Long-term efficacy and safety of sodium-glucose cotransporter-2 inhibitors as add-on to metformin treatment in the management of type 2 diabetes mellitus

Abstract

Background:Drug intensification is often required for patients with type 2 diabetes mellitus on stable metformin therapy. Among the potential candidates for a combination therapy, sodium-glucose transporter-2 (SGLT2) inhibitors have shown promising outcomes. This meta-analysis was performed to compare the efficacy and safety of SGLT2 inhibitors with non-SGLT2 combinations as add-on treatment to metformin.Methods:Literature search was carried out in multiple electronic databases for the acquisition of relevant randomized controlled trials (RCTs) by following a priori eligibility criteria. After the assessment of quality of the included RCTs, meta-analyses of mean differences or odds ratios (OR) were performed to achieve overall effect sizes of the changes from baseline in selected efficacy and safety endpoints reported in the individual studies. Between-studies heterogeneity was estimated with between-studies statistical heterogeneity (I2) index.Results:Six RCTs fulfilled the eligibility criteria. SGLT2 inhibitors as add-on to metformin treatment reduced % HbA1c significantly more than non-SGLT2 combinations after 52 weeks (P = .002) as well as after 104 weeks (P < .00001). Among other endpoints, SGLT2 inhibitors also reduced fasting plasma glucose levels, body weight, systolic, and diastolic blood pressures after 52 weeks and 104 weeks significantly (P < .00001) more than non-SGLT2 combinations. Incidence of hypoglycemia was significantly lower (P = .02) but incidence of suspected or confirmed genital tract infections was significantly higher (P < .00001) in SGLT2 inhibitors treated in comparison with non-SGLT2 combinations.Conclusion:As add-on to metformin treatment, SGLT2 inhibitors are found significantly more efficacious than non-SGLT2 inhibitor combinations in the management of type 2 diabetes mellitus, although, SGLT2 inhibitor therapy is associated with significantly higher incidence of suspected or confirmed genital tract infections.

Long‐term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104‐week VERTIS MET trial

“…The long‐term effect of ertugliflozin reflects the fact that it acts independently of β‐cell function and insulin secretion, and hence it is not affected by the progressive β‐cell failure observed in patients with T2DM. These data are consistent with glycaemic endpoints in other studies with ertugliflozin and other members of the SGLT2 inhibitor class . Additionally, as previously established in other studies with ertugliflozin and other SGLT2 inhibitors, ertugliflozin produces clinically relevant effects on important non‐glycaemic endpoints such as body weight and SBP.…”

“…These data are consistent with glycaemic endpoints in other studies with ertugliflozin [8][9][10][11][12][13] and other members of the SGLT2 inhibitor class. 17 Additionally, as previously established in other studies with ertugliflozin [8][9][10][11][12][13] and other SGLT2 inhibitors, 17 ertugliflozin produces clinically relevant effects on important non-glycaemic endpoints such as body weight and SBP.…”

Risk of amputations associated with SGLT2 inhibitors compared to DPP‐4 inhibitors: A propensity‐matched cohort study

“…1 Newer treatments associated with reductions in body weight and cardiovascular benefits are of particular interest given the increasing prevalence of patients with type 2 diabetes and metabolic disease. [3][4][5][6][7][8][9] In 2016, the United States (U.S.) Food and Drug Administration (FDA) issued a safety alert regarding amputations associated with canagliflozin. Clinical trials with SGLT2i report significant reductions in HbA1c, body weight, systolic blood pressure, and major adverse cardiac events.…”

“…Clinical trials with SGLT2i report significant reductions in HbA1c, body weight, systolic blood pressure, and major adverse cardiac events. [3][4][5][6][7][8][9] In 2016, the United States (U.S.) Food and Drug Administration (FDA) issued a safety alert regarding amputations associated with canagliflozin. The alert was based on a 2-fold increase in risk reported in the Canagliflozin Cardiovascular Assessment Study (CANVAS) program.…”

Efficacy of Canagliflozin as an Add-on to Triple Drug Treatment With Glimepiride, Metformin and Teneligliptin

“…24 Literature evidence suggests that the addition of SGLT2 inhibiters, such as canagliflozin to metformin therapy in T2DM patients, can provide significant efficacy compared to the combination with non-SGLT2 inhibitors. 25 Several studies have evaluated the efficacy of canagliflozin as an add-on to double drug treatment for achieving glycemic control in T2DM patients. Wilding et al (2013) have investigated the efficacy of canagliflozin as an add-on to metformin and sulfonylurea in T2DM patients in a 52-week randomized, double-blind, placebo-controlled, phase 3 trial.…”