins than was originally thought. In a retrospective cohort study of 23,000 adult HMO patients who received statins over a 5-year period, just 0.3% had severe transaminitis, defined as an alanine aminotransferase (ALT) level 10 times greater than normal. Of those 62 patients, only 17 had ALT elevation due to the statin, and the problem resolved after stopping the statin in 16 of those 17. Most patients were symptomatic at the time of the elevation, which usually occurred within 4 weeks of starting or changing therapy (Am. J. Med. 2005;118:618–24).

Another study, which included 1,014 primary care patients taking statins who had at least one transaminase measurement, only 1% (10) had a significant elevation and another 5 had moderate elevations, but none of those cases appeared to be related to statin use (Arch. Intern. Med. 2003;163:688–92).

Based on the data, it's reasonable to monitor liver function within the first 12 weeks of therapy and perhaps annually thereafter for the first 3–4 years. After that, if the patient has been on a stable dose and has not had an ALT elevation, it's not necessary to keep going. “I don't continue to monitor for years and years,” Dr. Paauw said.

Finally, grapefruit juice increases the bioavailability of drugs known to be metabolized by the CYP3A4 subunit of the P450 system, including simvastatin, lovastatin, and to a lesser degree, atorvastatin. Pravastatin, fluvastatin, and rosuvastatin do not rely on CYP3A4 and therefore do not interact with grapefruit juice.

While small amounts—a half of a grapefruit every 2 weeks, for example—are not likely to be clinically significant, a daily glass of juice at breakfast may cause a significant rise in statin bioavailability. Indeed, one study documented a 15-fold increase in mean peak serum lovastatin in 10 healthy volunteers who drank 200 mL of grapefruit juice, compared with subjects who drank water, three times a day for 3 days; subjects took one 80-mg dose of lovastatin on day 3 (Clin. Pharmacol. Ther. 1998;63:397–402). This highly significant effect may work to the advantage of some patients who have not achieved lipid control on statins, Dr. Paauw noted.

PHILADELPHIA — Be alert for potential interactions and side effects when prescribing statins, Dr. Douglas S. Paauw advised at the annual meeting of the American College of Physicians.

While hepatotoxicity and rhabdomyolysis are relatively rare, myalgias are quite common and often prompt patients to discontinue the drugs, said Dr. Paauw, professor of medicine at the University of Washington, Seattle.

And, although the overall risk of rhabdomyolysis is low, the chance is greater with the addition of other drugs.

In one frequently cited study, rates of toxicity were very low (2% myalgias, 0.4% myositis, and 0.4% hepatotoxicity) among 252 atherosclerotic patients receiving a statin plus gemfibrozil, leading the authors to conclude that the combination could be used safely in high-risk patients (Am. Heart J. 1999;138:151–5).

But those results may not reflect current clinical experience. Pravastatin, which is used less often today, was the statin most commonly used in the study (325.7 patient-years), followed by simvastatin (178.1), fluvastatin (54.0), lovastatin (20.3), and atorvastatin (15.5).

Simvastatin and lovastatin, both used more often today, are metabolized by a subunit of the cytochrome P450 system that is affected to a greater degree by gemfibrozil than are pravastatin or fluvastatin. Thus, in the study, the investigators were using “safer statins” in terms of drug interactions, Dr. Paauw noted.

If it is necessary to use both gemfibrozil and a statin—a very common scenario—it's important to document the reason for using the combination. Also, educate the patient about myalgias and rhabdomyolysis, including the importance of stopping the drug right away when muscle pain starts and then calling the physician afterward—especially if the symptoms occur during weekends or holidays.

Always ask patients about muscle pain, and monitor signs and symptoms at every office visit. There is no set policy about blood monitoring, but it's a good idea to measure creatinine phosphokinase (CPK) levels periodically and any time that symptoms develop, he advised.

Fibrates top a long list of other drugs that can increase statin toxicity, including azole antifungals, niacin, erythromycin/clarithromycin, protease inhibitors, verapamil/diltiazem, and cyclosporine. About half of all severe cases of rhabdomyolysis occur when three or more of these agents are taken together, such as in a patient who is already taking a fibrate plus a statin who is then prescribed erythromycin for 2 weeks. “It's that third drug that markedly increases the risk,” Dr. Paauw said.

Less attention has been paid to simple muscle pain and weakness. Published data suggest that this side effect occurs in only 1%–5% of patients on statins. “I really believe that that number is higher. In my practice, it's probably 20% at least,” he said.

Indeed, patients will often take themselves off the drug and report that the pain goes away. The problem appears to be both dose- and drug-related, with certain statins causing more problems than other drugs for some individuals.

In one study, muscle cell abnormalities were found on biopsy in patients who had normal CPK levels but who complained of muscle pain (Ann. Intern. Med. 2002;137:581–5). “If a CPK comes back normal, it doesn't tell us that the pain isn't from the statin. It simply tells us that the magnitude of the muscle problem doesn't put them at risk for rhabdomyolysis right now, but they could still be severely debilitated by the pain.”

Further complicating the picture, statin-induced muscle pain isn't necessarily uniform throughout the body. For example, a patient may complain of severe pain only in the left thigh. It may seem highly improbable that the statin is the problem, but quite often the pain goes away if you take the patient off the drug. “Take very seriously any pain syndrome in a patient on statins. If you can't find an alternative diagnosis, consider a short drug holiday and see what happens,” Dr. Paauw recommended.

Once the pain resolves—typically in 1–2 weeks—you can restart the same statin at a low dose, or try switching to a different one. If the patient still experiences muscle pain after trying two different statins, it may be necessary to consider a different category of lipid-lowering drug.

Hepatotoxicity appears to be less of an issue with statins than was originally thought. In a retrospective cohort study of 23,000 adult HMO patients who received statins over a 5-year period, just 0.3% had severe transaminitis, defined as an alanine aminotransferase (ALT) level 10 times greater than normal. Of those 62 patients, only 17 had ALT elevation due to the statin, and the problem resolved after stopping the statin in 16 of those 17. Most patients were symptomatic at the time of the elevation, which usually occurred within 4 weeks of starting or changing therapy (Am. J. Med. 2005;118:618–24).

Another study, which included 1,014 primary care patients taking statins who had at least one transaminase measurement, only 1% (10) had a significant elevation and another 5 had moderate elevations, but none of those cases appeared to be related to statin use (Arch. Intern. Med. 2003;163:688–92).

Based on the data, it's reasonable to monitor liver function within the first 12 weeks of therapy and perhaps annually thereafter for the first 3–4 years. After that, if the patient has been on a stable dose and has not had an ALT elevation, it's not necessary to keep going. “I don't continue to monitor for years and years,” Dr. Paauw said.

Finally, grapefruit juice increases the bioavailability of drugs known to be metabolized by the CYP3A4 subunit of the P450 system, including simvastatin, lovastatin, and to a lesser degree, atorvastatin. Pravastatin, fluvastatin, and rosuvastatin do not rely on CYP3A4 and therefore do not interact with grapefruit juice.

While small amounts—a half of a grapefruit every 2 weeks, for example—are not likely to be clinically significant, a daily glass of juice at breakfast may cause a significant rise in statin bioavailability. Indeed, one study documented a 15-fold increase in mean peak serum lovastatin in 10 healthy volunteers who drank 200 mL of grapefruit juice, compared with subjects who drank water, three times a day for 3 days; subjects took one 80-mg dose of lovastatin on day 3 (Clin. Pharmacol. Ther. 1998;63:397–402). This highly significant effect may work to the advantage of some patients who have not achieved lipid control on statins, Dr. Paauw noted.

LUCAYA, BAHAMAS — Whether atypical fibroxanthoma is an entity unto itself or simply a superficial form of malignant fibrous histiocytoma depends upon whether the observer is a clinician or a dermatopathologist.

While the two nonmelanoma skin cancers behave very differently from a clinical standpoint, "the pathologist can't tell the difference except for the depth," Dr. Henry W. Randle noted at a meeting of the American Society for Mohs Surgery.

Atypical fibroxanthoma (AFX)—also known as "malignant fibrous histiocytoma in situ"—is a rapidly growing and often ulcerated red nodule, typically seen on sun-damaged head and neck areas in elderly men. Although its histology appears ominous, prognosis is usually good. Indeed, of 140 patients, just 6.4% (9) had recurrences after standard excision, usually within the first year. Metastases are rare, usually to a regional node. Mortality is also infrequent, although there have been some recent case reports, he said.

These tumors can be treated with Mohs surgery, after which the recurrence rate is just 6.9%. Malignant fibrous histiocytoma (MFH), in contrast, recurs in 43% following Mohs surgery (J. Am. Acad. Dermatol. 2001;44:656–9).

Moreover, MFH invades the skin from the soft tissue and moves up to the surface rather than the other way around, and it is not associated with sun exposure—it typically appears on extremities, not the face and neck. MFH is a much more aggressive tumor than is AFX, with mortality rates of more than one-third at 3.5 years. "They really behave very differently, even though AFX is considered to be the more superficial form of MFH," noted Dr. Randle of the Mayo Clinic in Jacksonville, Fla.

The treatment of MFH requires staging. Wide excision is the standard, because the depth of these tumors makes the use of Mohs surgery questionable. Node dissection, radiation, and chemotherapy should also be considered, he noted.

Research is now focused on finding immunohistochemical markers that will help to distinguish the two tumors. Most are identical in both, with the only known difference thus far being that AFX has a weak positivity to CD74, while MFH is strongly positive. However, even this isn't absolute. Until better markers are found, pathologists typically consider the lesion to be MFH—and recommend aggressive treatment—if it extends into the subcutis and vascular invasion and tumor necrosis are present.

Dermatologic surgeons who treat these tumors need to take extra care beyond what is involved in minor procedures. In a disturbing case report, a surgeon who accidentally impaled his own hand while removing an MFH developed a genetically identical MFH 5 months later (N. Engl. J. Med. 1996;335:1494–7).

Malignant fibrous histiocytoma (right)is a much more aggressive tumor thanis atypical fibroxanthoma (above), with mortality rates of more than one-third at 3.5 years. Photos courtesy Dr. Henry W. Randle

LUCAYA, BAHAMAS — Whether atypical fibroxanthoma is an entity unto itself or simply a superficial form of malignant fibrous histiocytoma depends upon whether the observer is a clinician or a dermatopathologist.

While the two nonmelanoma skin cancers behave very differently from a clinical standpoint, "the pathologist can't tell the difference except for the depth," Dr. Henry W. Randle noted at a meeting of the American Society for Mohs Surgery.

Atypical fibroxanthoma (AFX)—also known as "malignant fibrous histiocytoma in situ"—is a rapidly growing and often ulcerated red nodule, typically seen on sun-damaged head and neck areas in elderly men. Although its histology appears ominous, prognosis is usually good. Indeed, of 140 patients, just 6.4% (9) had recurrences after standard excision, usually within the first year. Metastases are rare, usually to a regional node. Mortality is also infrequent, although there have been some recent case reports, he said.

These tumors can be treated with Mohs surgery, after which the recurrence rate is just 6.9%. Malignant fibrous histiocytoma (MFH), in contrast, recurs in 43% following Mohs surgery (J. Am. Acad. Dermatol. 2001;44:656–9).

Moreover, MFH invades the skin from the soft tissue and moves up to the surface rather than the other way around, and it is not associated with sun exposure—it typically appears on extremities, not the face and neck. MFH is a much more aggressive tumor than is AFX, with mortality rates of more than one-third at 3.5 years. "They really behave very differently, even though AFX is considered to be the more superficial form of MFH," noted Dr. Randle of the Mayo Clinic in Jacksonville, Fla.

The treatment of MFH requires staging. Wide excision is the standard, because the depth of these tumors makes the use of Mohs surgery questionable. Node dissection, radiation, and chemotherapy should also be considered, he noted.

Research is now focused on finding immunohistochemical markers that will help to distinguish the two tumors. Most are identical in both, with the only known difference thus far being that AFX has a weak positivity to CD74, while MFH is strongly positive. However, even this isn't absolute. Until better markers are found, pathologists typically consider the lesion to be MFH—and recommend aggressive treatment—if it extends into the subcutis and vascular invasion and tumor necrosis are present.

Dermatologic surgeons who treat these tumors need to take extra care beyond what is involved in minor procedures. In a disturbing case report, a surgeon who accidentally impaled his own hand while removing an MFH developed a genetically identical MFH 5 months later (N. Engl. J. Med. 1996;335:1494–7).

Malignant fibrous histiocytoma (right)is a much more aggressive tumor thanis atypical fibroxanthoma (above), with mortality rates of more than one-third at 3.5 years. Photos courtesy Dr. Henry W. Randle

LUCAYA, BAHAMAS — Whether atypical fibroxanthoma is an entity unto itself or simply a superficial form of malignant fibrous histiocytoma depends upon whether the observer is a clinician or a dermatopathologist.

While the two nonmelanoma skin cancers behave very differently from a clinical standpoint, "the pathologist can't tell the difference except for the depth," Dr. Henry W. Randle noted at a meeting of the American Society for Mohs Surgery.

Atypical fibroxanthoma (AFX)—also known as "malignant fibrous histiocytoma in situ"—is a rapidly growing and often ulcerated red nodule, typically seen on sun-damaged head and neck areas in elderly men. Although its histology appears ominous, prognosis is usually good. Indeed, of 140 patients, just 6.4% (9) had recurrences after standard excision, usually within the first year. Metastases are rare, usually to a regional node. Mortality is also infrequent, although there have been some recent case reports, he said.

These tumors can be treated with Mohs surgery, after which the recurrence rate is just 6.9%. Malignant fibrous histiocytoma (MFH), in contrast, recurs in 43% following Mohs surgery (J. Am. Acad. Dermatol. 2001;44:656–9).

Moreover, MFH invades the skin from the soft tissue and moves up to the surface rather than the other way around, and it is not associated with sun exposure—it typically appears on extremities, not the face and neck. MFH is a much more aggressive tumor than is AFX, with mortality rates of more than one-third at 3.5 years. "They really behave very differently, even though AFX is considered to be the more superficial form of MFH," noted Dr. Randle of the Mayo Clinic in Jacksonville, Fla.

The treatment of MFH requires staging. Wide excision is the standard, because the depth of these tumors makes the use of Mohs surgery questionable. Node dissection, radiation, and chemotherapy should also be considered, he noted.

Research is now focused on finding immunohistochemical markers that will help to distinguish the two tumors. Most are identical in both, with the only known difference thus far being that AFX has a weak positivity to CD74, while MFH is strongly positive. However, even this isn't absolute. Until better markers are found, pathologists typically consider the lesion to be MFH—and recommend aggressive treatment—if it extends into the subcutis and vascular invasion and tumor necrosis are present.

Dermatologic surgeons who treat these tumors need to take extra care beyond what is involved in minor procedures. In a disturbing case report, a surgeon who accidentally impaled his own hand while removing an MFH developed a genetically identical MFH 5 months later (N. Engl. J. Med. 1996;335:1494–7).

Malignant fibrous histiocytoma (right)is a much more aggressive tumor thanis atypical fibroxanthoma (above), with mortality rates of more than one-third at 3.5 years. Photos courtesy Dr. Henry W. Randle

PHILADELPHIA — Nonalcoholic fatty liver disease is emerging as a major health burden in the United States, Dr. K. Rajender Reddy said at the annual meeting of the American College of Physicians.

Often associated with obesity and underlying insulin resistance, nonalcoholic fatty liver disease (NAFLD) is believed to affect as much as 20%–30% of the U.S. population, said Dr. Reddy, professor of medicine and surgery and director of hepatology at the University of Pennsylvania, Philadelphia.

There is some debate about the amount of alcohol ingestion permitted to make the distinction between alcoholic steatosis and NAFLD, which is defined as increased liver weight by 5%–10% from fat accumulation (steatosis), in the absence of excessive alcohol consumption. Most experts agree, however, that overall alcohol consumption of less than 20 g per day is well below that which would be associated with significant alcoholic liver disease, noted Dr. Reddy, who is also medical director of liver transplantation at the university.

Classification of NAFLD falls into four types: Type 1 (fatty liver alone) and type 2 (fat accumulation and lobular inflammation) are considered to be NAFLD alone. The more serious types 3 (fat accumulation and ballooning degeneration) and 4 (fat accumulation, ballooning degeneration, and either Mallory hyaline and/or fibrosis) are characterized as nonalcoholic steatohepatitis (NASH).

“There is a tendency to use the term NASH loosely in everyone who has nonalcoholic fatty liver disease. You should use the general term NAFLD and reserve NASH only for those who have histologic evidence of steatohepatitis,” Dr. Reddy advised.

Overall, about 10% of patients with NAFLD have NASH. Limited data on the natural history of these conditions suggest that about 15%–20% of patients with steatosis will progress to steatohepatitis at some point. Of those, smaller numbers will go on to develop fibrosis, cirrhosis, and hepatocellular carcinoma.

Factors that predict progression from NAFLD to NASH include age greater than 45 years, type 2 diabetes, body mass index greater than 35 kg/m

Data pertaining to treatment of NAFLD are also limited, but weight management is considered a major priority for all patients because of proven benefits in cardiovascular risk profile. Small anecdotal studies have indicated an improvement in biochemical parameters and liver histology with exercise and/or diet, while weight reduction of 10% or more has been shown to correct aminotransferase abnormalities and decrease hepatomegaly.

PHILADELPHIA — Nonalcoholic fatty liver disease is emerging as a major health burden in the United States, Dr. K. Rajender Reddy said at the annual meeting of the American College of Physicians.

Often associated with obesity and underlying insulin resistance, nonalcoholic fatty liver disease (NAFLD) is believed to affect as much as 20%–30% of the U.S. population, said Dr. Reddy, professor of medicine and surgery and director of hepatology at the University of Pennsylvania, Philadelphia.

There is some debate about the amount of alcohol ingestion permitted to make the distinction between alcoholic steatosis and NAFLD, which is defined as increased liver weight by 5%–10% from fat accumulation (steatosis), in the absence of excessive alcohol consumption. Most experts agree, however, that overall alcohol consumption of less than 20 g per day is well below that which would be associated with significant alcoholic liver disease, noted Dr. Reddy, who is also medical director of liver transplantation at the university.

Classification of NAFLD falls into four types: Type 1 (fatty liver alone) and type 2 (fat accumulation and lobular inflammation) are considered to be NAFLD alone. The more serious types 3 (fat accumulation and ballooning degeneration) and 4 (fat accumulation, ballooning degeneration, and either Mallory hyaline and/or fibrosis) are characterized as nonalcoholic steatohepatitis (NASH).

“There is a tendency to use the term NASH loosely in everyone who has nonalcoholic fatty liver disease. You should use the general term NAFLD and reserve NASH only for those who have histologic evidence of steatohepatitis,” Dr. Reddy advised.

Overall, about 10% of patients with NAFLD have NASH. Limited data on the natural history of these conditions suggest that about 15%–20% of patients with steatosis will progress to steatohepatitis at some point. Of those, smaller numbers will go on to develop fibrosis, cirrhosis, and hepatocellular carcinoma.

Factors that predict progression from NAFLD to NASH include age greater than 45 years, type 2 diabetes, body mass index greater than 35 kg/m

Data pertaining to treatment of NAFLD are also limited, but weight management is considered a major priority for all patients because of proven benefits in cardiovascular risk profile. Small anecdotal studies have indicated an improvement in biochemical parameters and liver histology with exercise and/or diet, while weight reduction of 10% or more has been shown to correct aminotransferase abnormalities and decrease hepatomegaly.

PHILADELPHIA — Nonalcoholic fatty liver disease is emerging as a major health burden in the United States, Dr. K. Rajender Reddy said at the annual meeting of the American College of Physicians.

Often associated with obesity and underlying insulin resistance, nonalcoholic fatty liver disease (NAFLD) is believed to affect as much as 20%–30% of the U.S. population, said Dr. Reddy, professor of medicine and surgery and director of hepatology at the University of Pennsylvania, Philadelphia.

There is some debate about the amount of alcohol ingestion permitted to make the distinction between alcoholic steatosis and NAFLD, which is defined as increased liver weight by 5%–10% from fat accumulation (steatosis), in the absence of excessive alcohol consumption. Most experts agree, however, that overall alcohol consumption of less than 20 g per day is well below that which would be associated with significant alcoholic liver disease, noted Dr. Reddy, who is also medical director of liver transplantation at the university.

Classification of NAFLD falls into four types: Type 1 (fatty liver alone) and type 2 (fat accumulation and lobular inflammation) are considered to be NAFLD alone. The more serious types 3 (fat accumulation and ballooning degeneration) and 4 (fat accumulation, ballooning degeneration, and either Mallory hyaline and/or fibrosis) are characterized as nonalcoholic steatohepatitis (NASH).

“There is a tendency to use the term NASH loosely in everyone who has nonalcoholic fatty liver disease. You should use the general term NAFLD and reserve NASH only for those who have histologic evidence of steatohepatitis,” Dr. Reddy advised.

Overall, about 10% of patients with NAFLD have NASH. Limited data on the natural history of these conditions suggest that about 15%–20% of patients with steatosis will progress to steatohepatitis at some point. Of those, smaller numbers will go on to develop fibrosis, cirrhosis, and hepatocellular carcinoma.

Factors that predict progression from NAFLD to NASH include age greater than 45 years, type 2 diabetes, body mass index greater than 35 kg/m

Data pertaining to treatment of NAFLD are also limited, but weight management is considered a major priority for all patients because of proven benefits in cardiovascular risk profile. Small anecdotal studies have indicated an improvement in biochemical parameters and liver histology with exercise and/or diet, while weight reduction of 10% or more has been shown to correct aminotransferase abnormalities and decrease hepatomegaly.

ATLANTA — While the precise nature of the link between medical abortion and fatal toxic shock-like syndrome remains a mystery, the handful of case reports have prompted a difference in opinion about how such procedures should be carried out.

Activists have responded to the reports by calling for a removal of mifepristone (Mifeprex) from the U.S. market. Planned Parenthood, in contrast, has not stopped using mifepristone but has called for an end to the use of intravaginal misoprostol following oral mifepristone. This regimen is not approved by the Food and Drug Administration but is widely used and was associated with all five of the reported fatal Clostridium sordellii infections following medical abortion in the United States and Canada.

For its part, the American College of Obstetricians and Gynecologists will review the final report of the FDA panel before issuing any statements, Dr. Kevin Ault said in an interview.

Five cases of fatal C. sordellii infection have been reported against a background of approximately 560,000 medical abortions a year. “None of it is common. Clearly there are cases related to pregnancy that have nothing to do with pregnancy termination, and then there is the smaller group of nonpregnant cases. It's hard to find cause and effect here,” Dr. Ault said in an interview following a 1-day meeting on emerging clostridial disease sponsored by the Centers for Disease Control and Prevention that he attended on behalf of ACOG.

At the meeting, researchers discussed the latest information in order to draft a research agenda for C. sordellii and C. difficile, another emerging infection associated with toxin-mediated sepsis that has also affected pregnant women.

Dr. Marc Fischer, a medical epidemiologist at the CDC, summarized the published literature to date on infections involving C. sordellii, a gram-positive anaerobic bacillus that resides in soil and colonizes the gastrointestinal and/or genital tracts of healthy humans. In various case reports and series, the organism has been identified in cases of pneumonia, endocarditis, arthritis, peritonitis, corneal ulcer, and bacteremia, and in wound infections among patients with necrotizing fasciitis, tissue allograft infections, neonatal omphalitis, postpartum endometritis, and episiotomy infections.

Between 1977 and 2001, C. sordellii genital tract infections and toxic shock-like syndrome were reported in 10 women, among whom the preceding events were childbirth (8) and medical abortion (1), reported from Canada in 2001. Another four cases were identified between 2003 and 2005, all involving women who had undergone medical abortions using the common “off-label” regimen of 200 mg oral mifepristone followed by 800 mcg vaginal misoprostol, said Dr. Fischer, who was the lead author of the published report of those four cases (N. Engl. J. Med. 2005;353:2352–60).

The four recent cases were all previously healthy women from California who developed symptoms including tachycardia, hypotension, vomiting or diarrhea, and abdominal pain within 5 days of taking mifepristone. Clinical laboratory findings in three of the patients included leukemoid reaction in all three, hemoconcentration in two, and thrombocytopenia in two. All died within a day of hospitalization. The clinical and pathologic findings in these cases were similar to those of the 10 previously reported cases, Dr. Fischer said.

Dr. L. Clifford McDonald, also of the CDC, reported that three additional cases of fatal toxic shock-like syndrome following medical abortion are currently under investigation by the CDC. Each of these differs in various ways from the previous five: One, in a woman who had taken oral mifepristone followed by vaginal misoprostol, was associated with C. perfringens, not C. sordellii. A second case, also of C. perfringens, involved the use of misoprostol with the cervical dilator Laminaria, not mifepristone. The third, although initially reported as being associated with a medical abortion, could not be confirmed as such. Moreover, investigation has shown pathologic findings consistent with appendicitis, serositis, and pneumonia, he noted.

Meanwhile, there have been three reported cases of toxic shock-like syndrome following spontaneous abortion, all involving C. sordellii. One of these patients was coinfected with C. perfringens. Another patient, in whom the C. sordellii did not possess the genes encoding the lethal toxin, was the only one who survived.

Several speakers offered hypotheses as to the mechanism for the lethal infections. Dr. James A. McGregor, of the obstetrics and gynecology department at Keck School of Medicine, Los Angeles, noted that mifepristone is a potent inhibitor of both progesterone and glucocorticoid receptors. As such, mifepristone may impair host immune responses and predispose women to lethal infections caused by toxigenic C. sordellii and other pathogens that exist normally in low numbers in the reproductive tracts of many women (Contraception 2005;72:393).

Given that there are data to suggest that early pregnancy can be terminated medically using only vaginal misoprostol without mifepristone (Contraception 2004;70:121–6), this might be considered as a possible primary prevention strategy, Dr. McGregor said.

Alternatively, medical abortions could be limited to the FDA-approved regimen of 600 mg oral mifepristone followed within 2 days by 400 mcg oral misoprostol, as Planned Parenthood has done, he suggested.

Dr. Ault advised that physicians present patients with the risks and benefits of all of the medical and surgical termination options and obtain informed consent.

ATLANTA — While the precise nature of the link between medical abortion and fatal toxic shock-like syndrome remains a mystery, the handful of case reports have prompted a difference in opinion about how such procedures should be carried out.

Activists have responded to the reports by calling for a removal of mifepristone (Mifeprex) from the U.S. market. Planned Parenthood, in contrast, has not stopped using mifepristone but has called for an end to the use of intravaginal misoprostol following oral mifepristone. This regimen is not approved by the Food and Drug Administration but is widely used and was associated with all five of the reported fatal Clostridium sordellii infections following medical abortion in the United States and Canada.

For its part, the American College of Obstetricians and Gynecologists will review the final report of the FDA panel before issuing any statements, Dr. Kevin Ault said in an interview.

Five cases of fatal C. sordellii infection have been reported against a background of approximately 560,000 medical abortions a year. “None of it is common. Clearly there are cases related to pregnancy that have nothing to do with pregnancy termination, and then there is the smaller group of nonpregnant cases. It's hard to find cause and effect here,” Dr. Ault said in an interview following a 1-day meeting on emerging clostridial disease sponsored by the Centers for Disease Control and Prevention that he attended on behalf of ACOG.

At the meeting, researchers discussed the latest information in order to draft a research agenda for C. sordellii and C. difficile, another emerging infection associated with toxin-mediated sepsis that has also affected pregnant women.

Dr. Marc Fischer, a medical epidemiologist at the CDC, summarized the published literature to date on infections involving C. sordellii, a gram-positive anaerobic bacillus that resides in soil and colonizes the gastrointestinal and/or genital tracts of healthy humans. In various case reports and series, the organism has been identified in cases of pneumonia, endocarditis, arthritis, peritonitis, corneal ulcer, and bacteremia, and in wound infections among patients with necrotizing fasciitis, tissue allograft infections, neonatal omphalitis, postpartum endometritis, and episiotomy infections.

Between 1977 and 2001, C. sordellii genital tract infections and toxic shock-like syndrome were reported in 10 women, among whom the preceding events were childbirth (8) and medical abortion (1), reported from Canada in 2001. Another four cases were identified between 2003 and 2005, all involving women who had undergone medical abortions using the common “off-label” regimen of 200 mg oral mifepristone followed by 800 mcg vaginal misoprostol, said Dr. Fischer, who was the lead author of the published report of those four cases (N. Engl. J. Med. 2005;353:2352–60).

The four recent cases were all previously healthy women from California who developed symptoms including tachycardia, hypotension, vomiting or diarrhea, and abdominal pain within 5 days of taking mifepristone. Clinical laboratory findings in three of the patients included leukemoid reaction in all three, hemoconcentration in two, and thrombocytopenia in two. All died within a day of hospitalization. The clinical and pathologic findings in these cases were similar to those of the 10 previously reported cases, Dr. Fischer said.

Dr. L. Clifford McDonald, also of the CDC, reported that three additional cases of fatal toxic shock-like syndrome following medical abortion are currently under investigation by the CDC. Each of these differs in various ways from the previous five: One, in a woman who had taken oral mifepristone followed by vaginal misoprostol, was associated with C. perfringens, not C. sordellii. A second case, also of C. perfringens, involved the use of misoprostol with the cervical dilator Laminaria, not mifepristone. The third, although initially reported as being associated with a medical abortion, could not be confirmed as such. Moreover, investigation has shown pathologic findings consistent with appendicitis, serositis, and pneumonia, he noted.

Meanwhile, there have been three reported cases of toxic shock-like syndrome following spontaneous abortion, all involving C. sordellii. One of these patients was coinfected with C. perfringens. Another patient, in whom the C. sordellii did not possess the genes encoding the lethal toxin, was the only one who survived.

Several speakers offered hypotheses as to the mechanism for the lethal infections. Dr. James A. McGregor, of the obstetrics and gynecology department at Keck School of Medicine, Los Angeles, noted that mifepristone is a potent inhibitor of both progesterone and glucocorticoid receptors. As such, mifepristone may impair host immune responses and predispose women to lethal infections caused by toxigenic C. sordellii and other pathogens that exist normally in low numbers in the reproductive tracts of many women (Contraception 2005;72:393).

Given that there are data to suggest that early pregnancy can be terminated medically using only vaginal misoprostol without mifepristone (Contraception 2004;70:121–6), this might be considered as a possible primary prevention strategy, Dr. McGregor said.

Alternatively, medical abortions could be limited to the FDA-approved regimen of 600 mg oral mifepristone followed within 2 days by 400 mcg oral misoprostol, as Planned Parenthood has done, he suggested.

Dr. Ault advised that physicians present patients with the risks and benefits of all of the medical and surgical termination options and obtain informed consent.

ATLANTA — While the precise nature of the link between medical abortion and fatal toxic shock-like syndrome remains a mystery, the handful of case reports have prompted a difference in opinion about how such procedures should be carried out.

Activists have responded to the reports by calling for a removal of mifepristone (Mifeprex) from the U.S. market. Planned Parenthood, in contrast, has not stopped using mifepristone but has called for an end to the use of intravaginal misoprostol following oral mifepristone. This regimen is not approved by the Food and Drug Administration but is widely used and was associated with all five of the reported fatal Clostridium sordellii infections following medical abortion in the United States and Canada.

For its part, the American College of Obstetricians and Gynecologists will review the final report of the FDA panel before issuing any statements, Dr. Kevin Ault said in an interview.

Five cases of fatal C. sordellii infection have been reported against a background of approximately 560,000 medical abortions a year. “None of it is common. Clearly there are cases related to pregnancy that have nothing to do with pregnancy termination, and then there is the smaller group of nonpregnant cases. It's hard to find cause and effect here,” Dr. Ault said in an interview following a 1-day meeting on emerging clostridial disease sponsored by the Centers for Disease Control and Prevention that he attended on behalf of ACOG.

At the meeting, researchers discussed the latest information in order to draft a research agenda for C. sordellii and C. difficile, another emerging infection associated with toxin-mediated sepsis that has also affected pregnant women.

Dr. Marc Fischer, a medical epidemiologist at the CDC, summarized the published literature to date on infections involving C. sordellii, a gram-positive anaerobic bacillus that resides in soil and colonizes the gastrointestinal and/or genital tracts of healthy humans. In various case reports and series, the organism has been identified in cases of pneumonia, endocarditis, arthritis, peritonitis, corneal ulcer, and bacteremia, and in wound infections among patients with necrotizing fasciitis, tissue allograft infections, neonatal omphalitis, postpartum endometritis, and episiotomy infections.

Between 1977 and 2001, C. sordellii genital tract infections and toxic shock-like syndrome were reported in 10 women, among whom the preceding events were childbirth (8) and medical abortion (1), reported from Canada in 2001. Another four cases were identified between 2003 and 2005, all involving women who had undergone medical abortions using the common “off-label” regimen of 200 mg oral mifepristone followed by 800 mcg vaginal misoprostol, said Dr. Fischer, who was the lead author of the published report of those four cases (N. Engl. J. Med. 2005;353:2352–60).

The four recent cases were all previously healthy women from California who developed symptoms including tachycardia, hypotension, vomiting or diarrhea, and abdominal pain within 5 days of taking mifepristone. Clinical laboratory findings in three of the patients included leukemoid reaction in all three, hemoconcentration in two, and thrombocytopenia in two. All died within a day of hospitalization. The clinical and pathologic findings in these cases were similar to those of the 10 previously reported cases, Dr. Fischer said.

Dr. L. Clifford McDonald, also of the CDC, reported that three additional cases of fatal toxic shock-like syndrome following medical abortion are currently under investigation by the CDC. Each of these differs in various ways from the previous five: One, in a woman who had taken oral mifepristone followed by vaginal misoprostol, was associated with C. perfringens, not C. sordellii. A second case, also of C. perfringens, involved the use of misoprostol with the cervical dilator Laminaria, not mifepristone. The third, although initially reported as being associated with a medical abortion, could not be confirmed as such. Moreover, investigation has shown pathologic findings consistent with appendicitis, serositis, and pneumonia, he noted.

Meanwhile, there have been three reported cases of toxic shock-like syndrome following spontaneous abortion, all involving C. sordellii. One of these patients was coinfected with C. perfringens. Another patient, in whom the C. sordellii did not possess the genes encoding the lethal toxin, was the only one who survived.

Several speakers offered hypotheses as to the mechanism for the lethal infections. Dr. James A. McGregor, of the obstetrics and gynecology department at Keck School of Medicine, Los Angeles, noted that mifepristone is a potent inhibitor of both progesterone and glucocorticoid receptors. As such, mifepristone may impair host immune responses and predispose women to lethal infections caused by toxigenic C. sordellii and other pathogens that exist normally in low numbers in the reproductive tracts of many women (Contraception 2005;72:393).

Given that there are data to suggest that early pregnancy can be terminated medically using only vaginal misoprostol without mifepristone (Contraception 2004;70:121–6), this might be considered as a possible primary prevention strategy, Dr. McGregor said.

Alternatively, medical abortions could be limited to the FDA-approved regimen of 600 mg oral mifepristone followed within 2 days by 400 mcg oral misoprostol, as Planned Parenthood has done, he suggested.

Dr. Ault advised that physicians present patients with the risks and benefits of all of the medical and surgical termination options and obtain informed consent.

ATLANTA — Both health care-associated and community-acquired infections caused by the exotoxin-producing bacillus Clostridium difficile continue to increase, Dr. L. Clifford McDonald said during a meeting on emerging clostridial disease sponsored by the Centers for Disease Control and Prevention.

Better surveillance for C. difficile-associated disease (CDAD)—which can range in severity from mild diarrhea to fulminant colitis and death—has become a priority for the CDC.

The meeting, also sponsored by the Food and Drug Administration and the National Institute of Allergy and Infectious Diseases, was convened to develop a research agenda for studying both C. difficile and the related anaerobic bacterium Clostridium sordellii, which has been linked to complications following medical abortions (see related story).

The CDC plans to issue a formal statement saying that all health care facilities should conduct some type of surveillance for CDAD, a recommendation the agency has already made informally through its Web site and public presentations. The CDC is also using established networks, such as the Emerging Infections Programs' FoodNet project, and various pilot studies and state-based epidemiologic investigations to isolate CDAD cases that arise in the community, including human infections that have also appeared in food-producing animals and strains seen in pregnant women, said Dr. McDonald, a medical epidemiologist at the CDC's Division of Healthcare Quality Promotion.

Hospital discharges for which CDAD was listed as any diagnosis doubled between 2000 and 2003 (Emerg. Infect. Dis. 2006;12:409–15). And in the latest yearly update of an ongoing survey, CDAD rates rose by another 25% from 2003 to 2004, from 61 per 100,000 population (178,000 total discharges) to 75 per 100,000 (211,000 discharges). Rates have been highest among adults aged 65 years and older.

Although most CDAD cases are still thought to arise in health care facilities, recent reports of community-associated cases—including some without recent antimicrobial use—have prompted concern that the problem may be underrecognized. At present, C. difficile cases are not nationally reportable.

Last December, the CDC reported a total of 33 cases of community-acquired CDAD in four U.S. states, including 10 infections among pregnant women and 8 in patients who did not have recent antimicrobial use (MMWR 2005;54:1201–5).

More recently, the CDC found that community-associated CDAD is increasing among patients seeking care at the Atlanta Veterans Affairs Medical Center. As of March 2006, about 30% of all CDAD cases there have occurred in outpatients, compared with about 10% in 2003. Of 61 outpatients with CDAD seen at the VA during 2003–2006, 50 had not been hospitalized in the previous 3 months and 19 had not received antimicrobials in the prior 30 days, Dr. McDonald reported.

Use of proton-pump inhibitors (PPIs) appeared to increase the risk; the CDAD patients without antimicrobial exposure were more likely to have been exposed to PPIs than were those with antimicrobial exposure (65% vs. 12%), he said.

Following the report of the 10 CDAD cases among pregnant women, the CDC conducted a survey of 405 infectious disease clinicians. Of those, 17 reported having personally seen such cases and another 23 were aware of such cases in their community. Of the 48 cases reported by the survey respondents, 14 of the infections occurred prior to delivery, 20% of the women developed recurrent disease, and three developed toxic megacolon. There was one fetal loss and one maternal death. It is unknown whether any of these cases were among those previously reported.

The infection is also emerging in food-producing animals, with recent outbreaks among neonatal pigs, dairy calves, and beef. Recently, the CDC has investigated seven cases of human CDAD in seven different states; in these patients, the strains appeared genetically similar on pulsed field gel electrophoresis to the epidemic animal strains, which has not been found in the past.

ATLANTA — Both health care-associated and community-acquired infections caused by the exotoxin-producing bacillus Clostridium difficile continue to increase, Dr. L. Clifford McDonald said during a meeting on emerging clostridial disease sponsored by the Centers for Disease Control and Prevention.

Better surveillance for C. difficile-associated disease (CDAD)—which can range in severity from mild diarrhea to fulminant colitis and death—has become a priority for the CDC.

The meeting, also sponsored by the Food and Drug Administration and the National Institute of Allergy and Infectious Diseases, was convened to develop a research agenda for studying both C. difficile and the related anaerobic bacterium Clostridium sordellii, which has been linked to complications following medical abortions (see related story).

The CDC plans to issue a formal statement saying that all health care facilities should conduct some type of surveillance for CDAD, a recommendation the agency has already made informally through its Web site and public presentations. The CDC is also using established networks, such as the Emerging Infections Programs' FoodNet project, and various pilot studies and state-based epidemiologic investigations to isolate CDAD cases that arise in the community, including human infections that have also appeared in food-producing animals and strains seen in pregnant women, said Dr. McDonald, a medical epidemiologist at the CDC's Division of Healthcare Quality Promotion.

Hospital discharges for which CDAD was listed as any diagnosis doubled between 2000 and 2003 (Emerg. Infect. Dis. 2006;12:409–15). And in the latest yearly update of an ongoing survey, CDAD rates rose by another 25% from 2003 to 2004, from 61 per 100,000 population (178,000 total discharges) to 75 per 100,000 (211,000 discharges). Rates have been highest among adults aged 65 years and older.

Although most CDAD cases are still thought to arise in health care facilities, recent reports of community-associated cases—including some without recent antimicrobial use—have prompted concern that the problem may be underrecognized. At present, C. difficile cases are not nationally reportable.

Last December, the CDC reported a total of 33 cases of community-acquired CDAD in four U.S. states, including 10 infections among pregnant women and 8 in patients who did not have recent antimicrobial use (MMWR 2005;54:1201–5).

More recently, the CDC found that community-associated CDAD is increasing among patients seeking care at the Atlanta Veterans Affairs Medical Center. As of March 2006, about 30% of all CDAD cases there have occurred in outpatients, compared with about 10% in 2003. Of 61 outpatients with CDAD seen at the VA during 2003–2006, 50 had not been hospitalized in the previous 3 months and 19 had not received antimicrobials in the prior 30 days, Dr. McDonald reported.

Use of proton-pump inhibitors (PPIs) appeared to increase the risk; the CDAD patients without antimicrobial exposure were more likely to have been exposed to PPIs than were those with antimicrobial exposure (65% vs. 12%), he said.

Following the report of the 10 CDAD cases among pregnant women, the CDC conducted a survey of 405 infectious disease clinicians. Of those, 17 reported having personally seen such cases and another 23 were aware of such cases in their community. Of the 48 cases reported by the survey respondents, 14 of the infections occurred prior to delivery, 20% of the women developed recurrent disease, and three developed toxic megacolon. There was one fetal loss and one maternal death. It is unknown whether any of these cases were among those previously reported.

The infection is also emerging in food-producing animals, with recent outbreaks among neonatal pigs, dairy calves, and beef. Recently, the CDC has investigated seven cases of human CDAD in seven different states; in these patients, the strains appeared genetically similar on pulsed field gel electrophoresis to the epidemic animal strains, which has not been found in the past.

ATLANTA — Both health care-associated and community-acquired infections caused by the exotoxin-producing bacillus Clostridium difficile continue to increase, Dr. L. Clifford McDonald said during a meeting on emerging clostridial disease sponsored by the Centers for Disease Control and Prevention.

Better surveillance for C. difficile-associated disease (CDAD)—which can range in severity from mild diarrhea to fulminant colitis and death—has become a priority for the CDC.

The meeting, also sponsored by the Food and Drug Administration and the National Institute of Allergy and Infectious Diseases, was convened to develop a research agenda for studying both C. difficile and the related anaerobic bacterium Clostridium sordellii, which has been linked to complications following medical abortions (see related story).

The CDC plans to issue a formal statement saying that all health care facilities should conduct some type of surveillance for CDAD, a recommendation the agency has already made informally through its Web site and public presentations. The CDC is also using established networks, such as the Emerging Infections Programs' FoodNet project, and various pilot studies and state-based epidemiologic investigations to isolate CDAD cases that arise in the community, including human infections that have also appeared in food-producing animals and strains seen in pregnant women, said Dr. McDonald, a medical epidemiologist at the CDC's Division of Healthcare Quality Promotion.

Hospital discharges for which CDAD was listed as any diagnosis doubled between 2000 and 2003 (Emerg. Infect. Dis. 2006;12:409–15). And in the latest yearly update of an ongoing survey, CDAD rates rose by another 25% from 2003 to 2004, from 61 per 100,000 population (178,000 total discharges) to 75 per 100,000 (211,000 discharges). Rates have been highest among adults aged 65 years and older.

Although most CDAD cases are still thought to arise in health care facilities, recent reports of community-associated cases—including some without recent antimicrobial use—have prompted concern that the problem may be underrecognized. At present, C. difficile cases are not nationally reportable.

Last December, the CDC reported a total of 33 cases of community-acquired CDAD in four U.S. states, including 10 infections among pregnant women and 8 in patients who did not have recent antimicrobial use (MMWR 2005;54:1201–5).

More recently, the CDC found that community-associated CDAD is increasing among patients seeking care at the Atlanta Veterans Affairs Medical Center. As of March 2006, about 30% of all CDAD cases there have occurred in outpatients, compared with about 10% in 2003. Of 61 outpatients with CDAD seen at the VA during 2003–2006, 50 had not been hospitalized in the previous 3 months and 19 had not received antimicrobials in the prior 30 days, Dr. McDonald reported.

Use of proton-pump inhibitors (PPIs) appeared to increase the risk; the CDAD patients without antimicrobial exposure were more likely to have been exposed to PPIs than were those with antimicrobial exposure (65% vs. 12%), he said.

Following the report of the 10 CDAD cases among pregnant women, the CDC conducted a survey of 405 infectious disease clinicians. Of those, 17 reported having personally seen such cases and another 23 were aware of such cases in their community. Of the 48 cases reported by the survey respondents, 14 of the infections occurred prior to delivery, 20% of the women developed recurrent disease, and three developed toxic megacolon. There was one fetal loss and one maternal death. It is unknown whether any of these cases were among those previously reported.

The infection is also emerging in food-producing animals, with recent outbreaks among neonatal pigs, dairy calves, and beef. Recently, the CDC has investigated seven cases of human CDAD in seven different states; in these patients, the strains appeared genetically similar on pulsed field gel electrophoresis to the epidemic animal strains, which has not been found in the past.