User login
Type 2 diabetes (T2D) is characterized by altered glucose homeostasis, including decreased insulin sensitivity of target tissues, a gradual decline in β-cell insulin production and secretion, and a progressive inability to suppress pancreatic α-cell glucagon secretion.1 In the past, goals for therapy have focused primarily on insulin secretion, sensitization, and replacement. However, newer T2D medications utilize the incretin gut hormone pathway, a focus of scientific and clinical research for decades.2 The so-called insulin effect, known today as the incretin effect3 —ie, greater insulin secretion in response to nutrient ingestion—was identified in 1964 when Elrick et al4 demonstrated that orally administered glucose produced a significant and sustained increase in plasma insulin, whereas intravenously administered glucose produced a smaller and transient insulin increase. This finding was paramount in bringing incretin-based therapies to clinical practice.
The 2 most well characterized incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) ( Figure 1 ). Currently, therapeutic agents, acting as either an incretin mimetic (via GLP-1 analogs) or to inhibit the breakdown of GLP-1 (via dipeptidyl peptidase-4 [DPP-4] inhibitors) are available for treatment.2,3 Various DPP-4 inhibitors are in development, and 2 are approved by the US Food and Drug Administration (FDA): sitagliptin and the recently approved DPP-4 inhibitor, saxagliptin, are indicated for use in a broad range of patients, including those who are drug naïve or who have inadequate glycemic control on another oral antidiabetic drug (OAD). Both agents are approved as monotherapy and as an add-on to current antihyperglycemic therapy (ie, metformin [MET], sulfonylurea [SU], thiazolidinedione [TZD]), and are also approved as initial combination therapy with MET.5-7 Another DPP-4 inhibitor, alogliptin, failed to gain approval from the FDA, which indicated the need for additional data (Takeda Pharmaceutical Company Limited) ( Table 1 ).
Figure 1
DPP-4 Inhibitors: Mechanism of Glucose Control28
DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1.
Post–meal ingestion, GLP-1 and GIP are released from the small intestine and are rapidly degraded by the enzyme DPP-4. Inhibition of DPP-4 prevents the breakdown of GLP-1 and GIP and enhances glucose-stimulated insulin secretion (incretin action). GLP-1 and GIP act on the pancreatic β-cell to increase insulin release. GLP-1 also acts on the α-cell to suppress glucagon release and ultimately suppress hepatic glucose production. Together, the increased cellular glucose uptake and the decreased hepatic glucose output offer physiologic glucose control.
Table 1
DPP-4 Inhibitor Status and Availability
| Drug | Status | Trade name | Pharmaceutical Company |
|---|---|---|---|
| Alogliptin | Failed to gain approval | Not officially disclosed | Takeda Pharmaceutical Company Limited |
| Dutogliptin | Phase 3 | Not officially disclosed | Phenomix/Forest Laboratories, Inc. |
| Linagliptin | Phase 3 | Ondero® | Boehringer Ingelheim |
| Saxagliptin | Approved in the United States and Europe | Onglyza™ | Bristol-Myers Squibb/AstraZeneca |
| Sitagliptin | Approved in the United States and Europe | Januvia™, Janumet® | Merck & Co., Inc. |
| Vildagliptin | Approved in Europe | Galvus® | Novartis AG |
| DPP-4, dipeptidyl peptidase-4. | |||
The current therapeutic options for treating type 2 diabetes (T2D) include drug classes that lower blood glucose levels by different mechanisms of action ( Table ) through various target organs.1,2
Table
Drug classes that lower blood glucose levels
| Agent(s) | Mechanism of Action |
|---|---|
| • Insulin • Sulfonylureas • Glinides | Insulin replacement/secretion |
| • Thiazolidinediones | Insulin sensitization |
| • Biguanides | Decrease of hepatic glucose output |
| • α-Glucosidase inhibitors | Delay of intestinal carbohydrate absorption |
| • DPP-4 inhibitors • GLP-1 analogs | Incretin enhancement/replacement with subsequent effects on insulin and glucagon secretion |
| DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1. | |
Glucagon-like peptide-1 (GLP-1) is known to enhance insulin release from the pancreatic β-cells and inhibit glucagon release through the α-cells in a glucose-dependent manner.3 In the fasted state, circulating levels of GLP are low but rise within minutes of meal ingestion. GLP-1 is released from the L cells of the small intestine within minutes of food consumption; however, incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4).3 By inhibiting DPP-4, the DPP-4 inhibitors enhance the half-life of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), thereby augmenting their levels.1,4 Because the release of GLP-1 is glucose dependent, augmentation of GLP-1 by DPP-4 inhibition minimizes the risk for hypoglycemia, which proves to be clinically important in managing T2D.
The majority of antidiabetic agents act primarily by lowering fasting plasma glucose (FPG) (eg, sulfonylureas), whereas others act primarily by lowering postprandial glucose (PPG).5 DPP-4 inhibitors primarily have a postprandial effect but also show statistically significant reductions in fasting glucose levels.6 FPG and PPG are the essential components of lowering glycosylated hemoglobin (HbA1c), and PPG has a greater effect on lowering HbA1c at values <8.5%.7
References
1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-2157.
2. Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ. 2005;172:213-226.
3. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-165.
4. Stonehouse A, Okerson T, Kendall D, et al. Emerging incretin-based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors. Curr Diabetes Rev. 2008;4:101-109.
5. Leiter LA, Ceriello A, Davidson JA, et al. Postprandial glucose regulation: new data and new implications. Clin Ther. 2005;27(suppl B):S42-S56.
6. Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401-2411.
7. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26:881-885.
DPP-4 Inhibitors Offer Comprehensive Glycemic Management
Glycemic control efforts should be directed at the multiple pathophysiologic defects of T2D and should involve routine assessment of HbA1c, monitoring of daily blood glucose values, and treatment with combination regimens that target glucose levels both before and after meals. As monotherapy, DPP-4 inhibitors demonstrate reductions of approximately 0.5% to 0.8% in HbA1c, with concomitant reductions in postprandial glucose (PPG) and fasting plasma glucose (FPG) (eg, PPG reductions of –43 to –45 mg/dL at 120 minutes of an oral glucose tolerance test [OGTT] and FPG reductions of –9 to –15 mg/dL with saxagliptin monotherapy).8,9 Durability of that effect has been demonstrated with up to 2 years of treatment.10,11 DPP-4 inhibitors added to other OADs with complementary mechanisms of action have been proven to be particularly effective in lowering all 3 glycemic parameters in multiple studies ( Table 2 ), regardless of age ( ≤65 and >65 years), gender, race/ethnicity, or body mass index.12-18 DPP-4 inhibitors are also effective when used concurrently (initial combination) with MET in drug-naïve patients, lowering HbA1c by as much as 2.5% with concomitant decreases in FPG and PPG ( Figure 2 ) as demonstrated during a 3-hour OGTT.19
Table 2
DPP-4 Inhibitors in Combination with Other Oral Antidiabetic Drugs*
BL, baseline; DPP-4, dipeptidyl peptidase-4; HbA1c, glycosylated hemoglobin; FPG, fasting plasma glucose; PBO, placebo; PPG, postprandial glucose; Tx, treatment.
*To date, no head-to-head trials with DPP-4 inhibitors have been published.
†Includes placebo group.
‡Values represent placebo-adjusted mean change from baseline. Adjusted mean change from baseline values for vildagliptin treatment groups were not reported.
Figure 2
Changes in Glucose After 24 Weeks of Saxagliptin and Metformin Initial Combination Therapy19
FPG, fasting plasma glucose; MET, metformin; OGTT, oral glucose tolerance test; PPG, postprandial glucose; SAXA, saxagliptin.
Reprinted with permission. Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Jadzinsky M, Pfützner A, Paz-Pacheco E, Xu Z, Allen E, Chen R, for the CV181-039 Investigators. Copyright © 2009 Diabetes, Obesity and Metabolism. Reproduced with permission of Blackwell Publishing Ltd.
TOLERABILITY
DPP-4 inhibitors offer strategic advantages with regard to tolerability, including few side effects or drug interactions with commonly used agents as well as simple oral dosing. These agents have demonstrated low risk for hypoglycemia and are weight neutral.8,20,21 Tolerability profiles have been shown to be similar in patients aged ≤65 years and older patients (aged >65 years) with vildagliptin monotherapy.22 The incidence of discontinuation due to clinical adverse reactions has been shown to be similar to placebo.5 Sitagliptin requires a 2-step dose reduction; one for moderate renal impairment and a second for severe impairment and end-stage renal disease patients.5 Saxagliptin requires only a 1-step dose reduction if creatine clearance is ≤50 mL/min.7 DPP-4 inhibitors in combination with MET, an SU, or a TZD demonstrated favorable tolerability with an overall adverse event profile similar to monotherapy with MET, an SU, or a TZD.13,16-19,23-26 Modest increases in hypoglycemic events have been shown in studies with DPP-4 inhibitors in combination with an SU,17,27 whereas others have shown no increase in hypoglycemic events.14 When used in combination with MET, gastrointestinal side effects are not increased above those seen with MET alone.13
Conclusion
DPP-4 inhibitors are a new class of agents that improve long-term, 24-hour control of HbA1c, FPG (before meal) levels, and PPG (after meal) levels through decreased DPP-4–mediated degradation of incretin hormones. DPP-4 inhibitors provide a complementary mechanism of action to existing OADs and demonstrate significant efficacy when added to MET, an SU, or a TZD, with a well-tolerated profile, including a low risk for hypoglycemia and weight neutrality. DPP-4 inhibitors have been studied in a broad range of patients and have demonstrated similar efficacy, regardless of age, gender, or race/ethnicity. These agents offer an important addition to the treatment of patients with T2D by providing another mechanism to address the multiple pathophysiologic defects present in this disease.
Disclosure
Dr. Cobble has served on advisory boards for Abbott, AstraZeneca, Bristol-Myers Squibb, and Eli Lilly and Company; is the Chief Medical Officer for Atherotech Cardiodiagnostic Lipid Company; and has served as a lecturer for Pri-Med and the American Diabetes Association.
Acknowledgements
Funding for editorial support for this newsletter was provided by Bristol-Myers Squibb and AstraZeneca. Technical writing and editorial assistance for this newsletter was provided by Trina Ricci, PhD, of Innovex Medical Communications. This newsletter has been edited and peer reviewed by The Journal of Family Practice.
1. Ahrén B. β- and α-cell dysfunction in subjects developing impaired glucose tolerance: outcome of a 12-year prospective study in postmenopausal Caucasian women. Diabetes. 2009;58:726-731.
2. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298:194-206.
3. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-2157.
4. Elrick H, Stimmler L, Hlad CJ, Jr, et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076-1082.
5. Januvia [package insert]. South Granville, NSW: Merck & Co., Inc; 2007.
6. Janumet [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2007.
7. Onglyza [package insert]. Princeton, NJ/Wilmington, DE: Bristol-Myers Squibb/AstraZeneca; 2009.
8. Rosenstock J, Aguilar-Salinas C, Klein E, et al. for the CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401-2411.
9. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193-203.
10. Qi DS, Teng R, Jiang M. Two-year treatment with sitagliptin and initial combination therapy of sitagliptin and metformin provides substantial and durable glycaemic control in patients with type 2 diabetes. Diabetologia. 2008;51(suppl 1):S36.-
11. Göke B, Hershon K, Kerr D, et al. Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naive patients with type 2 diabetes: comparison with metformin. Horm Metab Res. 2008;40:892-895.
12. Goldstein BJ, Feinglos MN, Lunceford JK, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979-1987.
13. Nauck MA, Ellis GC, Fleck PR, et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63:46-55.
14. Pratley RE, Kipnes MS, Fleck PR, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009;11:167-176.
15. Pratley R, Reusch J, Fleck P, et al. Efficacy and safety of alogliptin added to pioglitazone therapy in patients with type 2 diabetes. Poster presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-10, 2008; San Francisco, CA.
16. DeFronzo RA, Hissa MN, Garber AJ, et al. for the Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32:1649-1655.
17. Chacra AR, Tan GH, Apanovitch S, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: A randomised controlled trial. Int J Clin Pract. 2009;63:1395-1406.
18. Hollander P, Li J, Allen E, et al. for the CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab. 2009;94(12).
19. Jadzinsky M, Pfützner A, Paz-Pacheco E, et al. for the CV181-039 Investigators. Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009;11:611-622.
20. Gilbert MP, Pratley RE. Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus. Am J Med. 2009;122(6 suppl):S11-S24.
21. DeFronzo RA, Fleck PR, Wilson CA, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31:2315-2317.
22. Pratley RE, Rosenstock J, Pi-Sunyer FX, et al. Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy. Diabetes Care. 2007;30:3017-3022.
23. Charbonnel B, Karasik A, Liu J, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638-2643.
24. Garber AJ, Schweizer A, Baron MA, et al. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9:166-174.
25. Rosenstock J, Brazg R, Andryuk PJ, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556-1568.
26. Bosi E, Camisasca RP, Collober C, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30:890-895.
27. Hermansen K, Kipnes M, Luo E, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733-745.
28. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929-2940.
Type 2 diabetes (T2D) is characterized by altered glucose homeostasis, including decreased insulin sensitivity of target tissues, a gradual decline in β-cell insulin production and secretion, and a progressive inability to suppress pancreatic α-cell glucagon secretion.1 In the past, goals for therapy have focused primarily on insulin secretion, sensitization, and replacement. However, newer T2D medications utilize the incretin gut hormone pathway, a focus of scientific and clinical research for decades.2 The so-called insulin effect, known today as the incretin effect3 —ie, greater insulin secretion in response to nutrient ingestion—was identified in 1964 when Elrick et al4 demonstrated that orally administered glucose produced a significant and sustained increase in plasma insulin, whereas intravenously administered glucose produced a smaller and transient insulin increase. This finding was paramount in bringing incretin-based therapies to clinical practice.
The 2 most well characterized incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) ( Figure 1 ). Currently, therapeutic agents, acting as either an incretin mimetic (via GLP-1 analogs) or to inhibit the breakdown of GLP-1 (via dipeptidyl peptidase-4 [DPP-4] inhibitors) are available for treatment.2,3 Various DPP-4 inhibitors are in development, and 2 are approved by the US Food and Drug Administration (FDA): sitagliptin and the recently approved DPP-4 inhibitor, saxagliptin, are indicated for use in a broad range of patients, including those who are drug naïve or who have inadequate glycemic control on another oral antidiabetic drug (OAD). Both agents are approved as monotherapy and as an add-on to current antihyperglycemic therapy (ie, metformin [MET], sulfonylurea [SU], thiazolidinedione [TZD]), and are also approved as initial combination therapy with MET.5-7 Another DPP-4 inhibitor, alogliptin, failed to gain approval from the FDA, which indicated the need for additional data (Takeda Pharmaceutical Company Limited) ( Table 1 ).
Figure 1
DPP-4 Inhibitors: Mechanism of Glucose Control28
DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1.
Post–meal ingestion, GLP-1 and GIP are released from the small intestine and are rapidly degraded by the enzyme DPP-4. Inhibition of DPP-4 prevents the breakdown of GLP-1 and GIP and enhances glucose-stimulated insulin secretion (incretin action). GLP-1 and GIP act on the pancreatic β-cell to increase insulin release. GLP-1 also acts on the α-cell to suppress glucagon release and ultimately suppress hepatic glucose production. Together, the increased cellular glucose uptake and the decreased hepatic glucose output offer physiologic glucose control.
Table 1
DPP-4 Inhibitor Status and Availability
| Drug | Status | Trade name | Pharmaceutical Company |
|---|---|---|---|
| Alogliptin | Failed to gain approval | Not officially disclosed | Takeda Pharmaceutical Company Limited |
| Dutogliptin | Phase 3 | Not officially disclosed | Phenomix/Forest Laboratories, Inc. |
| Linagliptin | Phase 3 | Ondero® | Boehringer Ingelheim |
| Saxagliptin | Approved in the United States and Europe | Onglyza™ | Bristol-Myers Squibb/AstraZeneca |
| Sitagliptin | Approved in the United States and Europe | Januvia™, Janumet® | Merck & Co., Inc. |
| Vildagliptin | Approved in Europe | Galvus® | Novartis AG |
| DPP-4, dipeptidyl peptidase-4. | |||
The current therapeutic options for treating type 2 diabetes (T2D) include drug classes that lower blood glucose levels by different mechanisms of action ( Table ) through various target organs.1,2
Table
Drug classes that lower blood glucose levels
| Agent(s) | Mechanism of Action |
|---|---|
| • Insulin • Sulfonylureas • Glinides | Insulin replacement/secretion |
| • Thiazolidinediones | Insulin sensitization |
| • Biguanides | Decrease of hepatic glucose output |
| • α-Glucosidase inhibitors | Delay of intestinal carbohydrate absorption |
| • DPP-4 inhibitors • GLP-1 analogs | Incretin enhancement/replacement with subsequent effects on insulin and glucagon secretion |
| DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1. | |
Glucagon-like peptide-1 (GLP-1) is known to enhance insulin release from the pancreatic β-cells and inhibit glucagon release through the α-cells in a glucose-dependent manner.3 In the fasted state, circulating levels of GLP are low but rise within minutes of meal ingestion. GLP-1 is released from the L cells of the small intestine within minutes of food consumption; however, incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4).3 By inhibiting DPP-4, the DPP-4 inhibitors enhance the half-life of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), thereby augmenting their levels.1,4 Because the release of GLP-1 is glucose dependent, augmentation of GLP-1 by DPP-4 inhibition minimizes the risk for hypoglycemia, which proves to be clinically important in managing T2D.
The majority of antidiabetic agents act primarily by lowering fasting plasma glucose (FPG) (eg, sulfonylureas), whereas others act primarily by lowering postprandial glucose (PPG).5 DPP-4 inhibitors primarily have a postprandial effect but also show statistically significant reductions in fasting glucose levels.6 FPG and PPG are the essential components of lowering glycosylated hemoglobin (HbA1c), and PPG has a greater effect on lowering HbA1c at values <8.5%.7
References
1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-2157.
2. Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ. 2005;172:213-226.
3. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-165.
4. Stonehouse A, Okerson T, Kendall D, et al. Emerging incretin-based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors. Curr Diabetes Rev. 2008;4:101-109.
5. Leiter LA, Ceriello A, Davidson JA, et al. Postprandial glucose regulation: new data and new implications. Clin Ther. 2005;27(suppl B):S42-S56.
6. Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401-2411.
7. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26:881-885.
DPP-4 Inhibitors Offer Comprehensive Glycemic Management
Glycemic control efforts should be directed at the multiple pathophysiologic defects of T2D and should involve routine assessment of HbA1c, monitoring of daily blood glucose values, and treatment with combination regimens that target glucose levels both before and after meals. As monotherapy, DPP-4 inhibitors demonstrate reductions of approximately 0.5% to 0.8% in HbA1c, with concomitant reductions in postprandial glucose (PPG) and fasting plasma glucose (FPG) (eg, PPG reductions of –43 to –45 mg/dL at 120 minutes of an oral glucose tolerance test [OGTT] and FPG reductions of –9 to –15 mg/dL with saxagliptin monotherapy).8,9 Durability of that effect has been demonstrated with up to 2 years of treatment.10,11 DPP-4 inhibitors added to other OADs with complementary mechanisms of action have been proven to be particularly effective in lowering all 3 glycemic parameters in multiple studies ( Table 2 ), regardless of age ( ≤65 and >65 years), gender, race/ethnicity, or body mass index.12-18 DPP-4 inhibitors are also effective when used concurrently (initial combination) with MET in drug-naïve patients, lowering HbA1c by as much as 2.5% with concomitant decreases in FPG and PPG ( Figure 2 ) as demonstrated during a 3-hour OGTT.19
Table 2
DPP-4 Inhibitors in Combination with Other Oral Antidiabetic Drugs*
BL, baseline; DPP-4, dipeptidyl peptidase-4; HbA1c, glycosylated hemoglobin; FPG, fasting plasma glucose; PBO, placebo; PPG, postprandial glucose; Tx, treatment.
*To date, no head-to-head trials with DPP-4 inhibitors have been published.
†Includes placebo group.
‡Values represent placebo-adjusted mean change from baseline. Adjusted mean change from baseline values for vildagliptin treatment groups were not reported.
Figure 2
Changes in Glucose After 24 Weeks of Saxagliptin and Metformin Initial Combination Therapy19
FPG, fasting plasma glucose; MET, metformin; OGTT, oral glucose tolerance test; PPG, postprandial glucose; SAXA, saxagliptin.
Reprinted with permission. Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Jadzinsky M, Pfützner A, Paz-Pacheco E, Xu Z, Allen E, Chen R, for the CV181-039 Investigators. Copyright © 2009 Diabetes, Obesity and Metabolism. Reproduced with permission of Blackwell Publishing Ltd.
TOLERABILITY
DPP-4 inhibitors offer strategic advantages with regard to tolerability, including few side effects or drug interactions with commonly used agents as well as simple oral dosing. These agents have demonstrated low risk for hypoglycemia and are weight neutral.8,20,21 Tolerability profiles have been shown to be similar in patients aged ≤65 years and older patients (aged >65 years) with vildagliptin monotherapy.22 The incidence of discontinuation due to clinical adverse reactions has been shown to be similar to placebo.5 Sitagliptin requires a 2-step dose reduction; one for moderate renal impairment and a second for severe impairment and end-stage renal disease patients.5 Saxagliptin requires only a 1-step dose reduction if creatine clearance is ≤50 mL/min.7 DPP-4 inhibitors in combination with MET, an SU, or a TZD demonstrated favorable tolerability with an overall adverse event profile similar to monotherapy with MET, an SU, or a TZD.13,16-19,23-26 Modest increases in hypoglycemic events have been shown in studies with DPP-4 inhibitors in combination with an SU,17,27 whereas others have shown no increase in hypoglycemic events.14 When used in combination with MET, gastrointestinal side effects are not increased above those seen with MET alone.13
Conclusion
DPP-4 inhibitors are a new class of agents that improve long-term, 24-hour control of HbA1c, FPG (before meal) levels, and PPG (after meal) levels through decreased DPP-4–mediated degradation of incretin hormones. DPP-4 inhibitors provide a complementary mechanism of action to existing OADs and demonstrate significant efficacy when added to MET, an SU, or a TZD, with a well-tolerated profile, including a low risk for hypoglycemia and weight neutrality. DPP-4 inhibitors have been studied in a broad range of patients and have demonstrated similar efficacy, regardless of age, gender, or race/ethnicity. These agents offer an important addition to the treatment of patients with T2D by providing another mechanism to address the multiple pathophysiologic defects present in this disease.
Disclosure
Dr. Cobble has served on advisory boards for Abbott, AstraZeneca, Bristol-Myers Squibb, and Eli Lilly and Company; is the Chief Medical Officer for Atherotech Cardiodiagnostic Lipid Company; and has served as a lecturer for Pri-Med and the American Diabetes Association.
Acknowledgements
Funding for editorial support for this newsletter was provided by Bristol-Myers Squibb and AstraZeneca. Technical writing and editorial assistance for this newsletter was provided by Trina Ricci, PhD, of Innovex Medical Communications. This newsletter has been edited and peer reviewed by The Journal of Family Practice.
Type 2 diabetes (T2D) is characterized by altered glucose homeostasis, including decreased insulin sensitivity of target tissues, a gradual decline in β-cell insulin production and secretion, and a progressive inability to suppress pancreatic α-cell glucagon secretion.1 In the past, goals for therapy have focused primarily on insulin secretion, sensitization, and replacement. However, newer T2D medications utilize the incretin gut hormone pathway, a focus of scientific and clinical research for decades.2 The so-called insulin effect, known today as the incretin effect3 —ie, greater insulin secretion in response to nutrient ingestion—was identified in 1964 when Elrick et al4 demonstrated that orally administered glucose produced a significant and sustained increase in plasma insulin, whereas intravenously administered glucose produced a smaller and transient insulin increase. This finding was paramount in bringing incretin-based therapies to clinical practice.
The 2 most well characterized incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) ( Figure 1 ). Currently, therapeutic agents, acting as either an incretin mimetic (via GLP-1 analogs) or to inhibit the breakdown of GLP-1 (via dipeptidyl peptidase-4 [DPP-4] inhibitors) are available for treatment.2,3 Various DPP-4 inhibitors are in development, and 2 are approved by the US Food and Drug Administration (FDA): sitagliptin and the recently approved DPP-4 inhibitor, saxagliptin, are indicated for use in a broad range of patients, including those who are drug naïve or who have inadequate glycemic control on another oral antidiabetic drug (OAD). Both agents are approved as monotherapy and as an add-on to current antihyperglycemic therapy (ie, metformin [MET], sulfonylurea [SU], thiazolidinedione [TZD]), and are also approved as initial combination therapy with MET.5-7 Another DPP-4 inhibitor, alogliptin, failed to gain approval from the FDA, which indicated the need for additional data (Takeda Pharmaceutical Company Limited) ( Table 1 ).
Figure 1
DPP-4 Inhibitors: Mechanism of Glucose Control28
DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1.
Post–meal ingestion, GLP-1 and GIP are released from the small intestine and are rapidly degraded by the enzyme DPP-4. Inhibition of DPP-4 prevents the breakdown of GLP-1 and GIP and enhances glucose-stimulated insulin secretion (incretin action). GLP-1 and GIP act on the pancreatic β-cell to increase insulin release. GLP-1 also acts on the α-cell to suppress glucagon release and ultimately suppress hepatic glucose production. Together, the increased cellular glucose uptake and the decreased hepatic glucose output offer physiologic glucose control.
Table 1
DPP-4 Inhibitor Status and Availability
| Drug | Status | Trade name | Pharmaceutical Company |
|---|---|---|---|
| Alogliptin | Failed to gain approval | Not officially disclosed | Takeda Pharmaceutical Company Limited |
| Dutogliptin | Phase 3 | Not officially disclosed | Phenomix/Forest Laboratories, Inc. |
| Linagliptin | Phase 3 | Ondero® | Boehringer Ingelheim |
| Saxagliptin | Approved in the United States and Europe | Onglyza™ | Bristol-Myers Squibb/AstraZeneca |
| Sitagliptin | Approved in the United States and Europe | Januvia™, Janumet® | Merck & Co., Inc. |
| Vildagliptin | Approved in Europe | Galvus® | Novartis AG |
| DPP-4, dipeptidyl peptidase-4. | |||
The current therapeutic options for treating type 2 diabetes (T2D) include drug classes that lower blood glucose levels by different mechanisms of action ( Table ) through various target organs.1,2
Table
Drug classes that lower blood glucose levels
| Agent(s) | Mechanism of Action |
|---|---|
| • Insulin • Sulfonylureas • Glinides | Insulin replacement/secretion |
| • Thiazolidinediones | Insulin sensitization |
| • Biguanides | Decrease of hepatic glucose output |
| • α-Glucosidase inhibitors | Delay of intestinal carbohydrate absorption |
| • DPP-4 inhibitors • GLP-1 analogs | Incretin enhancement/replacement with subsequent effects on insulin and glucagon secretion |
| DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1. | |
Glucagon-like peptide-1 (GLP-1) is known to enhance insulin release from the pancreatic β-cells and inhibit glucagon release through the α-cells in a glucose-dependent manner.3 In the fasted state, circulating levels of GLP are low but rise within minutes of meal ingestion. GLP-1 is released from the L cells of the small intestine within minutes of food consumption; however, incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4).3 By inhibiting DPP-4, the DPP-4 inhibitors enhance the half-life of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), thereby augmenting their levels.1,4 Because the release of GLP-1 is glucose dependent, augmentation of GLP-1 by DPP-4 inhibition minimizes the risk for hypoglycemia, which proves to be clinically important in managing T2D.
The majority of antidiabetic agents act primarily by lowering fasting plasma glucose (FPG) (eg, sulfonylureas), whereas others act primarily by lowering postprandial glucose (PPG).5 DPP-4 inhibitors primarily have a postprandial effect but also show statistically significant reductions in fasting glucose levels.6 FPG and PPG are the essential components of lowering glycosylated hemoglobin (HbA1c), and PPG has a greater effect on lowering HbA1c at values <8.5%.7
References
1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-2157.
2. Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ. 2005;172:213-226.
3. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-165.
4. Stonehouse A, Okerson T, Kendall D, et al. Emerging incretin-based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors. Curr Diabetes Rev. 2008;4:101-109.
5. Leiter LA, Ceriello A, Davidson JA, et al. Postprandial glucose regulation: new data and new implications. Clin Ther. 2005;27(suppl B):S42-S56.
6. Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401-2411.
7. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26:881-885.
DPP-4 Inhibitors Offer Comprehensive Glycemic Management
Glycemic control efforts should be directed at the multiple pathophysiologic defects of T2D and should involve routine assessment of HbA1c, monitoring of daily blood glucose values, and treatment with combination regimens that target glucose levels both before and after meals. As monotherapy, DPP-4 inhibitors demonstrate reductions of approximately 0.5% to 0.8% in HbA1c, with concomitant reductions in postprandial glucose (PPG) and fasting plasma glucose (FPG) (eg, PPG reductions of –43 to –45 mg/dL at 120 minutes of an oral glucose tolerance test [OGTT] and FPG reductions of –9 to –15 mg/dL with saxagliptin monotherapy).8,9 Durability of that effect has been demonstrated with up to 2 years of treatment.10,11 DPP-4 inhibitors added to other OADs with complementary mechanisms of action have been proven to be particularly effective in lowering all 3 glycemic parameters in multiple studies ( Table 2 ), regardless of age ( ≤65 and >65 years), gender, race/ethnicity, or body mass index.12-18 DPP-4 inhibitors are also effective when used concurrently (initial combination) with MET in drug-naïve patients, lowering HbA1c by as much as 2.5% with concomitant decreases in FPG and PPG ( Figure 2 ) as demonstrated during a 3-hour OGTT.19
Table 2
DPP-4 Inhibitors in Combination with Other Oral Antidiabetic Drugs*
BL, baseline; DPP-4, dipeptidyl peptidase-4; HbA1c, glycosylated hemoglobin; FPG, fasting plasma glucose; PBO, placebo; PPG, postprandial glucose; Tx, treatment.
*To date, no head-to-head trials with DPP-4 inhibitors have been published.
†Includes placebo group.
‡Values represent placebo-adjusted mean change from baseline. Adjusted mean change from baseline values for vildagliptin treatment groups were not reported.
Figure 2
Changes in Glucose After 24 Weeks of Saxagliptin and Metformin Initial Combination Therapy19
FPG, fasting plasma glucose; MET, metformin; OGTT, oral glucose tolerance test; PPG, postprandial glucose; SAXA, saxagliptin.
Reprinted with permission. Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Jadzinsky M, Pfützner A, Paz-Pacheco E, Xu Z, Allen E, Chen R, for the CV181-039 Investigators. Copyright © 2009 Diabetes, Obesity and Metabolism. Reproduced with permission of Blackwell Publishing Ltd.
TOLERABILITY
DPP-4 inhibitors offer strategic advantages with regard to tolerability, including few side effects or drug interactions with commonly used agents as well as simple oral dosing. These agents have demonstrated low risk for hypoglycemia and are weight neutral.8,20,21 Tolerability profiles have been shown to be similar in patients aged ≤65 years and older patients (aged >65 years) with vildagliptin monotherapy.22 The incidence of discontinuation due to clinical adverse reactions has been shown to be similar to placebo.5 Sitagliptin requires a 2-step dose reduction; one for moderate renal impairment and a second for severe impairment and end-stage renal disease patients.5 Saxagliptin requires only a 1-step dose reduction if creatine clearance is ≤50 mL/min.7 DPP-4 inhibitors in combination with MET, an SU, or a TZD demonstrated favorable tolerability with an overall adverse event profile similar to monotherapy with MET, an SU, or a TZD.13,16-19,23-26 Modest increases in hypoglycemic events have been shown in studies with DPP-4 inhibitors in combination with an SU,17,27 whereas others have shown no increase in hypoglycemic events.14 When used in combination with MET, gastrointestinal side effects are not increased above those seen with MET alone.13
Conclusion
DPP-4 inhibitors are a new class of agents that improve long-term, 24-hour control of HbA1c, FPG (before meal) levels, and PPG (after meal) levels through decreased DPP-4–mediated degradation of incretin hormones. DPP-4 inhibitors provide a complementary mechanism of action to existing OADs and demonstrate significant efficacy when added to MET, an SU, or a TZD, with a well-tolerated profile, including a low risk for hypoglycemia and weight neutrality. DPP-4 inhibitors have been studied in a broad range of patients and have demonstrated similar efficacy, regardless of age, gender, or race/ethnicity. These agents offer an important addition to the treatment of patients with T2D by providing another mechanism to address the multiple pathophysiologic defects present in this disease.
Disclosure
Dr. Cobble has served on advisory boards for Abbott, AstraZeneca, Bristol-Myers Squibb, and Eli Lilly and Company; is the Chief Medical Officer for Atherotech Cardiodiagnostic Lipid Company; and has served as a lecturer for Pri-Med and the American Diabetes Association.
Acknowledgements
Funding for editorial support for this newsletter was provided by Bristol-Myers Squibb and AstraZeneca. Technical writing and editorial assistance for this newsletter was provided by Trina Ricci, PhD, of Innovex Medical Communications. This newsletter has been edited and peer reviewed by The Journal of Family Practice.
1. Ahrén B. β- and α-cell dysfunction in subjects developing impaired glucose tolerance: outcome of a 12-year prospective study in postmenopausal Caucasian women. Diabetes. 2009;58:726-731.
2. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298:194-206.
3. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-2157.
4. Elrick H, Stimmler L, Hlad CJ, Jr, et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076-1082.
5. Januvia [package insert]. South Granville, NSW: Merck & Co., Inc; 2007.
6. Janumet [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2007.
7. Onglyza [package insert]. Princeton, NJ/Wilmington, DE: Bristol-Myers Squibb/AstraZeneca; 2009.
8. Rosenstock J, Aguilar-Salinas C, Klein E, et al. for the CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401-2411.
9. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193-203.
10. Qi DS, Teng R, Jiang M. Two-year treatment with sitagliptin and initial combination therapy of sitagliptin and metformin provides substantial and durable glycaemic control in patients with type 2 diabetes. Diabetologia. 2008;51(suppl 1):S36.-
11. Göke B, Hershon K, Kerr D, et al. Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naive patients with type 2 diabetes: comparison with metformin. Horm Metab Res. 2008;40:892-895.
12. Goldstein BJ, Feinglos MN, Lunceford JK, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979-1987.
13. Nauck MA, Ellis GC, Fleck PR, et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63:46-55.
14. Pratley RE, Kipnes MS, Fleck PR, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009;11:167-176.
15. Pratley R, Reusch J, Fleck P, et al. Efficacy and safety of alogliptin added to pioglitazone therapy in patients with type 2 diabetes. Poster presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-10, 2008; San Francisco, CA.
16. DeFronzo RA, Hissa MN, Garber AJ, et al. for the Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32:1649-1655.
17. Chacra AR, Tan GH, Apanovitch S, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: A randomised controlled trial. Int J Clin Pract. 2009;63:1395-1406.
18. Hollander P, Li J, Allen E, et al. for the CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab. 2009;94(12).
19. Jadzinsky M, Pfützner A, Paz-Pacheco E, et al. for the CV181-039 Investigators. Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009;11:611-622.
20. Gilbert MP, Pratley RE. Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus. Am J Med. 2009;122(6 suppl):S11-S24.
21. DeFronzo RA, Fleck PR, Wilson CA, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31:2315-2317.
22. Pratley RE, Rosenstock J, Pi-Sunyer FX, et al. Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy. Diabetes Care. 2007;30:3017-3022.
23. Charbonnel B, Karasik A, Liu J, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638-2643.
24. Garber AJ, Schweizer A, Baron MA, et al. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9:166-174.
25. Rosenstock J, Brazg R, Andryuk PJ, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556-1568.
26. Bosi E, Camisasca RP, Collober C, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30:890-895.
27. Hermansen K, Kipnes M, Luo E, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733-745.
28. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929-2940.
1. Ahrén B. β- and α-cell dysfunction in subjects developing impaired glucose tolerance: outcome of a 12-year prospective study in postmenopausal Caucasian women. Diabetes. 2009;58:726-731.
2. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298:194-206.
3. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-2157.
4. Elrick H, Stimmler L, Hlad CJ, Jr, et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076-1082.
5. Januvia [package insert]. South Granville, NSW: Merck & Co., Inc; 2007.
6. Janumet [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2007.
7. Onglyza [package insert]. Princeton, NJ/Wilmington, DE: Bristol-Myers Squibb/AstraZeneca; 2009.
8. Rosenstock J, Aguilar-Salinas C, Klein E, et al. for the CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401-2411.
9. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193-203.
10. Qi DS, Teng R, Jiang M. Two-year treatment with sitagliptin and initial combination therapy of sitagliptin and metformin provides substantial and durable glycaemic control in patients with type 2 diabetes. Diabetologia. 2008;51(suppl 1):S36.-
11. Göke B, Hershon K, Kerr D, et al. Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naive patients with type 2 diabetes: comparison with metformin. Horm Metab Res. 2008;40:892-895.
12. Goldstein BJ, Feinglos MN, Lunceford JK, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979-1987.
13. Nauck MA, Ellis GC, Fleck PR, et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63:46-55.
14. Pratley RE, Kipnes MS, Fleck PR, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009;11:167-176.
15. Pratley R, Reusch J, Fleck P, et al. Efficacy and safety of alogliptin added to pioglitazone therapy in patients with type 2 diabetes. Poster presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-10, 2008; San Francisco, CA.
16. DeFronzo RA, Hissa MN, Garber AJ, et al. for the Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32:1649-1655.
17. Chacra AR, Tan GH, Apanovitch S, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: A randomised controlled trial. Int J Clin Pract. 2009;63:1395-1406.
18. Hollander P, Li J, Allen E, et al. for the CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab. 2009;94(12).
19. Jadzinsky M, Pfützner A, Paz-Pacheco E, et al. for the CV181-039 Investigators. Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009;11:611-622.
20. Gilbert MP, Pratley RE. Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus. Am J Med. 2009;122(6 suppl):S11-S24.
21. DeFronzo RA, Fleck PR, Wilson CA, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31:2315-2317.
22. Pratley RE, Rosenstock J, Pi-Sunyer FX, et al. Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy. Diabetes Care. 2007;30:3017-3022.
23. Charbonnel B, Karasik A, Liu J, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638-2643.
24. Garber AJ, Schweizer A, Baron MA, et al. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9:166-174.
25. Rosenstock J, Brazg R, Andryuk PJ, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556-1568.
26. Bosi E, Camisasca RP, Collober C, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30:890-895.
27. Hermansen K, Kipnes M, Luo E, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733-745.
28. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929-2940.