A Multicenter Observational Study of Incretin-based Drugs and Heart Failure

Filion KB, Azoulay L, Platt RW, et al. CNODES Investigators.
N Engl J Med. 2016 Mar 24;374(12):1145-54. doi: 10.1056/NEJMoa1506115.

Background

Concerns have been raised about the safety of incretin-based drugs, among which dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, as they may give an increased risk of heart failure (HF) [1]. In the SAVOR-TIMI 53 trial, patients randomised to the DPP-4 inhibitor saxagliptin indeed showed a 27% higher risk of hospitalisation for HF (HFH) as compared to those on placebo [2,3]. The EXAMINE [4] and TECOS [5] on the other hand, did not show an increase in the overall risk of HFH in patients randomly assigned to alogliptin and sitagliptin, respectively.
This analysis examined data from multiple cohorts of patients, to determine whether data the use of incretin-based drugs, in comparison with oral antidiabetic-drug combinations, is associated with an increased risk of HF in routine clinical practice. The study is part of the Canadian Network for Observational Drug Effect Studies (CNODES) [6].
Data of type 2 diabetes patients with a first-ever prescription for a noninsulin antidiabetic drug of six sites in Canada, the United States and the United Kingdom were included. A nested case-control analysis was performed, with cases defined as those hospitalised for HF (both fatal and non-fatal events). Up to 20 controls were randomly selected for each case patient and matched based on sex, age, date of study-cohort entry, duration of treated diabetes, and duration of follow-up. The cohorts included 1499650 patients, of whom 29741 were hospitalised for HF (3242291 person-years of follow-up, crude incidence rate: 9.2 events per 1000 persons per year).

Main results

• Among 1419850 patients without a history of HF, 23205 patients were hospitalised for HF (crude incidence rate: 7.5 events per 1000 persons per year). In those with a history of HF (79800 patients), 6535 HFH occurred (crude incidence rate: 43.5 events per 1000 persons per year).
• Among those without a history of HF, treatment with incretin-based drugs was not associated with an increased risk of HFH, as compared with treatment with oral antidiabetic-drug combinations (HR: 0.82, 95%CI: 0.67-1.00).
  Similar results were seen when drug classes were analysed separately (DPP-4 inhibitors: HR: 0.84, 95%CI: 0.69-1.02; GLP-1 analogues: HR: 0.95, 95%CI: 0.83-1.10).
• No evidence of a duration-response relationship was seen, nor of effect-modification of a history of myocardial infarction or duration of treated diabetes.
• Similarly, in those with a history of HF, no increased risk of HFH was seen associated with incretin-based drugs (HR: 0.86, 95%CI: 0.62-1.19).
  This observation did not depend on drug class (DPP4-inhibitors: HR: 0.87, 95%CI: 0.63-1.21); GLP-1 analogues: HR: 0.75, 95%CI: 0.22-2.51), nor on history of MI or duration of treated diabetes.

Conclusion

In a large, retrospective analysis of patients with diabetes type 2 seen in routine clinical practice, no evidence was observed for an increased risk of hospitalisation for HF with use of incretin-based drugs, as compared with oral antidiabetic drugs. Results were consistent among analyses specified for patients with or without a history of HF and for patients taking DPP-4 inhibitors or GLP-1 analogues.

References

1. Udell JA, Cavender MA, Bhatt DL, et al. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analy- sis of randomised controlled trials. Lan- cet Diabetes Endocrinol 2015;3:356-66.
2. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular out- comes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.
3. Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR- TIMI 53 randomized trial. Circulation 2014;130:1579-88.
4. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.

5. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42.
6. Suissa S, Henry D, Caetano P, et al. CNODES: the Canadian Network for Ob- servational Drug Effect Studies. Open Med 2012;6(4):e134-40.