Cardiovascular Outcomes of DPP-4 Inhibitors

The dipeptidyl-peptidase-4 (DPP-4) inhibitors, a class of oral antihyperglycemic medications, have been shown as efficacious in the treatment of type 2 diabetes mellitus (DM2).1 The DPP-4 inhibitors restrict the breakdown of endogenous incretins, glucagon-like peptide 1 and gastric inhibitory peptide by dipeptidyl-peptidase-4 enzyme, thereby prolonging the half-life of incretin hormones.2

According to American Diabetes Association (ADA) 2016 guidelines,3 DPP-4 inhibitors are considered as second line oral medications for treatment of DM2. Currently available DPP-4 inhibitors are alogliption, saxagliptin, sitagliptin, linagliptin, and vidagliptin. The cardiovascular (CV) outcome trials were conducted using alogliptin, saxagliptin and sitagliptin; a phase 4 trial with linagliptin is ongoing for individuals with DM2.

Based on FDA guidance,4 the CV outcome studies were designed to study patients with diabetes comparing the addition of the study drug or placebo to standard of care. The major end points of these CV outcomes trials was to examine major adverse cardiovascular events (MACE). The outcomes were studied in patients who were already at high risk for CV disease. These trials were powered to assess non-inferiority of the DPP-4 inhibitor to placebo in a double blind study design. In addition to non-inferiority, some of these trials were also tested for superiority of the respective DPP-4 inhibitor to placebo. The CV safety trials were published for 3 DPP-4-inhibitors: sitagliptin, saxagliptin and alogliptin (Table 1).

EXAMINE Trial

The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial assessed the effect of alogliptin compared to placebo in 898 centers in 49 countries.5 The median follow-up was 18 months. The primary endpoint of this trial was the composite of death from CV events, nonfatal MI, and nonfatal stroke.  Secondary endpoints of this trial were the primary composite end points with the need for any urgent revascularization.

This study found similar CV event rates in alogliptin and placebo groups (11.3% vs 11.8%). There were no differences in any of the secondary outcomes assessed. Glycemic control and hemoglobin A1c (HbA1c) was significantly better in the alogliptin group, albeit by only 0.36 %.  Even though the incidence of hospitalization was not initially reported, the EXAMINE study investigators later published that alogliptin did not increase the rates of hospitalization for heart failure (3.1 vs 2.9%, p=0.657).6

SAVOR-TIMI Trial

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes-Thrombolysis in Myocardial Infarction (SAVOR-TIMI)7 examined the effect of saxagliptin compared to placebo on CV outcomes in patients with type 2 diabetes across 788 centers in 26 countries. The median follow-up for this study was 2.1 years. The primary CV endpoints was similar in the saxagliptin and placebo groups (7.5% vs 7.2%). For the secondary endpoints, the saxagliptin group had higher rates of hospitalization for heart failure when compared with the placebo group (3.5% vs 2.8%, p< 0.007).7

TECOS 

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) examined the effect of sitagliptin compared to placebo across 673 centers in 38 countries.8 The primary endpoint of this trial was the composite of death from CV events, non-fatal MI, non-fatal stroke and hospitalization for unstable angina. The median follow-up was 3 years.

The TECOS study results indicated similar event rates for the primary outcome in both the sitagliptin and placebo groups (11.4% vs 11.6%).8  There were no differences in glycemic control or secondary endpoints.  In this study, there was also no increase in the rates of hospitalization for heart failure (3.1% vs 3.1%, p=0.98). 

Commentary

The results of all 3 trials showed that none of the DPP-4 inhibitors increased the predefined primary CV outcomes.6,7,8 However, the main concern and subsequent discussion has focused on the higher incidence of hospitalization for heart failure seen with saxagliptin compared to placebo but in the trials evaluating alogliptin or sitagliptin. Since the incidence of heart failure was similar for all 3 studies (saxagliptin-3.5%, alopgliptin-3.1%, sitagliptin-3.1%), it is unclear why saxagliptin showed an increased incidence of heart failure.7

One possibility is that the characteristics of the study population differ across the studies. TECOS included patients with HbA1c between 6.5-8.0%8 while EXAMINE5,6 and SAVOR-TIMI7 involved patients with higher HbA1c percentages. Additionally, some metaanalyses showed that heart failure is not increased with DPP-4 inhibitors,9,10,11 while others showed an increase in heart failure.12,13 The different DDP-4 inhibitors also have differing pharmacologic activity.1 However, there is no clear evidence to explain the reason for increased rate of heart failure hospitalizations with saxagliptin but not with the other DPP-4 inhibitors.

Future head to head studies with the DPP-4 inhibitors are needed to fully elicit CV outcome differences between these oral diabetes agents. 

Sources

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2.         Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest. 2007;117(1):24-32.

3.         American Diabetes A. Standards of medical care in diabetes--2014. Diabetes Care. 2014;37 Suppl 1:S14-80.

4.         U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Guidance for industry: diabetes mellitus-evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring: U.S. Food and Drug Administration; 2016. Available from:http://www.fda.gov/downloads/Drug/GuidanceComplianceRegulatoryInformation/%20Guidances/ucm071627.psd. Accessed October 14, 2016.

5.         White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. New Engl J Med. 2013;369(14):1327-35.

6.         Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385(9982):2067-76.

7.         Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New Engl J Med. 2013;369(14):1317-26.

8.         Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes (TECOS). New Engl J Med. 2015;373(3):232-42.

9.         Savarese G, Perrone-Filardi P, D'Amore C, Vitale C, Trimarco B, Pani L, et al. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: A meta-analysis. Int J Cardiol. 2015;181:239-44.

10.       Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab. 2011;13(1):7-18.

11.       Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016;352:i610.  

12.       Wu S, Hopper I, Skiba M, Krum H. Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: meta-analysis of randomized clinical trials with 55,141 participants. Cardiovasc Ther. 2014;32(4):147-58.

13.       Kongwatcharapong J, Dilokthornsakul P, Nathisuwan S, Phrommintikul A, Chaiyakunapruk N. Effect of dipeptidyl peptidase-4 inhibitors on heart failure: A meta-analysis of randomized clinical trials. Int J Cardiol. 2016;211:88-95.