The use of GLP-1 receptor agonists in type 2 diabetes patients may prevent multiple risks.
One of the most important aspects of treating patients with diabetes is preventing both non-fatal and fatal cardiovascular events. Previous studies on Glucagon-like peptide-1 receptor agonists have shown inconsistent effects on cardiovascular outcomes in patients who have type 2 diabetes. Therefore, this systematic review and meta-analysis was done to examine the effects of the GLP-1 agonists on cardiovascular outcomes, kidney outcomes, and safety outcomes.
This study included large randomized, placebo-controlled trials that included patients with type 2 diabetes. They focused on studies that included primary outcomes of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Searches were made from MEDLINE and Cochrane Central Register of Controlled Trials up to June 15, 2019. Risk of bias was assessed. Outcomes of interest included a composite outcome of cardiovascular death, myocardial infarction, and stroke (MACE). Kidney outcomes included worsening of kidney function, new-onset macroalbuminuria, decline in estimated glomerular filtration (eGFR), progression to end stage renal disease, and death as a result of a kidney outcome. Safety outcomes included severe hypoglycemia, pancreatitis, pancreatic and thyroid cancers, and retinopathy. Treatment effects on MACE components were assessed by comparing primary vs. secondary preventions, high vs. low HbA1c, short vs. long duration of follow-up, daily vs. weekly drug dosing, human GLP-1 homology of the GLP-1 receptor agonist, BMI <30 kg/m2 vs. higher, age <65 vs. higher, and baseline eGFR <60 mL/min per m2 vs. higher. For statistical analysis, pooled hazard ratios were used, and heterogeneity was assessing by I2 along with Cochran’s Q test. Number needed to treat (NNT) for each outcome was determined to measure absolute risk for each outcome using the method of Altman and Anderson.
ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide),9 EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide) were included in this review. The trials yielded a total of 56,004 patients. In six of the seven trials, HbA1c mean difference between treatment groups was 0.3-0.7%. Mean age at baseline ranged from 60 to 66. Proportion of women ranged from 31% to 46%. Established cardiovascular disease at baseline ranged from 31% to 100%. Median eGFR ranged from 74 to 80 mL/min/m2. Estimated median follow-up was 3.2 years. Only ELIXA enrolled patients with recent acute coronary syndrome; other trials had patients with stable CV disease or CV risk factors. Treatment with a GLP-1 receptor agonist led to a 12% decrease in MACE (pooled HR 0.88, 95% CI: 0.82—0.94; p<0.0001). NNT to prevent MACE was 75 (95% CI 50-151). When assessing MACE individually, reduction in risk of death from a cardiovascular cause (HR 0.88, 95% CI 0.81–0.96; p<0.0001), fatal or nonfatal stroke (0.84, 0.76–0.93; p<0.0001), and fatal or nonfatal myocardial infarction (0.91, 0.84–1.00; p=0.043). No statistical heterogeneity was found between primary prevention groups and patients with cardiovascular disease at baseline, baseline HbA1c, shorter vs. longer follow-up period, or drug dosing interval. GLP-1 agonists reduced all-cause mortality by 12% (HR 0.88, 95% CI 0.83–0.95; p=0.001). NNT to prevent one death of 108 (77–260). Risk of hospital admission for heart failure was reduced by 9% (HR 0.91, 95% CI 0.83–0.99; p=0.028). NNT to prevent one event of 312 (165–2810). Regarding Kidney outcomes, a reduction of 17% (HR 0.83, 95% CI 0.78–0.89), with an NNT to prevent one event of 62 (48–96) as a result of reduction in urinary albumin excretion. Effect on worsening of kidney function outcome was not significant. The likelihood of severe hypoglycemia, pancreatitis, retinopathy, pancreatic and thyroid cancer did not differ between placebo and GLP-1 agonists. Subgroup analysis provided that the reduction in relative risk in primary prevention was not like secondary prevention (HR 0.95 (95% CI 0.83–1.08) for primary prevention and 0.86 (0.79–0.94) for secondary prevention (pinteraction=0.22). Low vs high HbA1c, shorter vs. longer trial follow-up (<3 years vs ≥3 years), daily vs weekly dosing had no heterogeneity for the effect of GLP-1 receptor agonist therapy. Possible insignificant heterogeneity was found in lixisenatide and exenatide (both are more homologous with human GLP-1).
Overall, this study established the cardiovascular benefit of using GLP-1 agonists to patients’ drug regimen for managing type 2 diabetes. A benefit that was highlighted was the reduction of hospitalization for heart failure by GLP-1 agonists. A proposed mechanism would be an anti- atherothrombotic effect. The risk of pancreatitis, pancreatic cancer, and thyroid cancer was eliminated by this review. Future studies should further investigate the great reduction in myocardial infarction produced by albiglutide and liraglutide. Limitations include not having systemic eye examinations implemented by the studies and not having patient-level data.
- The addition of GLP-1 receptor agonists can reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with type 2 diabetes.
- Treatment with GLP-1 receptor agonists decreases the development of macroalbuminuria resulting in decreasing the risk of worse kidney function.
- GLP-1 receptor agonists do not have the risk for severe hypoglycemia, pancreatitis, pancreatic cancer, or thyroid cancer.
Kristensen, Søren L, et al. “Cardiovascular, Mortality, and Kidney Outcomes with GLP-1 Receptor Agonistsin Patients with Type 2 Diabetes: a Systematic Review and Meta-Analysis of Cardiovascular Outcome Trials.” The Lancet Diabetes & Endocrinology, 2019
Nour Salhab, Pharm.D. Candidate, USF College of Pharmacy
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