Cardiovascular and renal outcomes of initial combination therapy with glucose-lowering agents versus stepwise approach in newly diagnosed or treatment naïve type 2 diabetes: a systematic review and meta-analysis.

BackgroundIt is uncertain if initial combination therapy with glucose-lowering agents provides longer-term beneficial cardio-renal outcomes compared to stepwise therapy in patients with newly diagnosed type 2 diabetes (T2D). Using a systematic review and meta-analysis of observational cohort studies and randomised controlled trials (RCTs), we evaluated the efficacy and safety of the initial combination therapy vs a stepwise approach in newly diagnosed T2D.MethodsStudies were identified from MEDLINE, Embase, the Cochrane Library, and search of bibliographies to January 2022. Study-specific risk ratios (RRs) and mean differences with 95% confidence intervals (CIs) were pooled. Quality of the evidence was assessed using GRADE.ResultsEight articles comprising 4 unique RCTs (n = 5527 participants) and one observational cohort study (n = 200) that compared initial combination therapy vs stepwise therapy were included. The RR (95% CI) for myocardial infarction comparing initial combination therapy vs stepwise therapy was 1.21 (0.74-2.00). Initial combination therapy reduced levels of fasting plasma glucose and HbA1c: mean differences (95% CIs) of -0.97 mmoL/L (-1.41, -0.53) and -0.13 % (-0.20, -0.07), respectively. Initial combination therapy vs stepwise therapy reduced lipid levels, blood pressure and intima media thickness, with no differences in body composition parameters, neuropathy, retinopathy, and adverse events. Single study results showed initial combination therapy reduced creatinine levels and urine albumin excretion rate. The quality of the evidence ranged from moderate to very low.ConclusionsExcept for improving cardiometabolic and glycaemic parameters, a limited number of studies characterised by small sample sizes show that initial combination therapy for newly diagnosed T2D may be similar in efficacy and safety to stepwise therapy with respect to cardio-renal outcomes. There is a lack of sufficient evidence to recommend initial combination therapy with glucose-lowering agents in newly diagnosed T2D with the aim of preventing cardio-renal outcomes. Definitive RCTs are warranted. This article is protected by copyright. All rights reserved