The dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of oral drugs for the treatment of type 2 diabetes. They inhibit the breakdown of glucagon-like peptide-1 (GLP-1) and increase the incretin effect in patients with type 2 diabetes. In clinical practice they are associated with significant reductions in HbA1c, no weight gain and a low risk of hypoglycemia. Initial cardiovascular safety studies have shown no increase in cardiovascular risk. Indeed, the suggestion of possible cardiovascular benefit seen in the safety studies is now being formally examined in large randomized-controlled trials with primary cardiovascular end points….
One recent advance in the management of type 2 diabetes has been the development and clinical use of DPP-4 inhibitors and GLP-1 receptor agonists. The development of these two classes of drugs was based upon observations from the early twentieth century when it was noted that factors secreted from the gut participated in the regulation of pancreatic endocrine secretion. These factors were collectively termed ‘incretins’. When insulin assays became widely available in the 1960s, it became evident that the insulin secretory response to an oral glucose load was greater than when an identical amount was administered parenterally. This phenomenon was termed the incretin response. We will examine the role of DPP-4 inhibitors in clinical practice
In humans, two incretin peptide hormones have been identified. Glucose-dependent insulin-releasing polypeptide (GIP) and GLP-1 are both secreted in response to food ingestion and potentiate the glucose-induced insulin response (figure 1). These hormones are secreted from intestinal mucosal cells, and GLP-1 can be detected in the circulation minutes after oral ingestion of nutrients. Both of these peptides are rapidly degraded by the enzyme DPP-4, which is expressed in a number of sites, including the endothelial cells of small gut arterioles. As a result, the majority of GLP-1 and GIP is inactivated before reaching the systemic circulation.
The incretin effect is diminished in type 2 diabetes. While secretion of GLP-1 is markedly reduced, GIP secretion remains unaffected. Administration of exogenous GLP-1 (but not GIP) leads to a significant increase in endogenous insulin secretion. GLP-1 also has important effects on reducing food intake, reduction of inappropriate glucagon production and delays gastric emptying. Consequently, manipulating the effects of GLP-1 has been seen as having interesting potential as a therapeutic target in type 2 diabetes. At present there are two classes of drug that potentiate the incretin effect as a means of improving glycemic control in type 2 diabetes. DPP-4 inhibitors prevent degradation of GLP-1 thereby increasing its systemic concentration.
There are currently three drugs available in the U.S. for clinical use in this class: sitagliptin, linagliptin, saxagliptin plus vildagliptin in Europe. In clinical trials, all four of these drugs have been shown to reduce HbA1c by 0.6-0.7% when used either as monotherapy or in combination with metformin, sulphonylureas or a combination of both. They are also associated with lower rates of hypoglycemia and have also been shown to be weight neutral.
The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) developed an algorithm to assist providers in managing type 2 diabetes. When developing the algorithm, the AACE and ACE identified minimizing hypoglycemia and weight gain as their top priorities in drug therapy selection. As a result of that, initial recommendations focus on the use of metformin or a thiazolidinedione if metformin is contraindicated, followed by a GLP-1 agonist or a DPP-4 inhibitor.13
DPP-4 inhibitors are well tolerated, with hypoglycemia only occurring when used in combination with sulphonylurea therapy. The current drugs are cleared by hepatic metabolism and renal excretion. Sitagliptin and vildagliptin are not licensed for use in renal impairment, whereas saxagliptin can be used at a reduced dose and linagliptin can be used at the only strength available. There is a suggestion from pooled data of increased rates of infections, specifically nasopharyngitis and urinary tract infections, which suggests a role for DPP-4 activity in normal immune surveillance, but whether this is clinically significant is still to be established.
Trials of Safety and Efficacy
There is now extensive research concerning the efficacy and general safety of the first four DPP-4 inhibitors: sitagliptin, linagliptin, vildagliptin and saxagliptin. These have been pulled together in a useful meta-analysis by Monami and colleagues, published in 2010. In the meta-analysis they included 32 published trials and nine unpublished trials with a duration greater than 12 weeks. They confirmed that, compared with placebo, the DPP-4 inhibitors reduced HbA1c by around 0.7%. The efficacy was similar in monotherapy and in combination with other agents. When comparisons were made with other oral drugs used in type 2 diabetes, the reductions in HbA1c were comparable with glitazones, but slightly less than with metformin or sulphonylureas. There was no weight gain and a very low risk of hypoglycemia.
The DPP-4 inhibitors have not demonstrated any sustained or clinically significant reduction in other cardiovascular risk factors, such as blood pressure or lipids. As a class, the DPP-4 inhibitors have also not shown any suggestion of cardiovascular risk. Cardiovascular events were included in the meta-analysis by Monami and colleagues. The risk of cardiovascular events was non-significantly reduced to 0.76 (95% confidence interval [CI] 0.46-1.28) and the risk of all-cause mortality was non-significantly reduced to 0.78 (95% CI 0.40-1.51). There has now been individual publication of pooled safety data for the three available DPP-4 inhibitors.[7-9] For sitagliptin, no differences in cardiac events were observed compared with placebo in an analysis of 5,429 patients, and similar results were found for vildagliptin against all comparators in data from 7,509 patients. Also DPP-4’s are being studied for possible reduction in cardiovascular events. 
To be able to confirm possible cardiovascular benefits of DPP-4 inhibitors requires large, double-blind, randomized trials with formal adjudication of cardiovascular end points. The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) is a study comparing sitagliptin with placebo in diabetic patients with a previous history of cardiovascular disease. It aims to recruit 14,000 subjects. The primary outcome is a composite cardiovascular end point, and it hopes to show non-inferiority with a conditional secondary superiority analysis. The Saxagliptin Assessment of Vascular Outcomes (SAVOR-TIMI 53) study is a similar study in 12,000 patients comparing saxagliptin with placebo in diabetic patients with high cardiovascular risk. The primary outcome is also a composite cardiovascular end point, and the aim is to show superiority over placebo.
The clinical management of patients with type 2 diabetes has to balance the potential benefits of controlling hyperglycemia on microvascular and macrovascular complications, with possible side effects of treatment and possible harm from over intensive control of glycemia. From the perspective of the patient with diabetes, weight gain and hypoglycemia are undesirable and unwanted side effects. Of the older therapies, sulphonylureas, insulin and glitazones are all associated with significant weight gain, whereas metformin is associated with slight weight loss. As a class, the DPP-4 inhibitors are weight neutral, causing neither weight gain nor weight loss. As the majority of patients with type 2 diabetes are overweight or obese this offers a potential advantage over older, established therapies, and DPP-4 inhibitors are being used in clinical practice as second-line therapy in addition to metformin in overweight and obese patients who fail to reach glycemic targets with metformin monotherapy. The very low rates of hypoglycemia are an additional advantage in vulnerable patients, such as the elderly or patients who live alone.
The preliminary cardiovascular safety data for DPP-4 inhibitors are promising, and, if the results of long-term cardiovascular studies demonstrate reductions in hard cardiovascular end points, then this may consolidate the position of the DPP-4 inhibitors as the second-line choice for combination with metformin.
Notes: As of Oct. 2011 sitaglipitin/simvastatin is now available as a combination product. Sitaglipitin was the first DPP-4 to be approved by the FDA with the most aftermarket studies.
- Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral drugs for type 2 diabetes that inhibit the breakdown of glucagon-like peptide-1 (GLP-1) and increase the release of insulin in response to a meal.
- In clinical practice, they do not cause weight gain and are weight neutral, with a very low incidence of hypoglycemia as a side effect.
- Results of cardiovascular safety studies have not shown any indication of cardiovascular harm, with possible suggestion of cardiovascular benefit.
- The results of long-term safety studies and cardiovascular end point studies will determine the future role of these drugs.
- Scheen AJ, Radermecker RP. Addition of incretin therapy to metformin in type 2 diabetes. Lancet 2010;375:1410–12.
- Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic individuals. J Clin Invest 1967;46:1954–62.
- Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis 2010;20:224–35.
- Verge D, Lopez X. Impact of GLP-1 and GLP-1 receptor agonists on cardiovascular risk factors in type 2 diabetes. Curr Diabetes Rev 2010;6:191–200.
- McGrane D, McKay GA, Fisher M. Drugs for diabetes: part 3 thiazolidendiones. Br J Cardiol 2011;18:24–7.
- Drucker DJ, Goldfine AB. Cardiovascular safety and diabetes drug development. Lancet 2011;377:977–9.
- Williams-Herman D, Engel SE, Round E et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord 2010;10:7.
- Schweizer A, Dejager S, Foley JE et al. Assessing the cardio-cerebrovascular safety of vildagliptin; meta-analysis of adjudicated events from a large Phase III type 2 diabetes population. Diabetes Obes Metab 2010;12:485–94.
- Frederich R, Alexander JH, Fiodereck FT et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 2010;122:16–27.
- University of Oxford. Diabetes Trials Unit. Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Available from: www.dtu.ox.ac.uk/tecos [accessed 3 April 2011].
- The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–72.
- The ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364:818–28.
- 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 European Association for the Study of Diabetes. Diabetes Care. 2009;32:193-203.