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What role will ‘gliptins’ play in glycemic control?
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Zachary Bloomgarden, MD
Andrew Drexler, MD

The “gliptins”—the nickname for dipeptidyl peptidase 4 (DPP-4) inhibitors—are one of the newest classes of drugs for the treatment of type 2 diabetes mellitus.

These drugs work by prolonging the action of gut hormones called incretins, which boost insulin levels. The greatest advantage of the gliptins appears to be their ability to stimulate insulin production with little risk of corresponding hypoglycemia.

Sitagliptin (Januvia), the first commercially available DPP-4 inhibitor, has been approved by the US Food and Drug Administration (FDA) and is currently in clinical use, and vildagliptin (Galvus) awaits FDA approval at the time of this writing. Other drugs of this class are in development.

However, because these drugs are so new, a number of questions remain about their use. In this article, we discuss the rationale behind gliptin drugs, the evidence to date on their use alone or in combination with current oral hypoglycemic drugs (and even with insulin), and when and how to use them in daily practice.

THE NEED FOR MORE EFFECTIVE DIABETES TREATMENT

As the number of patients with type 2 diabetes continues its steep and steady rise,1,2 much work has gone into studying treatment goals and how to achieve them. Although experts generally agree on glycemic goals,3 we currently fail to achieve those goals in close to two-thirds of patients: only 37% have a hemo-globin A1c (HbA1c) value at or below the goal of 7%, and the same number have levels exceeding 8%.4

Part of the problem is that treatment regimens are not adjusted in a timely fashion. In a prescribing database of almost 4,000 patients with type 2 diabetes,5 the mean time from the first HbA1c reading above 8% to an actual change in therapy was about 15 months for those taking metformin (Glucophage) alone, and 21 months for those taking a sulfonylurea alone. Another part of the problem is that, on average, patients with an HbA1c of 8.0% to 8.9% can expect only a 0.6% lowering with the addition of one agent.6 Clearly, we need new pharmacologic approaches and new management paradigms. One new approach is the use of gliptins.

HOW GLIPTINS WORK

Incretins promote insulin secretion

We have known for more than 20 years that insulin levels rise considerably higher in response to an oral glucose load than to an intravenous glucose infusion, even though the plasma glucose concentrations may be similar.7 This phenomenon involves a myriad of neural and nutritional factors, but the gut hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) appear to be key.

These peptides—called incretins—have a high degree of homology, and both promote insulin secretion. However, GLP-1, produced by the L cells of the ileum and colon, inhibits glucagon secretion and slows gastric emptying, whereas GIP, secreted from the K cells of the duodenum, has no effect on glucagon and little effect on gastric emptying. Both peptides appear to promote pancreatic beta cell growth and survival,8,9 an effect that in theory might allow us to slow the progressive loss of insulin secretory capacity in type 2 diabetes.

Furthermore, the effect of GLP-1 on insulin secretion depends on the plasma glucose concentration, with a greater insulin secretory effect at higher glucose levels and minimal effect at euglycemic levels.10 This phenomenon suggests that drugs that boost GLP-1 activity should not cause the troublesome hypoglycemia typically seen in patients taking insulin, insulin secretagogues, sulfonyl-ureas, or the meglitinides repaglinide (Prandin) or nateglinide (Starlix). Studies of combination treatment with metformin and the GLP-1 receptor agonist exenatide (Byetta) have shown little risk of hypoglycemia,11 offering evidence favoring this conjecture.

Inhibition of DPP-4 boosts incretin action

The challenge for creating treatments that take advantage of the beneficial effects of GLP-1 and GIP is that they have very short physiologic half-lives, ie, less than 10 minutes. GLP-1 and GIP both have two N-terminal amino acids that are quickly cleaved by DPP-4,12 an enzyme present in the circulation13 and on endothelial cells.14

Currently, there are two classes of drugs based on incretins. One class, the incretin mimetics or GLP-1 receptor agonists, includes drugs that mimic the effect of GLP-1 but are not so quickly degraded by DPP-4. Examples of these drugs are exenatide, which is currently FDA-approved, and liraglutide, which is not yet approved.

On the other hand, by inhibiting the cleaving action of DPP-4, the gliptins can prolong the half-life of endogenous GLP-1, increasing its physiologic effects.

Studies comparing gliptins with GLP-1 receptor agonists are only at the preclinical phase. Liraglutide showed an antiglycemic effect similar to that of vildagliptin in an animal model of glucose intolerance.15 This and other16,17 preclinical studies have shown evidence of improved beta cell growth and survival with DPP-4 inhibitor treatment, to an extent similar to that reported with thiazo-lidinediones, whereas sulfonylureas show no evidence either of increase in beta cells or of improved intrinsic beta cell secretory function in these models. Of course, animal studies can only be cautiously extrapolated to potential effects in humans, and it is uncertain whether such benefits will occur with the therapeutic use of DPP-4 inhibitors.

 

 

RANDOMIZED CLINICAL TRIALS OF SITAGLIPTIN

Sitagliptin and vildagliptin have undergone a large number of studies in patients with type 2 diabetes. Several dosing regimens were tested, but we will restrict this discussion to studies that used 100 mg once a day or 50 mg twice a day. Of note, the effect of 50 mg twice daily may somewhat exceed that of 100 mg once daily,18 so these studies should be interpreted with caution. Table 1 summarizes the effect of sitagliptin on HbA1c values in these studies.19–25

Sitagliptin is effective when used by itself,reducing a baseline HbA1c level of about 8% by 0.6% to 0.8%,19,20,24 and is similarly effective when combined with metformin21,22,25 or pioglitazone (Actos, a thiazolidinedione).23 It also decreases fasting blood glucose levels and improves other measures of glucose control.

A study comparing sitagliptin and the sul-fonylurea glipizide (Glucotrol) showed identical glucose-lowering over a 1-year period, with less hypoglycemia and weight gain with sitagliptin.25 Hypoglycemic episodes occurred in 32% of patients taking glipizide but in only 5% of those taking sitagliptin.

Studies noted several trends in laboratory values, though none was associated with clinical evidence of adverse outcome:

  • White blood cell counts were noted to increase in three of the studies by 4.7% to 10%, owing to increases in neutro-phils19,20,22
  • Alkaline phosphatase concentrations decreased in four studies19,20,22,23
  • Uric acid levels increased in four studies.19,20,22,23

RENAL INSUFFICIENCY SLOWS SITAGLIPTIN CLEARANCE

Lower doses and periodic monitoring of renal function are recommended in patients taking sitagliptin who have some degree of renal insufficiency. Clearance of sitagliptin is delayed in patients with renal insufficiency (creatinine clearance < 50 mL/minute).

In a placebo-controlled study of sitagliptin safety, Scott et al26 found that the area under the sitagliptin concentration-time curve was 2.3 times greater in patients with moderate renal insufficiency (creatinine clearance rate 30–49.9 mL/minute), 3.8 times greater in those with severe renal insufficiency (15–29.9 mL/minute), and 4.5 times greater in those with end-stage renal disease (< 15 mL/minute).

The Januvia package insert27 recommends that the daily dose be decreased to 50 mg in patients with creatinine clearance rates of 30 to 49.9 mL/minute (serum creatinine > 1.7 mg/dL in men, > 1.5 mg/dL in women), and that the dose be decreased to 25 mg per day in those with creatinine clearance rates below 30 mL/minute (creatinine > 3.0/2.5 mg/dL).

CLINICAL TRIALS OF VILDAGLIPTIN BEGIN

Vildagliptin has also undergone extensive clinical testing (Table 2).28–36 The trials to date indicate that it is effective when used alone, reducing HbA1c levels by 0.5% to 0.9% from a baseline of 8%.28,29,34–36 The effect appears to be similar when vildagliptin is used in combination with metformin30,31 or pioglita-zone.32,36

A study comparing vildagliptin against metformin34 showed less glucose-lowering over a 1-year period with vildagliptin, albeit with fewer gastrointestinal side effects, while comparisons with rosiglitazone (Avandia)35 and with pioglitazone36 showed similar glucose-lowering ability.

In a 24-week study,33 256 patients with type 2 diabetes who had a mean body mass index of 33 kg/m2 and who were taking more than 30 units of insulin daily (an average of 82 units) were randomized to additionally receive either vildagliptin 50 mg twice daily or placebo. The HbA1c decreased by 0.5% with vildagliptin and by 0.2% with placebo, from a baseline level of 8.5%. Of interest, 33 patients receiving vildagliptin had a hypo-glycemic episode (a total of 113 events), compared with 45 patients in the placebo group (185 events). None of the episodes in the vildagliptin group was classified as severe, whereas six episodes in the placebo group were classified as severe. This suggests that adding vildagliptin in patients taking insulin can improve glycemia without causing excessive hypoglycemia.

A weakness of the design of this study is that it did not include patients who were receiving an insulin sensitizer, an approach that is typically taken. Given this, it is understandable that overall glycemic control was relatively poor. More effort is needed to explore the use of gliptins with insulin.

WHAT ROLE FOR GLIPTINS?

The evidence from the studies reviewed in this article suggests that gliptins can play an important role in the treatment of type 2 diabetes. In certain patient groups such as the elderly, who cannot take either metformin or a thiazolidinedione and in whom concerns about hypoglycemia are greatest, thus precluding sulfonylurea therapy, gliptins may be the agents of choice. The trials reviewed here suggest that gliptins have glucose-lowering efficacy similar to that of these classes of agents. Gliptins are also effective when combined with metformin or a thiazolidinedione and, as discussed above, may prove to be useful in combination with insulin.

The eventual role of gliptins in the treatment of type 2 diabetes will depend on the answers to several questions. For example, do they preserve beta cell function and reverse the progression of diabetes? Do they affect insulin resistance? Do they have cardiovascular benefits beyond glucose-lowering? Also, since DPP-4 is widely distributed in the body, and since we do not yet know the effects of all the proteins cleaved by this enzyme, will this affect the long-term safety of these drugs?

For now, we can state with reasonable certainty that gliptins lower blood sugar levels to a degree similar to that of other oral hypo-glycemic therapies, with minimal risk of hypo-glycemia, with few immediate adverse effects, and without requiring dose titration. These characteristics suggest that gliptins should be considered useful agents in monotherapy and combination therapy for the treatment of type 2 diabetes.

References
  1. National Diabetes Surveillance System. www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. Last accessed February 28, 2008.
  2. Narayan KM, Boyle JP, Geiss LS, Saaddine JB, Thompson TJ. Impact of recent increase in incidence on future diabetes burden: US, 2005–2050. Diabetes Care 2006; 29:2114–2116.
  3. American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care 2007; 30 suppl 1:S4–S41.
  4. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004; 291:335–342.
  5. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care 2004; 27:1535–1540.
  6. Bloomgarden ZT, Dodis R, Viscoli CM, Holmboe ES, Inzucchi SE. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis. Diabetes Care 2006; 29:2137–2139.
  7. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986; 29:46–52.
  8. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003; 26:2929–2940.
  9. Bloomgarden ZT. Gut hormones and related concepts. Diabetes Care 2006; 29:2319–2324.
  10. Nauck MA, Kleine N, Orskov C, et al. Normalization of fasting hyper-glycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36:741–744.
  11. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28:1092–1100.
  12. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995; 44:1126–1131.
  13. Holst JJ, Deacon CF. Glucagon-like peptide-1 mediates the therapeutic actions of DPP-4 inhibitors. Diabetologia 2005; 48:612–615.
  14. Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide-1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 1999; 140:5356–5363.
  15. Raun K, von Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB. Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 2007; 56:8–15.
  16. Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipeptidyl peptidase IV with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 2006; 55:1695–1704.
  17. Pospisilik JA, Martin J, Doty T, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 2003; 52:741–750.
  18. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91:4612–4619.
  19. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006; 29:2632–2637.
  20. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006; 49:2564–2571.
  21. Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9:186–193.
  22. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. 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.
  23. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P Sitagliptin Study 019 Group. 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.
  24. Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract 2007; 61:171–180.
  25. Nauck MA, Meininger JG, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9:194–205.
  26. Scott RS, Hartley P, Luo E, et al. Use of sitagliptin in patients with type 2 diabetes and renal insufficiency [abtract]. Diabetes 2006; 55 suppl 1:A462.
  27. Januvia prescribing information. www.merck.com/product/usa/pi_circulars/j/products_j.html. Last accessed February 28, 2008.
  28. Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab 2005; 7:692–698.
  29. Dejager S, Baron M, Razac S, Foley JE, Dickinson S, Schweizer S. Effect of vildagliptin on drug-naïve patients with type 2 diabetes. Diabetologia 2006; 49 suppl 1:479–480.
  30. Ahrén B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase iv inhibitor laf237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004; 27:2874–2880.
  31. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. 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.
  32. Garber A, Schweizer A, Baron MA, Rochotte E, Dejager S. 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.
  33. Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia 2007; 50:1148–1155.
  34. Dejager S, LeBeaut A, Couturier A, Schweizer A. Sustained reduction in HbA1c during one-year treatment with vildagliptin in patients with type 2 diabetes (T2DM) [abstract]. Diabetes 2006; 55 suppl 1:A29.
  35. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes. Diabetes Care 2007; 30:217–223.
  36. Rosenstock J, Baron MA, Camisasca R-P, Cressier F, Couturier A, Dejager S. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9:175–185.
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Zachary Bloomgarden, MD
Clinical Professor, Department of Medicine, Division of Endocrinology, Mount Sinai School of Medicine, New York, NY

Andrew Drexler, MD
Professor of Medicine and Co-Chief, Division of Clinical Endocrinology, Diabetes, and Hypertension, UCLA David Geffen School of Medicine, and Director, Gonda (Goldschmied) Diabetes Center, Los Angeles, CA

Address: Zachary T. Bloomgarden, MD, Department of Medicine, Mount Sinai School of Medicine, 35 East 85th Street, New York, NY 10028; e-mail zbloomgard@aol.com

Dr. Bloomgarden has disclosed that he has received honoraria for teaching and speaking from Eli Lilly, Amylin, and Novo Nordisk companies; ownership interest for consulting from Novartis; and honoraria and consulting fees from Merck, Takeda, and Daiichi-Sankyo.

Dr. Drexler has disclosed that he has received honoraria for teaching and speaking from Novo Nordisk, Eli Lilly, and Amylin, and from Takeda for serving on advisory committees or review panels.

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Type 2 Diabetes ICYMI
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Zachary Bloomgarden, MD
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Zachary Bloomgarden, MD
Clinical Professor, Department of Medicine, Division of Endocrinology, Mount Sinai School of Medicine, New York, NY

Andrew Drexler, MD
Professor of Medicine and Co-Chief, Division of Clinical Endocrinology, Diabetes, and Hypertension, UCLA David Geffen School of Medicine, and Director, Gonda (Goldschmied) Diabetes Center, Los Angeles, CA

Address: Zachary T. Bloomgarden, MD, Department of Medicine, Mount Sinai School of Medicine, 35 East 85th Street, New York, NY 10028; e-mail zbloomgard@aol.com

Dr. Bloomgarden has disclosed that he has received honoraria for teaching and speaking from Eli Lilly, Amylin, and Novo Nordisk companies; ownership interest for consulting from Novartis; and honoraria and consulting fees from Merck, Takeda, and Daiichi-Sankyo.

Dr. Drexler has disclosed that he has received honoraria for teaching and speaking from Novo Nordisk, Eli Lilly, and Amylin, and from Takeda for serving on advisory committees or review panels.

Author and Disclosure Information

Zachary Bloomgarden, MD
Clinical Professor, Department of Medicine, Division of Endocrinology, Mount Sinai School of Medicine, New York, NY

Andrew Drexler, MD
Professor of Medicine and Co-Chief, Division of Clinical Endocrinology, Diabetes, and Hypertension, UCLA David Geffen School of Medicine, and Director, Gonda (Goldschmied) Diabetes Center, Los Angeles, CA

Address: Zachary T. Bloomgarden, MD, Department of Medicine, Mount Sinai School of Medicine, 35 East 85th Street, New York, NY 10028; e-mail zbloomgard@aol.com

Dr. Bloomgarden has disclosed that he has received honoraria for teaching and speaking from Eli Lilly, Amylin, and Novo Nordisk companies; ownership interest for consulting from Novartis; and honoraria and consulting fees from Merck, Takeda, and Daiichi-Sankyo.

Dr. Drexler has disclosed that he has received honoraria for teaching and speaking from Novo Nordisk, Eli Lilly, and Amylin, and from Takeda for serving on advisory committees or review panels.

Article PDF
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Article PDF
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The “gliptins”—the nickname for dipeptidyl peptidase 4 (DPP-4) inhibitors—are one of the newest classes of drugs for the treatment of type 2 diabetes mellitus.

These drugs work by prolonging the action of gut hormones called incretins, which boost insulin levels. The greatest advantage of the gliptins appears to be their ability to stimulate insulin production with little risk of corresponding hypoglycemia.

Sitagliptin (Januvia), the first commercially available DPP-4 inhibitor, has been approved by the US Food and Drug Administration (FDA) and is currently in clinical use, and vildagliptin (Galvus) awaits FDA approval at the time of this writing. Other drugs of this class are in development.

However, because these drugs are so new, a number of questions remain about their use. In this article, we discuss the rationale behind gliptin drugs, the evidence to date on their use alone or in combination with current oral hypoglycemic drugs (and even with insulin), and when and how to use them in daily practice.

THE NEED FOR MORE EFFECTIVE DIABETES TREATMENT

As the number of patients with type 2 diabetes continues its steep and steady rise,1,2 much work has gone into studying treatment goals and how to achieve them. Although experts generally agree on glycemic goals,3 we currently fail to achieve those goals in close to two-thirds of patients: only 37% have a hemo-globin A1c (HbA1c) value at or below the goal of 7%, and the same number have levels exceeding 8%.4

Part of the problem is that treatment regimens are not adjusted in a timely fashion. In a prescribing database of almost 4,000 patients with type 2 diabetes,5 the mean time from the first HbA1c reading above 8% to an actual change in therapy was about 15 months for those taking metformin (Glucophage) alone, and 21 months for those taking a sulfonylurea alone. Another part of the problem is that, on average, patients with an HbA1c of 8.0% to 8.9% can expect only a 0.6% lowering with the addition of one agent.6 Clearly, we need new pharmacologic approaches and new management paradigms. One new approach is the use of gliptins.

HOW GLIPTINS WORK

Incretins promote insulin secretion

We have known for more than 20 years that insulin levels rise considerably higher in response to an oral glucose load than to an intravenous glucose infusion, even though the plasma glucose concentrations may be similar.7 This phenomenon involves a myriad of neural and nutritional factors, but the gut hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) appear to be key.

These peptides—called incretins—have a high degree of homology, and both promote insulin secretion. However, GLP-1, produced by the L cells of the ileum and colon, inhibits glucagon secretion and slows gastric emptying, whereas GIP, secreted from the K cells of the duodenum, has no effect on glucagon and little effect on gastric emptying. Both peptides appear to promote pancreatic beta cell growth and survival,8,9 an effect that in theory might allow us to slow the progressive loss of insulin secretory capacity in type 2 diabetes.

Furthermore, the effect of GLP-1 on insulin secretion depends on the plasma glucose concentration, with a greater insulin secretory effect at higher glucose levels and minimal effect at euglycemic levels.10 This phenomenon suggests that drugs that boost GLP-1 activity should not cause the troublesome hypoglycemia typically seen in patients taking insulin, insulin secretagogues, sulfonyl-ureas, or the meglitinides repaglinide (Prandin) or nateglinide (Starlix). Studies of combination treatment with metformin and the GLP-1 receptor agonist exenatide (Byetta) have shown little risk of hypoglycemia,11 offering evidence favoring this conjecture.

Inhibition of DPP-4 boosts incretin action

The challenge for creating treatments that take advantage of the beneficial effects of GLP-1 and GIP is that they have very short physiologic half-lives, ie, less than 10 minutes. GLP-1 and GIP both have two N-terminal amino acids that are quickly cleaved by DPP-4,12 an enzyme present in the circulation13 and on endothelial cells.14

Currently, there are two classes of drugs based on incretins. One class, the incretin mimetics or GLP-1 receptor agonists, includes drugs that mimic the effect of GLP-1 but are not so quickly degraded by DPP-4. Examples of these drugs are exenatide, which is currently FDA-approved, and liraglutide, which is not yet approved.

On the other hand, by inhibiting the cleaving action of DPP-4, the gliptins can prolong the half-life of endogenous GLP-1, increasing its physiologic effects.

Studies comparing gliptins with GLP-1 receptor agonists are only at the preclinical phase. Liraglutide showed an antiglycemic effect similar to that of vildagliptin in an animal model of glucose intolerance.15 This and other16,17 preclinical studies have shown evidence of improved beta cell growth and survival with DPP-4 inhibitor treatment, to an extent similar to that reported with thiazo-lidinediones, whereas sulfonylureas show no evidence either of increase in beta cells or of improved intrinsic beta cell secretory function in these models. Of course, animal studies can only be cautiously extrapolated to potential effects in humans, and it is uncertain whether such benefits will occur with the therapeutic use of DPP-4 inhibitors.

 

 

RANDOMIZED CLINICAL TRIALS OF SITAGLIPTIN

Sitagliptin and vildagliptin have undergone a large number of studies in patients with type 2 diabetes. Several dosing regimens were tested, but we will restrict this discussion to studies that used 100 mg once a day or 50 mg twice a day. Of note, the effect of 50 mg twice daily may somewhat exceed that of 100 mg once daily,18 so these studies should be interpreted with caution. Table 1 summarizes the effect of sitagliptin on HbA1c values in these studies.19–25

Sitagliptin is effective when used by itself,reducing a baseline HbA1c level of about 8% by 0.6% to 0.8%,19,20,24 and is similarly effective when combined with metformin21,22,25 or pioglitazone (Actos, a thiazolidinedione).23 It also decreases fasting blood glucose levels and improves other measures of glucose control.

A study comparing sitagliptin and the sul-fonylurea glipizide (Glucotrol) showed identical glucose-lowering over a 1-year period, with less hypoglycemia and weight gain with sitagliptin.25 Hypoglycemic episodes occurred in 32% of patients taking glipizide but in only 5% of those taking sitagliptin.

Studies noted several trends in laboratory values, though none was associated with clinical evidence of adverse outcome:

  • White blood cell counts were noted to increase in three of the studies by 4.7% to 10%, owing to increases in neutro-phils19,20,22
  • Alkaline phosphatase concentrations decreased in four studies19,20,22,23
  • Uric acid levels increased in four studies.19,20,22,23

RENAL INSUFFICIENCY SLOWS SITAGLIPTIN CLEARANCE

Lower doses and periodic monitoring of renal function are recommended in patients taking sitagliptin who have some degree of renal insufficiency. Clearance of sitagliptin is delayed in patients with renal insufficiency (creatinine clearance < 50 mL/minute).

In a placebo-controlled study of sitagliptin safety, Scott et al26 found that the area under the sitagliptin concentration-time curve was 2.3 times greater in patients with moderate renal insufficiency (creatinine clearance rate 30–49.9 mL/minute), 3.8 times greater in those with severe renal insufficiency (15–29.9 mL/minute), and 4.5 times greater in those with end-stage renal disease (< 15 mL/minute).

The Januvia package insert27 recommends that the daily dose be decreased to 50 mg in patients with creatinine clearance rates of 30 to 49.9 mL/minute (serum creatinine > 1.7 mg/dL in men, > 1.5 mg/dL in women), and that the dose be decreased to 25 mg per day in those with creatinine clearance rates below 30 mL/minute (creatinine > 3.0/2.5 mg/dL).

CLINICAL TRIALS OF VILDAGLIPTIN BEGIN

Vildagliptin has also undergone extensive clinical testing (Table 2).28–36 The trials to date indicate that it is effective when used alone, reducing HbA1c levels by 0.5% to 0.9% from a baseline of 8%.28,29,34–36 The effect appears to be similar when vildagliptin is used in combination with metformin30,31 or pioglita-zone.32,36

A study comparing vildagliptin against metformin34 showed less glucose-lowering over a 1-year period with vildagliptin, albeit with fewer gastrointestinal side effects, while comparisons with rosiglitazone (Avandia)35 and with pioglitazone36 showed similar glucose-lowering ability.

In a 24-week study,33 256 patients with type 2 diabetes who had a mean body mass index of 33 kg/m2 and who were taking more than 30 units of insulin daily (an average of 82 units) were randomized to additionally receive either vildagliptin 50 mg twice daily or placebo. The HbA1c decreased by 0.5% with vildagliptin and by 0.2% with placebo, from a baseline level of 8.5%. Of interest, 33 patients receiving vildagliptin had a hypo-glycemic episode (a total of 113 events), compared with 45 patients in the placebo group (185 events). None of the episodes in the vildagliptin group was classified as severe, whereas six episodes in the placebo group were classified as severe. This suggests that adding vildagliptin in patients taking insulin can improve glycemia without causing excessive hypoglycemia.

A weakness of the design of this study is that it did not include patients who were receiving an insulin sensitizer, an approach that is typically taken. Given this, it is understandable that overall glycemic control was relatively poor. More effort is needed to explore the use of gliptins with insulin.

WHAT ROLE FOR GLIPTINS?

The evidence from the studies reviewed in this article suggests that gliptins can play an important role in the treatment of type 2 diabetes. In certain patient groups such as the elderly, who cannot take either metformin or a thiazolidinedione and in whom concerns about hypoglycemia are greatest, thus precluding sulfonylurea therapy, gliptins may be the agents of choice. The trials reviewed here suggest that gliptins have glucose-lowering efficacy similar to that of these classes of agents. Gliptins are also effective when combined with metformin or a thiazolidinedione and, as discussed above, may prove to be useful in combination with insulin.

The eventual role of gliptins in the treatment of type 2 diabetes will depend on the answers to several questions. For example, do they preserve beta cell function and reverse the progression of diabetes? Do they affect insulin resistance? Do they have cardiovascular benefits beyond glucose-lowering? Also, since DPP-4 is widely distributed in the body, and since we do not yet know the effects of all the proteins cleaved by this enzyme, will this affect the long-term safety of these drugs?

For now, we can state with reasonable certainty that gliptins lower blood sugar levels to a degree similar to that of other oral hypo-glycemic therapies, with minimal risk of hypo-glycemia, with few immediate adverse effects, and without requiring dose titration. These characteristics suggest that gliptins should be considered useful agents in monotherapy and combination therapy for the treatment of type 2 diabetes.

The “gliptins”—the nickname for dipeptidyl peptidase 4 (DPP-4) inhibitors—are one of the newest classes of drugs for the treatment of type 2 diabetes mellitus.

These drugs work by prolonging the action of gut hormones called incretins, which boost insulin levels. The greatest advantage of the gliptins appears to be their ability to stimulate insulin production with little risk of corresponding hypoglycemia.

Sitagliptin (Januvia), the first commercially available DPP-4 inhibitor, has been approved by the US Food and Drug Administration (FDA) and is currently in clinical use, and vildagliptin (Galvus) awaits FDA approval at the time of this writing. Other drugs of this class are in development.

However, because these drugs are so new, a number of questions remain about their use. In this article, we discuss the rationale behind gliptin drugs, the evidence to date on their use alone or in combination with current oral hypoglycemic drugs (and even with insulin), and when and how to use them in daily practice.

THE NEED FOR MORE EFFECTIVE DIABETES TREATMENT

As the number of patients with type 2 diabetes continues its steep and steady rise,1,2 much work has gone into studying treatment goals and how to achieve them. Although experts generally agree on glycemic goals,3 we currently fail to achieve those goals in close to two-thirds of patients: only 37% have a hemo-globin A1c (HbA1c) value at or below the goal of 7%, and the same number have levels exceeding 8%.4

Part of the problem is that treatment regimens are not adjusted in a timely fashion. In a prescribing database of almost 4,000 patients with type 2 diabetes,5 the mean time from the first HbA1c reading above 8% to an actual change in therapy was about 15 months for those taking metformin (Glucophage) alone, and 21 months for those taking a sulfonylurea alone. Another part of the problem is that, on average, patients with an HbA1c of 8.0% to 8.9% can expect only a 0.6% lowering with the addition of one agent.6 Clearly, we need new pharmacologic approaches and new management paradigms. One new approach is the use of gliptins.

HOW GLIPTINS WORK

Incretins promote insulin secretion

We have known for more than 20 years that insulin levels rise considerably higher in response to an oral glucose load than to an intravenous glucose infusion, even though the plasma glucose concentrations may be similar.7 This phenomenon involves a myriad of neural and nutritional factors, but the gut hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) appear to be key.

These peptides—called incretins—have a high degree of homology, and both promote insulin secretion. However, GLP-1, produced by the L cells of the ileum and colon, inhibits glucagon secretion and slows gastric emptying, whereas GIP, secreted from the K cells of the duodenum, has no effect on glucagon and little effect on gastric emptying. Both peptides appear to promote pancreatic beta cell growth and survival,8,9 an effect that in theory might allow us to slow the progressive loss of insulin secretory capacity in type 2 diabetes.

Furthermore, the effect of GLP-1 on insulin secretion depends on the plasma glucose concentration, with a greater insulin secretory effect at higher glucose levels and minimal effect at euglycemic levels.10 This phenomenon suggests that drugs that boost GLP-1 activity should not cause the troublesome hypoglycemia typically seen in patients taking insulin, insulin secretagogues, sulfonyl-ureas, or the meglitinides repaglinide (Prandin) or nateglinide (Starlix). Studies of combination treatment with metformin and the GLP-1 receptor agonist exenatide (Byetta) have shown little risk of hypoglycemia,11 offering evidence favoring this conjecture.

Inhibition of DPP-4 boosts incretin action

The challenge for creating treatments that take advantage of the beneficial effects of GLP-1 and GIP is that they have very short physiologic half-lives, ie, less than 10 minutes. GLP-1 and GIP both have two N-terminal amino acids that are quickly cleaved by DPP-4,12 an enzyme present in the circulation13 and on endothelial cells.14

Currently, there are two classes of drugs based on incretins. One class, the incretin mimetics or GLP-1 receptor agonists, includes drugs that mimic the effect of GLP-1 but are not so quickly degraded by DPP-4. Examples of these drugs are exenatide, which is currently FDA-approved, and liraglutide, which is not yet approved.

On the other hand, by inhibiting the cleaving action of DPP-4, the gliptins can prolong the half-life of endogenous GLP-1, increasing its physiologic effects.

Studies comparing gliptins with GLP-1 receptor agonists are only at the preclinical phase. Liraglutide showed an antiglycemic effect similar to that of vildagliptin in an animal model of glucose intolerance.15 This and other16,17 preclinical studies have shown evidence of improved beta cell growth and survival with DPP-4 inhibitor treatment, to an extent similar to that reported with thiazo-lidinediones, whereas sulfonylureas show no evidence either of increase in beta cells or of improved intrinsic beta cell secretory function in these models. Of course, animal studies can only be cautiously extrapolated to potential effects in humans, and it is uncertain whether such benefits will occur with the therapeutic use of DPP-4 inhibitors.

 

 

RANDOMIZED CLINICAL TRIALS OF SITAGLIPTIN

Sitagliptin and vildagliptin have undergone a large number of studies in patients with type 2 diabetes. Several dosing regimens were tested, but we will restrict this discussion to studies that used 100 mg once a day or 50 mg twice a day. Of note, the effect of 50 mg twice daily may somewhat exceed that of 100 mg once daily,18 so these studies should be interpreted with caution. Table 1 summarizes the effect of sitagliptin on HbA1c values in these studies.19–25

Sitagliptin is effective when used by itself,reducing a baseline HbA1c level of about 8% by 0.6% to 0.8%,19,20,24 and is similarly effective when combined with metformin21,22,25 or pioglitazone (Actos, a thiazolidinedione).23 It also decreases fasting blood glucose levels and improves other measures of glucose control.

A study comparing sitagliptin and the sul-fonylurea glipizide (Glucotrol) showed identical glucose-lowering over a 1-year period, with less hypoglycemia and weight gain with sitagliptin.25 Hypoglycemic episodes occurred in 32% of patients taking glipizide but in only 5% of those taking sitagliptin.

Studies noted several trends in laboratory values, though none was associated with clinical evidence of adverse outcome:

  • White blood cell counts were noted to increase in three of the studies by 4.7% to 10%, owing to increases in neutro-phils19,20,22
  • Alkaline phosphatase concentrations decreased in four studies19,20,22,23
  • Uric acid levels increased in four studies.19,20,22,23

RENAL INSUFFICIENCY SLOWS SITAGLIPTIN CLEARANCE

Lower doses and periodic monitoring of renal function are recommended in patients taking sitagliptin who have some degree of renal insufficiency. Clearance of sitagliptin is delayed in patients with renal insufficiency (creatinine clearance < 50 mL/minute).

In a placebo-controlled study of sitagliptin safety, Scott et al26 found that the area under the sitagliptin concentration-time curve was 2.3 times greater in patients with moderate renal insufficiency (creatinine clearance rate 30–49.9 mL/minute), 3.8 times greater in those with severe renal insufficiency (15–29.9 mL/minute), and 4.5 times greater in those with end-stage renal disease (< 15 mL/minute).

The Januvia package insert27 recommends that the daily dose be decreased to 50 mg in patients with creatinine clearance rates of 30 to 49.9 mL/minute (serum creatinine > 1.7 mg/dL in men, > 1.5 mg/dL in women), and that the dose be decreased to 25 mg per day in those with creatinine clearance rates below 30 mL/minute (creatinine > 3.0/2.5 mg/dL).

CLINICAL TRIALS OF VILDAGLIPTIN BEGIN

Vildagliptin has also undergone extensive clinical testing (Table 2).28–36 The trials to date indicate that it is effective when used alone, reducing HbA1c levels by 0.5% to 0.9% from a baseline of 8%.28,29,34–36 The effect appears to be similar when vildagliptin is used in combination with metformin30,31 or pioglita-zone.32,36

A study comparing vildagliptin against metformin34 showed less glucose-lowering over a 1-year period with vildagliptin, albeit with fewer gastrointestinal side effects, while comparisons with rosiglitazone (Avandia)35 and with pioglitazone36 showed similar glucose-lowering ability.

In a 24-week study,33 256 patients with type 2 diabetes who had a mean body mass index of 33 kg/m2 and who were taking more than 30 units of insulin daily (an average of 82 units) were randomized to additionally receive either vildagliptin 50 mg twice daily or placebo. The HbA1c decreased by 0.5% with vildagliptin and by 0.2% with placebo, from a baseline level of 8.5%. Of interest, 33 patients receiving vildagliptin had a hypo-glycemic episode (a total of 113 events), compared with 45 patients in the placebo group (185 events). None of the episodes in the vildagliptin group was classified as severe, whereas six episodes in the placebo group were classified as severe. This suggests that adding vildagliptin in patients taking insulin can improve glycemia without causing excessive hypoglycemia.

A weakness of the design of this study is that it did not include patients who were receiving an insulin sensitizer, an approach that is typically taken. Given this, it is understandable that overall glycemic control was relatively poor. More effort is needed to explore the use of gliptins with insulin.

WHAT ROLE FOR GLIPTINS?

The evidence from the studies reviewed in this article suggests that gliptins can play an important role in the treatment of type 2 diabetes. In certain patient groups such as the elderly, who cannot take either metformin or a thiazolidinedione and in whom concerns about hypoglycemia are greatest, thus precluding sulfonylurea therapy, gliptins may be the agents of choice. The trials reviewed here suggest that gliptins have glucose-lowering efficacy similar to that of these classes of agents. Gliptins are also effective when combined with metformin or a thiazolidinedione and, as discussed above, may prove to be useful in combination with insulin.

The eventual role of gliptins in the treatment of type 2 diabetes will depend on the answers to several questions. For example, do they preserve beta cell function and reverse the progression of diabetes? Do they affect insulin resistance? Do they have cardiovascular benefits beyond glucose-lowering? Also, since DPP-4 is widely distributed in the body, and since we do not yet know the effects of all the proteins cleaved by this enzyme, will this affect the long-term safety of these drugs?

For now, we can state with reasonable certainty that gliptins lower blood sugar levels to a degree similar to that of other oral hypo-glycemic therapies, with minimal risk of hypo-glycemia, with few immediate adverse effects, and without requiring dose titration. These characteristics suggest that gliptins should be considered useful agents in monotherapy and combination therapy for the treatment of type 2 diabetes.

References
  1. National Diabetes Surveillance System. www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. Last accessed February 28, 2008.
  2. Narayan KM, Boyle JP, Geiss LS, Saaddine JB, Thompson TJ. Impact of recent increase in incidence on future diabetes burden: US, 2005–2050. Diabetes Care 2006; 29:2114–2116.
  3. American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care 2007; 30 suppl 1:S4–S41.
  4. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004; 291:335–342.
  5. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care 2004; 27:1535–1540.
  6. Bloomgarden ZT, Dodis R, Viscoli CM, Holmboe ES, Inzucchi SE. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis. Diabetes Care 2006; 29:2137–2139.
  7. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986; 29:46–52.
  8. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003; 26:2929–2940.
  9. Bloomgarden ZT. Gut hormones and related concepts. Diabetes Care 2006; 29:2319–2324.
  10. Nauck MA, Kleine N, Orskov C, et al. Normalization of fasting hyper-glycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36:741–744.
  11. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28:1092–1100.
  12. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995; 44:1126–1131.
  13. Holst JJ, Deacon CF. Glucagon-like peptide-1 mediates the therapeutic actions of DPP-4 inhibitors. Diabetologia 2005; 48:612–615.
  14. Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide-1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 1999; 140:5356–5363.
  15. Raun K, von Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB. Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 2007; 56:8–15.
  16. Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipeptidyl peptidase IV with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 2006; 55:1695–1704.
  17. Pospisilik JA, Martin J, Doty T, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 2003; 52:741–750.
  18. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91:4612–4619.
  19. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006; 29:2632–2637.
  20. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006; 49:2564–2571.
  21. Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9:186–193.
  22. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. 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.
  23. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P Sitagliptin Study 019 Group. 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.
  24. Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract 2007; 61:171–180.
  25. Nauck MA, Meininger JG, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9:194–205.
  26. Scott RS, Hartley P, Luo E, et al. Use of sitagliptin in patients with type 2 diabetes and renal insufficiency [abtract]. Diabetes 2006; 55 suppl 1:A462.
  27. Januvia prescribing information. www.merck.com/product/usa/pi_circulars/j/products_j.html. Last accessed February 28, 2008.
  28. Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab 2005; 7:692–698.
  29. Dejager S, Baron M, Razac S, Foley JE, Dickinson S, Schweizer S. Effect of vildagliptin on drug-naïve patients with type 2 diabetes. Diabetologia 2006; 49 suppl 1:479–480.
  30. Ahrén B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase iv inhibitor laf237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004; 27:2874–2880.
  31. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. 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.
  32. Garber A, Schweizer A, Baron MA, Rochotte E, Dejager S. 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.
  33. Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia 2007; 50:1148–1155.
  34. Dejager S, LeBeaut A, Couturier A, Schweizer A. Sustained reduction in HbA1c during one-year treatment with vildagliptin in patients with type 2 diabetes (T2DM) [abstract]. Diabetes 2006; 55 suppl 1:A29.
  35. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes. Diabetes Care 2007; 30:217–223.
  36. Rosenstock J, Baron MA, Camisasca R-P, Cressier F, Couturier A, Dejager S. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9:175–185.
References
  1. National Diabetes Surveillance System. www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. Last accessed February 28, 2008.
  2. Narayan KM, Boyle JP, Geiss LS, Saaddine JB, Thompson TJ. Impact of recent increase in incidence on future diabetes burden: US, 2005–2050. Diabetes Care 2006; 29:2114–2116.
  3. American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care 2007; 30 suppl 1:S4–S41.
  4. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004; 291:335–342.
  5. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care 2004; 27:1535–1540.
  6. Bloomgarden ZT, Dodis R, Viscoli CM, Holmboe ES, Inzucchi SE. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis. Diabetes Care 2006; 29:2137–2139.
  7. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986; 29:46–52.
  8. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003; 26:2929–2940.
  9. Bloomgarden ZT. Gut hormones and related concepts. Diabetes Care 2006; 29:2319–2324.
  10. Nauck MA, Kleine N, Orskov C, et al. Normalization of fasting hyper-glycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36:741–744.
  11. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28:1092–1100.
  12. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995; 44:1126–1131.
  13. Holst JJ, Deacon CF. Glucagon-like peptide-1 mediates the therapeutic actions of DPP-4 inhibitors. Diabetologia 2005; 48:612–615.
  14. Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide-1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 1999; 140:5356–5363.
  15. Raun K, von Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB. Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 2007; 56:8–15.
  16. Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipeptidyl peptidase IV with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 2006; 55:1695–1704.
  17. Pospisilik JA, Martin J, Doty T, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 2003; 52:741–750.
  18. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91:4612–4619.
  19. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006; 29:2632–2637.
  20. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006; 49:2564–2571.
  21. Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9:186–193.
  22. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. 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.
  23. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P Sitagliptin Study 019 Group. 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.
  24. Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract 2007; 61:171–180.
  25. Nauck MA, Meininger JG, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9:194–205.
  26. Scott RS, Hartley P, Luo E, et al. Use of sitagliptin in patients with type 2 diabetes and renal insufficiency [abtract]. Diabetes 2006; 55 suppl 1:A462.
  27. Januvia prescribing information. www.merck.com/product/usa/pi_circulars/j/products_j.html. Last accessed February 28, 2008.
  28. Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab 2005; 7:692–698.
  29. Dejager S, Baron M, Razac S, Foley JE, Dickinson S, Schweizer S. Effect of vildagliptin on drug-naïve patients with type 2 diabetes. Diabetologia 2006; 49 suppl 1:479–480.
  30. Ahrén B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase iv inhibitor laf237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004; 27:2874–2880.
  31. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. 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.
  32. Garber A, Schweizer A, Baron MA, Rochotte E, Dejager S. 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.
  33. Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia 2007; 50:1148–1155.
  34. Dejager S, LeBeaut A, Couturier A, Schweizer A. Sustained reduction in HbA1c during one-year treatment with vildagliptin in patients with type 2 diabetes (T2DM) [abstract]. Diabetes 2006; 55 suppl 1:A29.
  35. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes. Diabetes Care 2007; 30:217–223.
  36. Rosenstock J, Baron MA, Camisasca R-P, Cressier F, Couturier A, Dejager S. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9:175–185.
Issue
Cleveland Clinic Journal of Medicine - 75(4)
Issue
Cleveland Clinic Journal of Medicine - 75(4)
Page Number
305-310
Page Number
305-310
Publications
Cleveland Clinic Journal of Medicine
Type 2 Diabetes ICYMI
Publications
Cleveland Clinic Journal of Medicine
Type 2 Diabetes ICYMI
Topics
Diabetes
Drug Therapy
Endocrinology
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What role will ‘gliptins’ play in glycemic control?
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What role will ‘gliptins’ play in glycemic control?
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Current Drug Therapy
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KEY POINTS

  • Sitagliptin (Januvia) is now available, and vildagliptin (Galvus) is awaiting approval. Other gliptins are under development.
  • The gliptins effectively lower blood glucose levels, do not require titration, are unlikely to cause hypoglycemia, do not cause weight gain or loss, and are well tolerated.
  • Gliptins can be used alone or in combination with metformin (Glucophage) or a thiazolidinedione. Preliminary studies also show evidence of benefit when they are used in combination with insulin.
  • Comparative studies suggest that gliptins lower blood glucose levels by about the same amount as other oral hypoglycemic agents.
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