Metformin in combination with various insulin secretagogues in type 2 diabetes and associated risk of cardiovascular morbidity and mortality: A retrospective nationwide study

TY - JOUR

T1 - Metformin in combination with various insulin secretagogues in type 2 diabetes and associated risk of cardiovascular morbidity and mortality

T2 - A retrospective nationwide study

AU - Mogensen, Ulrik Madvig

AU - Andersson, Charlotte

AU - Fosbøl, Emil Loldrup

AU - Schramm, Tina Ken

AU - Vaag, Allan

AU - Scheller, Nikolai Madrid

AU - Torp-Pedersen, Christian

AU - Gislason, Gunnar

AU - Køber, Lars

N1 - Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

PY - 2015/1

Y1 - 2015/1

N2 - AIMS: Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs.METHODS: Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference.RESULTS: A total of 56,827 patients were included, 56% male, the mean age was 61 ± 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005).CONCLUSION: Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study.

AB - AIMS: Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs.METHODS: Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference.RESULTS: A total of 56,827 patients were included, 56% male, the mean age was 61 ± 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005).CONCLUSION: Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study.

KW - Aged

KW - Carbamates

KW - Cardiovascular Diseases

KW - Denmark

KW - Diabetes Mellitus, Type 2

KW - Drug Therapy, Combination

KW - Female

KW - Gliclazide

KW - Glipizide

KW - Glyburide

KW - Humans

KW - Hypoglycemic Agents

KW - Male

KW - Metformin

KW - Middle Aged

KW - Morbidity

KW - Myocardial Infarction

KW - Piperidines

KW - Registries

KW - Retrospective Studies

KW - Risk Factors

KW - Stroke

KW - Sulfonylurea Compounds

KW - Tolbutamide

U2 - 10.1016/j.diabres.2014.09.047

DO - 10.1016/j.diabres.2014.09.047

M3 - Journal article

C2 - 25458330

SN - 0168-8227

VL - 107

SP - 104

EP - 112

JO - Diabetes Research and Clinical Practice

JF - Diabetes Research and Clinical Practice

IS - 1

ER -