Meta-Analysis Compares Cardiometabolic Effects, Safety of Once-Weekly GLP-1 Receptor Agonists

A new network meta-analysis that indirectly compared once-weekly glucagon-like peptide 1 (GLP-1) receptor agonists has revealed a few differences in their cardiometabolic effects and safety profiles.

“The number of glucose-lowering drugs in the last [few] years has increased exponentially, as different classes of drugs are now available, each acting with specific mechanisms. For the same class, moreover, several drugs are available,” study researcher Francesco Zaccardi, MD, of the Diabetes Research Centre at Leicester General Hospital in the United Kingdom, said in an email interview with Endocrinology Advisor.

“Current guidelines for the treatment of hyperglycemia in type 2 diabetes suggest considering the pros and cons for each class, with no specific indication about which drug should be preferred within the same class.”

Evaluating the Evidence

Once-weekly GLP-1 receptor agonists are relatively new glucose-lowering agents, noted Dr Zaccardi. “In this view, it was important to assess similarities and differences among these treatments to help physicians make a more informed choice.”

Adding to the growing options for the treatment of hyperglycemia, GLP-1 receptor agonists are a group of medications that inhibit glucagon and stimulate insulin. According to the paper, which was published in the Annals of Internal Medicine, they are associated with decreased food intake, slowing of gastric emptying, reduced weight, and improved glucose control. 

Although randomized, controlled trials have been conducted to assess the safety and efficacy of once-weekly GLP-1 receptor agonists compared with daily formulations, no studies have directly compared the once-weekly formulations with one another.

To estimate the comparative efficacy and safety of once-weekly GLP-1 receptor agonists in patients with type 2 diabetes, Dr Zaccardi and colleagues conducted a meta-analysis of phase 3 randomized, controlled trials lasting at least 24 weeks that involved adults with type 2 diabetes who were treated with at least 1 once-weekly GLP-1 receptor agonist.

“The analytical approach used to compare these drugs is a network meta-analysis. This method allows ‘indirect’ comparison among drugs when direct ‘head-to-head’ trials are unavailable,” explained Dr Zaccardi.

“Indeed, direct comparisons among drugs of the same class are rarely performed. Ideally, these results should be combined with future direct evidence to further help clarify their comparative tolerability and efficacy.”

In total, 35 studies met inclusion criteria, with 21 126 participants studied from 24 to 156 weeks.

All the once-weekly GLP-1 receptor agonists were linked to reductions in HbA1c and fasting plasma glucose (FPG), according to the data, while taspoglutide 20 mg and dulaglutide 1.5 mg were associated with decreases in body weight.

For HbA1c, differences were greatest between dulaglutide 1.5 mg and taspoglutide 10 mg (-0.4%; 95% CI, -0.7% to -0.2%). For FPG, differences were greatest between once-weekly exenatide and albiglutide (-0.7 mmol; 95% CI, -1.1 mmol/L to -0.2 mmol/L). For body weight, differences were greatest between taspoglutide 20 mg and dulaglutide 0.75 mg (-1.5 kg; 95% CI, -2.2 to -0.8).¹

There were no significant differences between the once-weekly GLP-1 receptor agonists for total cholesterol, diastolic blood pressure, or C-reactive protein, and only marginal differences were noted for LDL and HDL cholesterol, systolic blood pressure, and triglycerides. However, once-weekly exenatide was associated with an increased heart rate, as compared with albiglutide and dulaglutide (1.24 to 2.3 beats per minute).¹

The meta-analysis also showed that taspoglutide 10 mg, once-weekly exenatide, albiglutide, dulaglutide 1.5 mg, and dulaglutide 0.75 mg increased the risk for hypoglycemia compared with placebo. However, the risk for hypoglycemia was similar for all once-weekly GLP-1 receptor agonists studied.¹

Finally, among the once-weekly GLP-1 receptor agonists, taspoglutide 20 mg was associated with the highest risk for nausea.¹

“The results indicate several differences on key indicators of efficacy and safety. Dulaglutide 1.5 mg, once-weekly exenatide, and taspoglutide 20 mg showed a greater reduction of HbA1c, fasting plasma glucose, and body weight compared to other once-weekly [GLP-1 receptor agonists],” noted Dr Zaccardi.

“Maximum differences in absolute terms were 0.4%, 13 mg/dL, and 1.5 kg, respectively. For side effects, taspoglutide 20 mg had the highest risk of nausea while the risk of hypoglycemia among once-weekly [GLP-1 receptor agonists] was comparable.”

View Results with Caution

In an accompanying editorial, Victor Montori, MD, and Rene Rodriguez-Gutierrez, MD, both from the divisions of endocrinology, diabetes, metabolism, and nutrition research at the Mayo Clinic in Rochester, Minnesota, emphasized that the trials assessed in the meta-analysis had large losses to follow-up, inadequate blinding, and limited data on quality of life, morbidity, treatment burden, and mortality.²

“Because of the low reliability of the evidence summarized, claims of differences between agents should be met with skepticism, including rankings that suggest that, within the once-weekly preparations, exenatide and dulaglutide are associated with the biggest reduction in hemoglobin A1c level and weight while being well-tolerated,” they wrote.

The editorial also pointed out that patients and clinicians will benefit most from high-quality comparative studies so they can make informed decisions regarding treatment choice.²

“Zaccardi and colleagues’ network meta-analysis shows that meeting this basic standard in diabetes care remains, frustratingly and unfairly, a work in progress,” wrote Drs Montori and Rodriguez-Gutierrez.

Disclosure: The study was funded by a grant from Sanofi Aventis. Drs. Khunti and Davies report receiving grants and acting as consultants for pharmaceutical companies. Drs Montori and Rodriguez-Gutierrez report no relevant conflicts of interest.

References

1. Zaccardi F, Htike ZZ, Webb DR, Khunti K, Davies MJ. Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysis. Ann Intern Med. 2015;doi:10.7326/M15-1432.
2. Montori VM, Rodriguez-Gutierrez R. The Triumph of Innovation and the Hard Work of Caring for Patients With Diabetes. Ann Intern Med. 2015;doi:10.7326/M15-2610.