Cardiovascular safety of glucose‐lowering agents as add‐on medication to metformin treatment in type 2 diabetes: report from the Swedish National Diabetes Register

Abstract

Aim 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. Research design and methods 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. Results 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. Conclusions 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.

Long‐term comparative safety analysis of the risks associated with adding or switching to a sulfonylurea as second‐line Type 2 diabetes mellitus treatment in a US veteran population

“…Also, they report an elevated risk for add‐on sulfonylureas compared with add‐on thiazolidinediones (specifically pioglitazone). Similar findings have been found from data from other healthcare systems, such as the Taiwan National Health Insurance Database , the Swedish National Diabetes Registry and the Korean National Health Insurance Database .…”

Novel oral glucose‐lowering drugs are associated with lower risk of all‐cause mortality, cardiovascular events and severe hypoglycaemia compared with insulin in patients with type 2 diabetes

“…To the best of our knowledge, no randomized study using CVD endpoints has compared patients treated with insulin with either DPP‐4 inhibitor and/or SGLT2 inhibitor treatment. In the absence of outcome results from randomized clinical trials, observational studies comparing insulin with alternative per oral GLDs are the best available evidence …”

“…Although insulin initiation can improve glycaemic control rapidly, the complexity of injection regimens, the need to frequently titrate doses, as well as the risk of weight gain and hypoglycaemia remain problematic for many patients . Furthermore, safety concerns have been raised regarding increased risk of cardiovascular disease (CVD) and all‐cause mortality in patients with T2D treated with insulin …”

Effects on clinical outcomes of intensifying triple oral antidiabetic drug (OAD) therapy by initiating insulin versus enhancing OAD therapy in patients with type 2 diabetes: A nationwide population‐based, propensity‐score‐matched cohort study

“…These study findings should be interpreted with caution, however, because the studies included a limited number of cardiovascular events and shorter follow‐up periods, the sulphonylureas used might also have had detrimental effects on cardiovascular disease (CVD), and the study populations were specific to either patients at an early stage of diabetes or those with existing CVD . Conversely, longitudinal cohort studies have shown an association between insulin therapy and increased risk of CVD and all‐cause mortality in patients with T2DM, but the effects of insulin therapy were only assessed in patients at an early stage of the antidiabetic treatment course, with insulin being used as monotherapy, or as second‐line or third‐line antidiabetic treatment …”