Dipeptidyl Peptidase-4 Inhibitors

After a long period of very few drug choices for the management of type 2 diabetes, during the past 15 years a range of new drug classes has been developed (1). One of these is the dipeptidyl peptidase 4 (DPP-4) inhibitors, including drugs such as sitagliptin, saxagliptin, vildagliptin, alogliptin, and linagliptin.

These agents inhibit the enzyme DPP-4, which acts to degrade glucagon-like peptide-1 (GLP-1), an incretin hormone. GLP-1 triggers glucose-dependent insulin secretion, reduces glucagon release, and delays gastric emptying (2). The action of GLP-1 depends on the presence of the N-terminal amino acids, which are cleaved by the enzyme DPP-4 (2). Thus, inhibitors that inhibit this enzyme, DPP-4, lead to increased concentrations of active GLP-1, an action that lowers fasting and postprandial glucose concentrations. It needs to be appreciated that DPP-4 inhibits other hormones, including gastric inhibitory peptide, an incretin, along with numerous other peptides. The relevance of the action of DPP-4 on these other hormones has not been fully determined.

Current guidelines from both American and European diabetes organizations recommend that first-line treatment should be with metformin (3). After metformin, DPP-4 inhibitors are considered appropriate as a second choice, particularly if there is no indication for specific cardiovascular (CV) or renoprotection. In terms of glycemic control, they are as potent as most other oral agents, although they are not as effective at glucose lowering as injectables such as insulin or GLP-1 analogs (4). The advantages of these drugs include neutrality on weight in contrast to insulin, sulphonylureas, or thiazolodinediones, which are associated with weight gain. Furthermore, hypoglycemia is not seen with these agents unless they are administered with drugs that are associated with hypoglycemia, such as insulin and sulphonylureas.

A major reason for the widespread use of this class of glucose-lowering drug is the low risk of side effects. In most major trials with these agents, no increase in side effects was seen versus placebo. This contrasts with the common side effects seen with most other classes of antidiabetic drugs. However, a few side effects, albeit rare, have been identified as a result of very large clinical trials including thousands of patients and over a decade of millions of patients with type 2 diabetes receiving long-term treatment with these drugs. Side effects include a less than twofold increase in pancreatitis (5). The issue of an increased risk of pancreatic cancer with these agents has been raised but has not been confirmed in meta-analyses of studies with these drugs. Finally, a rare bullous skin disorder, pemphigoid, has been confirmed to be increased with various DPP-4 inhibitors and is likely to be a class-related side effect (6).

Given that DPP-4 inhibitors are often prescribed as second-line drugs, a common clinical scenario is the combined use of these agents with metformin. This has led to the development of fixed combinations of metformin and DPP-4 inhibitors, which are widely prescribed in clinical practice.

Most DPP-4 inhibitors are primarily cleared by the kidney (7). Thus, as GFR declines most DPP-4 inhibitors need their dose reduced. With such dose reductions, these drugs are considered safe in patients with renal impairment, including those using dialysis. However, one particular DPP-4 inhibitor, linagliptin, is not cleared by the kidney, and thus no dose reduction is required with increasing renal impairment with this agent (7).

In addition to combinations with metformin, this class of drugs can be added to most other antidiabetic drugs except GLP-1 analogs. This includes use with sulphonylureas and thiazolidinediones. Furthermore, with increasing evidence of a role for sodium glucose co-transporter 2 (SGLT-2) inhibitors in type 2 diabetes, fixed combinations of SGLT-2 and DPP-4 inhibitors are now available, including linagliptin/empagliflozin, saxagliptin/dapagliflozin, and sitagliptin/ertugliflozin. These combinations act in a complementary manner synergistically to reduce HbA1c more than either agent as a monotherapy (8). Finally, clinical trial data indicate that these agents can be used with insulin to afford a further improvement in HbA1c.

As a result of an initiative by the U.S. Food and Drug Administration to confirm the CV safety of new antidiabetic drugs, large clinical trials have been performed with various DPP-4 inhibitors. On the basis of meta-analyses of phase 2 trials of these agents, it was predicted that they may confer CV protection. Unfortunately, no such benefit was identified, but in general these agents were deemed to have CV safety with no increase in CV events, based on the 3P-MACE, a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke (Table 1). However, an increase in hospitalization for heart failure was identified in the SAVOR-TIMI trial with saxagliptin, an adverse event not seen in the TECOS trial with sitagliptin or the CARMELINA trial with linagliptin.

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Since kidney disease remains a major complication in type 2 diabetes, the role of this drug class on albuminuria and decline in GFR has been examined. Initial trials, albeit predominantly post hoc analyses of small trials, suggested an anti-albuminuric effect of these agents in that clinical context (9). With linagliptin widely used in patients with reduced GFR because no dose change is required and renal safety had been reported previously, a number of trials with this agent prospectively assessed the renal effects of this agent.

Unfortunately, the MARLINA-2D study failed to show a statistically impressive effect on reducing albuminuria although there was a trend toward reduced progression of renal disease (10). The more recent CARMELINA study, which included renal as well as CV endpoints, showed no benefit of linagliptin on influencing decline in GFR, but there was a modest effect on reducing albuminuria (11). Thus, in contrast to SGLT-2 inhibitors and GLP-1 agonists, these agents are not considered in the latest international guidelines as renoprotective agents (3).

Finally, since these drugs are usually considered second line after metformin, a major unresolved issue is their advantage over other glucose-lowering agents such as the cheaper alternative, including sulphonylureas. The CAROLINA study has compared the DPP-4 inhibitor linagliptin with the widely prescribed sulphonylurea glimepiride (12). CV safety has been reported with linagliptin in that trial, but as yet no renal endpoints have been reported

In summary, DPP-4 inhibitors are widely used oral antidiabetic drugs with an excellent side effect profile and with documented renal and CV safety. They can be used in patients with renal disease, although dose reductions need to be considered with certain but not all DPP-4 inhibitors.

August 2019 (Vol. 11, Number 8)

References

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3. Davies MJ, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41:2669–2701.

4. Davidson JA. The placement of DPP-4 inhibitors in clinical practice recommendations for the treatment of type 2 diabetes. Endocr Pract 2013; 19:1050–1061.

5. Tkac I, Raz I. Combined analysis of three large interventional trials with gliptins indicates increased incidence of acute pancreatitis in patients with type 2 diabetes. Diabetes Care 2017; 40:284–286.

6. Lee SG, et al. Association of dipeptidyl peptidase 4 inhibitor use with risk of bullous pemphigoid in patients with diabetes. JAMA Dermatol 2019; 155:172–177.

7. Deacon CF, Lebovitz HE. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obes Metab 2016; 18:333–347.

8. Rosenstock J, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: A randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care 2015; 38:376–383.

9. Cooper ME, et al. Kidney disease end points in a pooled analysis of individual patient-level data from a large clinical trials program of the dipeptidyl peptidase 4 inhibitor linagliptin in type 2 diabetes. Am J Kidney Dis 2015; 66:441–449.

10. Groop PH, et al. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: The randomized MARLINA-T2D trial. Diabetes Obes Metab 2017; 19:1610–1619.

11. Rosenstock J, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: The CARMELINA randomized clinical trial. JAMA 2019; 321:69–79.

12. Marx N, et al. Design and baseline characteristics of the CARdiovascular Outcome trial of LINAgliptin versus glimepiride in type 2 diabetes (CAROLINA®). Diab Vasc Dis Res 2015; 12:164–174.