Meta-analysis fails to differentiate effect on mortality of antidiabetic drugs

Data from 301 clinical trials covering nine glucose-lowering drugs showed no significant difference between their impact on serious adverse effects.

Woman self injecting with insulin

Different classes of antidiabetic drugs have similar effects on cardiovascular or all-cause mortality in patients with type 2 diabetes, according to a network meta-analysis.

Researchers looked at data from 301 clinical trials involving nine classes of glucose-lowering drugs, including insulin. There were 177 trials of diabetes monotherapy, 109 trials of dual therapy (metformin plus another drug), and 29 trials of triple therapy (metformin, sulfonylurea and another drug).

The team found no association with any drug class, either alone or in combination, with cardiovascular death or all-cause mortality among a total of 118,094 patients with type 2 diabetes. The analysis also showed that there was nothing to distinguish between the drug classes’ effects on serious adverse events, heart attack or stroke.

“Despite more than 300 available clinical trials involving nearly 120,000 adults and 1.4 million patient-months of treatment, there was limited evidence that any glucose-lowering drug stratified by co-existing treatment prolonged life expectancy or prevented cardiovascular disease,” say the authors, led by Giovanni Strippoli, a nephrologist at the University of Bari, Italy.

The team analysed nine classes of antidiabetic drugs: metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose linked transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, basal insulin, meglitinides, and α-glucosidase inhibitors. They found that metformin monotherapy was associated with moderately lower HbA1C levels compared with other drugs and that all drugs provided additional efficacy in lowering HbA1C when added to metformin.

Reporting in JAMA
(online, 19 July 2016), the researchers say their findings support National Institute for Health and Care Excellence (NICE) guideline recommendations to use initial metformin for patients with type 2 diabetes with the addition of other drugs as needed on an individual basis.

Emily Burns, research communications manager at Diabetes UK, says: “NICE currently recommends that metformin be used as a first-line treatment for people with type 2 diabetes, and this study adds weight to that guidance.

“It’s important that people living with this condition have access to glucose-lowering medications, as they help to effectively manage type 2 diabetes and reduce the risk of serious and life-threatening complications,” she adds.

Despite the findings of the network analysis, however, some emerging evidence has suggested that SGLT2 inhibitors and GLP-1 agonists might lower the risk of cardiovascular death.

A trial of the SGLT-2 inhibitor empagliflozin[2]
showed a reduction in cardiovascular and all-cause mortality when added to standard care. And on 28 June 2016, an advisory panel at the US Food and Drug Administration (FDA) voted narrowly to support the claim by the drug’s manufacturers, Eli Lilly and Boehringer Ingelheim, that it can reduce cardiovascular mortality.

But data from the empagliflozin trial and the LEADER trial[3]
, which showed an effect of liraglutide on cardiovascular mortality in high-risk patients, were not included in the network analysis because they did not analyse the treatments as monotherapy or when added to metformin.

“Future trials might prioritise comparisons of SGLT-2 inhibitors against metformin or added to metformin to compare specific dual-therapy regimens,” the authors suggest. 


[1] Palmer SC, Mavridis D, Nicolucci A et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes. JAMA 2016;316:313-324. doi: 10.1001/jama.2016.9400

[2] Zinman B, Wanner C, Lachin J et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015. doi: 10.1056/NEJMoa1504720

[3] Marso SP, Daniels GH, Brown-Frandsen K et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-322. doi: 10.1056/NEJMoa1603827

Last updated
The Pharmaceutical Journal, Meta-analysis fails to differentiate effect on mortality of antidiabetic drugs;Online:DOI:10.1211/PJ.2016.20201516

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