Association of Second-line Antidiabetic Medications With Cardiovascular Events Among Insured Adults With Type 2 Diabetes

Abstract

IMPORTANCE Understanding cardiovascular outcomes of initiating second-line antidiabetic medications (ADMs) may help inform treatment decisions after metformin alone is not sufficient or not tolerated. To date, no studies have compared the cardiovascular effects of all major second-line ADMs during this early decision point in the pharmacologic management of type 2 diabetes. OBJECTIVE To examine the association of second-line ADM classes with major adverse cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study among 132 737 insured adults with type 2 diabetes who started therapy with a second-line ADM after taking either metformin alone or no prior ADM. This study used 2011-2015 US nationwide administrative claims data. Data analysis was performed from January 2017 to October 2018. EXPOSURES Dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, thiazolidinediones (TZDs), basal insulin, and sulfonylureas or meglitinides (both referred to as sulfonylureas hereafter). The DPP-4 inhibitors served as the comparison group in all analyses. MAIN OUTCOMES AND MEASURES The primary outcome was time to first cardiovascular event after starting the second-line ADM. This composite outcome was based on hospitalization for the following cardiovascular conditions: congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease. RESULTS Among 132 737 insured adult patients with type 2 diabetes (men, 55%; aged 45-64 years, 58%; white, 63%), there were 3480 incident cardiovascular events during 169 384 person-years of follow-up. Patients were censored after the first cardiovascular event, discontinuation of insurance coverage, transition from International Classification of Diseases, Ninth Revision (ICD-9) to end of ICD-9 coding, or 2 years of follow-up. After adjusting for patient, prescriber, and health plan characteristics, the risk of composite cardiovascular events after starting GLP-1 receptor agonists was lower than DPP-4 inhibitors (hazard ratio [HR], 0.78; 95% CI, 0.63-0.96), but this finding was not significant in all sensitivity analyses. Cardiovascular event rates after starting treatment with SGLT-2 inhibitors (HR, 0.81; 95% CI, 0.57-1.53) and TZDs (HR, 0.92; 95% CI, 0.76-1.11) were not statistically different from DPP-4 inhibitors. The comparative risk of cardiovascular events was higher after starting treatment with sulfonylureas (HR, 1.36; 95% CI, 1.23-1.49) or basal insulin (HR, 2.03; 95% CI, 1.81-2.27) than DPP-4 inhibitors.

Effects of the low carbohydrate, high fat diet on glycemic control and body weight in patients with type 2 diabetes: experience from a community-based cohort

“…While controversial, some studies suggest patients who take insulin may have a dose-dependent increased risk of cardiovascular events. [36][37][38][39] The possible increased cardiovascular morbidity may be related to weight gain and hypoglycemic events, which can accompany the use of sulfonylurea drugs and insulin particularly at higher doses. Highlighting the potential beneficial impact of the LCHF diet, in which sulfonylureas were routinely discontinued and insulin doses were initially reduced, and many of our patients in the LCHF group were able to further reduce or eliminate insulin.…”

Insulin treatment and clinical outcomes in patients with diabetes and heart failure with preserved ejection fraction

“…Insulin, a traditional second‐line treatment for type 2 diabetes, leads to sodium and water retention, weight gain and hypoglycaemia, with resultant sympathetic nervous system activation . Theoretically, insulin may be detrimental to patients with concomitant HF, but this has yet to be tested in a randomized clinical trial in patients with established HF.…”

“…7 -10 Insulin, a traditional second-line treatment for type 2 diabetes, leads to sodium and water retention, weight gain and hypoglycaemia, with resultant sympathetic nervous system activation. 11,12 Theoretically, insulin may be detrimental to patients with concomitant HF, but this has yet to be tested in a randomized clinical trial in patients with established HF. In a post-hoc analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) trial, insulin therapy was associated with higher risks of mortality and HF hospitalization in patients with HF and reduced ejection fraction (HFrEF) and similar findings have been reported from other HFrEF clinical trials.…”

12th Roche Diabetes Care Network Meeting: April 11–13, 2019, Copenhagen, Denmark

“…In a recent study that looked at CV risk associated with adding a second medication to type 2 patients treated with metformin, O'Brien reported that the newer medications conferred a significantly lower risk for incidence of a first major CV event compared with sulfonylurea or glargine treatment. 17 Moreover, in the EMPA-REG study, investigators reported significant reductions in CV events in T2D patients treated with empagliflozin (SGLT-2 inhibitor). 18 Other SGLT-1/SGLT-1&2 studies have also shown reductions in risk for renal disease.…”