Cardiovascular safety of combination therapies with incretin-based drugs and metformin compared with a combination of metformin and sulphonylurea in type 2 diabetes mellitus - a retrospective nationwide study
Mogensen, U. M.2; Andersson, C.2; Fosbol, E. L.2; Schramm, T. K.2; Vaag, A.2; Scheller, N. M.2; Torp-Pedersen, C.2; Gislason, G.4; Kober, L.2
1 Research Programme on Health and Morbidity in Denmark, National Institute of Public Health, Det Sundhedsvidenskabelige Fakultet, SDU2 unknown3 Health Promotion and Prevention, National Institute of Public Health, Det Sundhedsvidenskabelige Fakultet, SDU4 Health Promotion and Prevention, National Institute of Public Health, Det Sundhedsvidenskabelige Fakultet, SDU
a retrospective nationwide study
AimDipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are widely used in combinations with metformin in the treatment of type 2 diabetes; however, data on long-term safety compared with conventional combination therapies are limited. MethodsDanish individuals without prior myocardial infarction or stroke that initiated combinations of metformin with sulphonylurea (SU), DPP-4 inhibitors, GLP-1 agonists or insulin between 9 May 2007 and 31 December 2011 were followed up for the risk of all-cause mortality, cardiovascular (CV) mortality or a combined end point of myocardial infarction, stroke and CV mortality. Rate ratios (RR) were calculated using time-dependent multivariable Poisson regression analysis. ResultsA total of 40 028 patients (59% men, mean age 60 13 years) used metformin with SU (n = 25 092), DPP-4 inhibitor (n = 11 138), GLP-1 agonist (n = 4345) or insulin (n = 6858). Crude incidence rates per 1000 patient years for the combined end point were 18 (SU), 10 (DPP-4 inhibitor), 8 (GLP-1 agonist) and 21 (insulin). In adjusted analyses with metformin + SU as reference, metformin + DPP-4 inhibitor was associated with an RR of 0.65 (0.54-0.80) for mortality, an RR of 0.57 (0.40-0.80) for CV mortality and an RR of 0.70 (0.57-0.85) for the combined end point. For metformin + GLP-1 agonist, the RR for mortality was 0.77 (0.51-1.17), for CV mortality 0.89 (0.47-1.68), and for the combined end point 0.82 (0.55-1.21). Conclusion Incretin-based drugs combined with metformin were safe compared with conventional combinations of glucose-lowering therapy. Use of incretin-based therapy may be target for strategies to lower CV risk in type 2 diabetes, although it should be recognized that the multivariable analysis may not have fully accounted for important baseline differences.
Diabetes, Obesity and Metabolism, 2014, Vol 16, Issue 10, p. 1001-1008