Current Drug Therapy

What role will ‘gliptins’ play in glycemic control?

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ABSTRACTThe gliptins, a new class of oral drugs for type 2 diabetes mellitus, lower blood glucose levels by a novel mechanism: ie, by inhibiting the enzyme dipeptidyl peptidase 4, thereby increasing the circulating levels of incretins (gut hormones that can boost insulin levels). This article reviews the current evidence on the effectiveness of gliptins and suggests several ways in which these agents could be used in diabetes treatment.


  • 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.



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.


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.


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.

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