New data alleviate CV safety concerns over DPP-4 inhibitor

Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs
A Retrospective Cohort Study

Literature - Toh S et al., Ann Intern Med 2016

Toh S, Hampp C, Reichman ME, et al.
Ann Intern Med 2016; published online ahead of print


DPP-4 inhibitors reduce fasting and postprandial glucose concentrations by decelerating the inactivation of incretin [1]. Results from post-marketing trials with DDP-4 inhibitors regarding CV safety are conflicting:
  • the SAVOR-TIMI 53 trial showed a higher incidence of hospitalised HF (hHF) in the saxagliptin group [2]
  • the EXAMINE and the TECOS trials showed no statistically significant difference in the risk for hHF in the alogliptin and the sitagliptin groups [3,4]
The reason of the observed higher incidence of hHF with saxagliptin is not clear. It may be due to the drug properties, a difference in patient characteristics between trials, or a random error due to multiple hypothesis testing.  Since DM patients are at higher hHF risk [5,6], it is important to examine whether this risk is aggravated by antihyperglycaemic therapy.
In this population-based, retrospective study, the associations of hHF with the DPP-4 inhibitors saxagliptin and sitagliptin was evaluated in a large cohort of T2DM patients, who initiated therapy with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas, or long-acting insulin products from 2006 to 2013. 78 553 saxagliptin users and 298 124 sitagliptin users contributed an average of 7 to 9 months of follow-up data to 1 or more pairwise comparisons.

Main results

The proportion with a prior HF diagnosis was:
  • 5% for saxagliptin users
  • 7% for sitagliptin users
  • 7% for sulfonylurea users
  • 11% for insulin users
The risk for hHF was not higher with DPP-4 inhibitors than with the other study drugs. The DRS (disease risk score) stratified HRs were:
  • 0.83 (95% CI: 0.70 - 0.99) for saxagliptin versus sitagliptin
  • 0.63 (95% CI: 0.47 - 0.85) for saxagliptin versus pioglitazone
  • 0.69 (95% CI: 0.54 - 0.87) for saxagliptin versus sulfonylureas
  • 0.61 (95% CI: 0.50 - 0.73) for saxagliptin versus insulin
  • 0.74 (95% CI: 0.64 - 0.85) for sitagliptin versus pioglitazone
  • 0.86 (95% CI: 0.77 - 0.95) for sitagliptin versus sulfonylureas
  • 0.71 (95% CI: 0.64 - 0.78) for sitagliptin versus insulin
The results from the 1:1 propensity score–matched analyses were similar.
Results in subgroups of patients with and without prior CVD were also similar.


In a large cohort study, the DPP-4 inhibitors saxagliptin and sitagliptin were not associated with an increased risk of hospitalised HF compared with pioglitazone, second-generation sulfonylureas, or long-acting insulin products.

Editorial comment [7]

In contrast to earlier worrisome trial findings, Toh et al. find that HF risk in users of saxagliptin and sitagliptin was similar and comparable to or lower than risk in all other comparator groups. “Saxagliptin users were slightly healthier than users of comparator medications at baseline, but potential confounding differences were controlled for through use of 2 distinct approaches.” (…) “Beyond allaying concern over saxagliptin,”Selby comments on the value of large, longitudinal databases containing clinical and administrative data of multiple institutions, like the one used by Toh et al, to examine whether the concerns over saxagliptin related to HF can be confirmed or not. ’The large cohort size allowed for extension of the study beyond clinical trial participants to all patients treated in practice and for creation of multiple specific comparator groups. Patients in a placebo-controlled group receive an unknown mix of additional antidiabetic agents to control glycemia, some of which may increase risk for heart failure, making comparisons to “placebo” difficult to interpret. Observational studies are not substitutes for randomised safety trials, but they are valuable complements.’ And he concludes: ‘In a country with a health care system as partitioned as that of the United States, sharing complementary data resources could go a long way toward answering safety and effectiveness questions quickly and more definitively, linking clinical trial investigation with real-world experience, eliminating waste and redundancy in research data collection, and incorporating the voices of patients and other stakeholders. My compliments to Toh and colleagues and others who work to achieve this vision.‘

Find this article online at Ann Intern Med


1. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab. 2011;13:7-18.
2. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-26.
3. Zannad F, Cannon CP, Cushman WC, et al; EXAMINE Investigators. 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;385:2067-76.
4. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232-42.
5. Voors AA, van der Horst IC. Diabetes: a driver for heart failure. Heart. 2011;97:774-80.
6. McMurray JJ, Gerstein HC, Holman RR, et al. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014;2:843-51.
7.  Selby JV. Complementary Efforts Make for Efficient Research. Ann Intern Med 2016; published online ahead of print.

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