Impact of Glucose-lowering Drugs or Strategies on CV Events in Individuals with or at Risk of T2DM

Introduction

A systematic review and meta-analysis on trials related to cardiovascular (CV) outcomes associated with glucose-lowering drugs or strategies in people with or at risk of type-2 diabetes mellitus (T2DM) was conducted in 2015. This analysis had demonstrated a modest reduction in atherosclerotic CV events and an increased risk of heart failure (HF). Nevertheless, these findings were heterogeneous with respect to effects by drug or intervention type. Many large CV outcome completed after the publication of this previous analysis, have demonstrated beneficial effects of novel glucose lowering drugs or strategies on CV outcomes.  

Aim

To update the meta-analysis by incorporating the findings of newer trials and to determine the factors that might impact the CV effects of newer diabetes therapies

Study Specification

• Large-scale (minimum study population; 1000 adults) randomized controlled trials (RCTs) that evaluated the CV outcomes associated with glucose lowering drug therapy or strategy focused on a single risk factor (i.e., blood glucose or bodyweight) in patients with T2DM or at risk of T2DM
• The RCTs included in this analysis compared the glucose-lowering drug or strategy with standard care or placebo and demonstrated an improvement in glycemic control between treatment groups
• All the included trials had included major adverse cardiac events (MACE) as an outcome and had a follow-up of at least 12 months.

Methods

Study Design

• A systematic review and meta-analysis

Outcomes

• MACE [defined as a composite of CV death, myocardial infarction (MI), or stroke] and HF.
• Pooled risk ratios (RRs) and 95% confidence intervals (CIs) with inverse-variance random-effects models were calculated
• Treatment effects per difference in bodyweight achieved (determined using a meta-regression analysis)

Results

• Thirty trials providing data of 225305 subjects were included in the systematic review and meta-analysis.
• The mean age of the study subjects was 63.0 years, mean BMI was 31.1 kg/m² and mean bodyweight was 88.7 kg. Mean duration of diabetes was 9.4 years and mean follow-up period was of 3.8 years.
• As compared to standard care or placebo, use of glucose-lowering drugs or strategies was associated with a lower risk of MACE, CV death, all-cause mortality, fatal and non-fatal MI, and fatal and non-fatal stroke (RR,; 95% CI, 0.89–0.95; p<0.0001). (Table 1)

• There was no overall impact on the risk of HF (RR; 0.98, 95% CI, 0.90–1.08, p=0.71), but the magnitude and directionality of RR for HF varied (p_interaction<0.0001) across drug classes or strategies, with meta-regression showing that 1 Kg decrease in bodyweight was associated with a 5.9% relative decrease in the risk of HF (p<0.0001).
• Considering the trials that assessed drug classes or strategies associated with weight loss [intensive lifestyle changes, glucagon like peptide-1 receptor agonist (GLP-1 RA), or sodium glucose cotransporter-2 (SGLT2) inhibitors], the risk reduction for MACE remained consistent among subjects with established CVD at baseline (RR, 0.87; 95% CI, 0.83–0.92) and without established CVD at baseline (RR, 0.92; 95% CI, 0.83–1.02) (p_interaction=0.33).
• With regards to HF, the RR for drug classes or strategies associated with weight loss remained consistent among subjects with CVD (RR, 0.80; 95% CI, 0.73–0.89) and without CVD (RR, 0.84; 95% CI, 0.74–0.95) at baseline (p_interaction=0.63).
• There was risk reduction for HF failure overall with therapies or strategies that lower bodyweight (0·81, 0·74–0·89, p<0·0001; pinteraction=0·0004), with a greater reduction of risk with SGLT2 inhibitors (RR, 0·68; 95% CI, 0·60–0·76; p<0·0001) than with intensive lifestyle changes (RR, 0·80; 95% CI, 0·62–1·04; p=0·10) or GLP-1 receptor agonists (RR, 0·91; 95% CI, 0·84–0·999; p=0·049).

Conclusions

• This updated systematic review and meta-analysis demonstrated an overall reduction in risk of fatal and non-fatal atherosclerotic events with the use of glucose-lowering drugs or strategies.
• Overall, the impact of glucose lowering drugs or strategies on HF was neutral, though it varied substantially as per the intervention type.  Interventions associated with weight loss including use of SGLT2 inhibitors, GLP-1 RA, and intensive lifestyle changes exerted a beneficial impact.
• Patients without established CVD may also experience the CV and HF benefits of interventions associated with weight loss.

Lancet Diabetes Endocrinol. 2020; 8: 418–35.