Glucose-lowering drugs or other strategies that lower glucose reduced the risk of fatal and nonfatal cardiovascular (CV) events as well as all-cause mortality in patients with, or at risk for, type 2 diabetes, an updated systematic review and meta-analysis of cardiovascular disease (CVD) outcome trials has shown.
In contrast, the same strategies had no effect on heart failure although modest weight loss did lower the incidence of heart failure in patients with and without CVD at baseline, the same meta-analysis found.
In a systematic review and meta-analysis of CVD outcome trials published in 2015, researchers found that a variety of glucose-lowering drugs or strategies in patients with or at risk for type 2 diabetes led to a modest 5% relative risk reduction in CV events, driven by an 8% reduction in non-fatal myocardial infarction (MI), Olivia Ghosh-Swaby, Schulich School of Medicine and Dentistry, Western University, London, Ontario and colleagues pointed out in the Lancet Diabetes & Endocrinology.
However, this gain came at the expense of an overall relative risk increase in the incidence of heart failure, they also noted.
With an additional 16 outcome trials now incorporated into the previous meta-analysis, overall, glucose-lowering drugs or strategies significantly decreased the risk of major acute cardiovascular events (MACE) by 8% at a relative risk reduction of 0.92 (95% CI, 0.89-0.95; P<0.001), investigators reported.
The updated meta-analysis also showed that a 1 kg difference in weight between treatment groups in the outcome trials led to a 5.9% (95% CI, 3.9-8.0%) difference in the relative risk of heart failure (P<0.0001).
Importantly, however, glucose-lowering drugs or strategies per se had no effect on the risk of heart failure compared with standard care or placebo.
Drugs that lower body weight include the SGLT2 inhibitors (also called the gliflozins), the glucagon-like peptide-1 (GLP-1) receptor agonists as well as intensive lifestyle change.
“To the best of our knowledge, our study is the most comprehensive meta-analysis of large cardiovascular outcome trials in people with or at risk of type 2 diabetes,” Ghosh-Swaby and colleagues stated.
“These data suggest a potential broad cardiovascular benefit of using diabetes therapies that reduce bodyweight in routine clinical practice,” the authors suggested.
The updated review and meta-analysis included a total of 30 trials involving a total of 225,305 participants.
“The primary outcomes of interest were heart failure and MACE (defined as a composite of cardiovascular death, myocardial infarction, or stroke),” researchers explained.
During a mean follow-up of 3.8 years, 10.2% of trial participants experienced a MACE: 3.6% had heart failure; 4.9% had an MI; 2.9% had a stroke and 4.5% died from any CV cause. Some 7.3% of participants died from any cause.
Overall, glucose-lowering drugs or strategies significantly reduced the risk for all components of the primary outcomes of interest, leading to:
- An 8% reduction in fatal and non-fatal MI (RR 0.92; 95% CI, 88-0.96; P=0.0002).
- A 7% reduction in fatal and non-fatal stroke (RR 0.93; 95% CI, 0.89-0.98; P=0.006).
- An 8% reduction in CV death (RR 0.92; 95% CI, 0.87-0.97; P=0.004).
- A 6% reduction in all-cause mortality (RR 0.94; 95% CI, 90-0.98; P=0.004).
“There was also a [19%] reduced risk of heart failure overall with therapies or strategies that lower bodyweight,” the authors noted, at a RR of 0.81 (95% CI, 0.74-0.89; P<.0001).
However, the reduction in the risk of heart failure at 32% was much higher with SGLT2 inhibitors at a RR 0.68 (95% CI, 0.60-0.76; P<0.0001) than it was for intensive lifestyle change at 20% (RR 0.80; 95% CI, 0.621.04; P=0.10) or with GLP-1 receptor agonists at 9% (RR of 0.91; 95% CI, 0.84-0.99; P=0.049), investigators added.
MACE risk reduction with therapies or strategies that reduce body weight was also consistent among study participants with or without CVD at baseline as well as those with and without baseline heart failure or chronic kidney disease.
The authors also found significant risk reductions ranging from 10% to 15% for MACE, all-cause mortality, MI, and stroke when they confined the analysis to therapies or strategies that lower body weight.
“The results from our updated analysis dispel perceptions that risk reduction for MACE is confined to GLP-1 receptor agonists and that for heart failure is confined to SGLT2 inhibitors,” researchers observed.
“Our results also emphasize that intensive lifestyle changes still warrant consideration,” they added, even though the authors acknowledged that adherence to intensive lifestyle change can be difficult and thus less effective than drugs that facilitate easier weight loss.
Commenting on the findings, Angelo Avogaro, MD, and Gian Paolo Fadini, MD, both from the University of Padova in Italy, pointed out that even though the incidence of MACE was reduced in 3 out of 4 reported SGLT2 inhibitor trials and 4 out of 6 GLP-1 receptor agonist trials, treatment effects on each of the components of MACE varied between the trials.
“This is an important shortcoming because, in the clinic, patients experience one event at a time, not a composite outcome,” Avogaro and Fadini pointed out.
The editorialists also noted that “probably the most intriguing observation” from the current study was the fact that for every 1 kg of body weight lost with glucose-lowering interventions, there was a 5.9% decrease in the relative risk of heart failure, driven by, but not limited to, SGLT2 inhibitor trials.
“Thus, weight loss emerges as a major driver of a drug’s ability to reduce heart failure risk,” they observed.
However, the beneficial effect of weight loss, normally associated with loss of visceral fat, may not explain the CV benefit seen in this particular patient population.
Instead, body fluid status may be more important than visceral fat loss to explain the CV benefit seen in this meta-analysis, the editorialists suggested. For example, the glitazones increase subcutaneous fat, though not visceral fat, and they can also precipitate heart failure by causing fluid overload.
“By contrast, change in body composition with SGLT2 inhibitors is a topic of some controversy, but reduction of extracellular volume could account for [their] protection from heart failure,” Avagaro and Fadini said.
The editorialists also observed that insulin does not protect patients from— nor worsen—heart failure in patients with diabetes in spite of the fact that insulin often induces weight gain and causes fluid retention.
“Thus, the mechanism by which modest weight loss could protect [patients] from heart failure remains elusive,” the editorialists wrote.
“[This] meta-analysis… once more establishes GLP-1 receptor agonists and SGLT2 inhibitors as disease-modifying drugs,” they emphasized.
Strategies that lower glucose including drugs like the SGLT2 inhibitors and the GLP-1 receptor agonists reduced fatal and nonfatal CV events in patients with or at risk for type 2 diabetes.
A modest weight loss of only 1 kg through drugs or lifestyle change significantly reduced the risk of heart failure in patients with or at risk for type 2 diabetes.
Pam Harrison, Contributing Writer, BreakingMED™
Ghosh-Swaby has received research grant support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring,
Daiichi Sankyo, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen/Johnson & Johnson, Matrizyme, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, and Tenax Therapeutics. She has also received speaker or consulting honoraria (advisory boards) from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Fenix Group International, Ferring Pharmaceuticals, HLS Therapeutics, Merck, Novartis, Pfizer, Regeneron, Sanofi, and Tenax Therapeutics.
Avogaro has received research grants, lecture fees, or advisory board fees from Merck Sharp & Dohme, AstraZeneca, Novartis, Mundipharma, Boeringher Ingelheim, Sanofi, GlaxoSmithKline, Novo Nordisk, Lilly, Servier, and Takeda.
Fadini has received lecture fees or grant support from Abbott, AstraZeneca, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme, Mundipharma, Novartis, Novo Nordisk, Sanofi, and Servier.
Cat ID: 12
Topic ID: 76,12,730,914,12,13,669,918