Cardiovascular safety of glucose-lowering agents as add-on medication to metformin treatment in type 2 diabetes: report from the Swedish National Diabetes Register.
To investigate the relative safety of various glucose-lowering agents as add-on medication to metformin in type 2 diabetes in an observational study linking five national health registers.



Patients with type 2 diabetes who had been on metformin monotherapy and started another agent in addition to metformin were eligible for inclusion. The study period was 2005-2012. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality, cardiovascular disease (CVD), coronary heart disease (CHD), stroke and congestive heart failure (CHF) were estimated using Cox proportional hazards models, weighted for a propensity score.



Of the 20 422 patients included in the study, 43% started on second-line treatment with sulphonylurea (SU), 21% basal insulin, 12% thiazolidinedione (TZD), 11% meglitinide, 10% dipeptidyl peptidase-4 (DPP-4) inhibitor, 1% glucagon-like peptide-1 (GLP-1) receptor agonist and 1% acarbose. At the index date, the mean patient age was ~60 years for all groups except the GLP-1 receptor agonist (56.0 years) and SU (62.9 years) groups. Diabetes duration and glycated haemoglobin levels were similar in all groups. When compared with SU, basal insulin was associated with an 18% higher risk and TZD with a 24% lower risk of mortality [HR 1.18 (95% CI 1.03-1.36) and 0.76 (95% CI 0.62-0.94)], respectively. DPP-4 inhibitor treatment was associated with significantly lower risks of CVD, fatal CVD, CHD, fatal CHD and CHF.



This nationwide observational study showed that second-line treatment with TZD and DPP-4 inhibitor as add-on medication to metformin were associated with significantly lower risks of mortality and cardiovascular events compared with SU, whereas basal insulin was associated with a higher risk of mortality.
Department of Medicine, University of Gothenburg, Gothenburg, Sweden. nils.ekstrom@ki.se.|Department of Medicine Solna, Center for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden. nils.ekstrom@ki.se.
Nils
N
Ekström
Center of Registers in Region Västra Götaland, Gothenburg, Sweden.
Ann-Marie
AM
Svensson
Center of Registers in Region Västra Götaland, Gothenburg, Sweden.
Mervete
M
Miftaraj
Center of Registers in Region Västra Götaland, Gothenburg, Sweden.
Stefan
S
Franzén
Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.|Medical Products Agency, Uppsala, Sweden.
Björn
B
Zethelius
Department of Medicine, University of Gothenburg, Gothenburg, Sweden.
Björn
B
Eliasson
Department of Medicine, University of Gothenburg, Gothenburg, Sweden.|Center of Registers in Region Västra Götaland, Gothenburg, Sweden.
Soffia
S
Gudbjörnsdottir
D000368:Aged; D001786:Blood Glucose / Q000187:drug effects; D066126:Cardiotoxicity / Q000453:epidemiology; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology* / Q000401:mortality; D003327:Coronary Disease / Q000139:chemically induced / Q000453:epidemiology / Q000401:mortality; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology* / Q000401:mortality; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000819:agonists; D006333:Heart Failure / Q000139:chemically induced / Q000453:epidemiology / Q000401:mortality; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D012042:Registries / Q000706:statistics & numerical data; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D013548:Sweden / Q000453:epidemiology; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D052216:Glucagon-Like Peptide 1; D008687:Metformin
cardiovascular complications; glucose-lowering agents; metformin; pharmacoepidemiology; type 2 diabetes