Meta-analysis Supports ADA Guidelines for Type 2 Diabetes Drugs

Marlene Busko

July 19, 2016

In a systemic review and network meta-analysis, the available drugs classes for type 2 diabetes were associated with similar odds of cardiovascular and all-cause mortality. Patients receiving metformin monotherapy had lower HbA1c levels than or similar to those receiving sulfonylureas, thiazolidinediones, or α-glucosidase inhibitor monotherapy.

These findings support the current American Diabetes Association (ADA) recommendations for initial monotherapy with metformin for type 2 diabetes patients, followed by individualized therapy, according to the researchers, with lead author Suetonia C Palmer, PhD, from the University of Otago, New Zealand, and senior investigator Giovanni FM Strippoli, PhDm from the University of Sydney, Australia and Diaverum, Sweden.

The study, which was published in the July 19 issue of the Journal of the American Medical Association, looked at nine classes of antidiabetic drugs: metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose linked transporter 2 (SGLT2) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, basal insulin, meglitinides, and α-glucosidase inhibitors.

The researchers analyzed data from 177 trials of diabetes monotherapy, 109 trials of dual therapy (defined as metformin plus another drug), and 29 trials of the most widely used triple therapy (metformin, sulfonylurea, and another drug).

"Our study shows that metformin is as good as most other treatments for lowering blood glucose, and when patients particularly wish to avoid weight gain, GLP-1 receptor agonists as single treatment are a good start," Drs Palmer and Strippoli told Medscape Medical News in an email.

The study doesn't answer the question about whether some patients should receive insulin as a first-line treatment, although it suggests that metformin is as good as basal insulin, they note.

"We need large-scale trials that compare different drugs with each other, used as monotherapy or added to metformin," they urge. Future trials should consider using real-world settings in individuals at higher risk of death, since the rates of cardiovascular mortality were very low in the individual trials in this network analysis.

"Efficient trial design will facilitate these types of studies being done in real-life clinical care and at a much lower cost than existing trials, which can be very expensive," according to the researchers.

Nine Classes of Glucose-Lowering Drugs, EMPA-REG, LEADER Excluded

Head-to-head clinical trials of therapies for type 2 diabetes cannot compare all treatments simultaneously, Dr Palmer and colleagues write. Thus, they conducted a systematic review and network meta-analysis to compare and rank nine drug classes of glucose- lowering treatments for type 2 diabetes.

This type of analysis allows indirect comparisons of different glucose-lowering drugs, Drs Palmer and Strippoli explain. "For example, if there is no trial that directly compares a GLP-1 receptor agonist with an SGLT2 inhibitor, but there are trials of each drug class vs placebo, the trials are combined" in a network analysis, whereas "a standard meta-analysis, on the other hand, looks only at head-to-head trials."

The study excluded trials that did not specifically analyze glucose-lowering agents as monotherapy or dual therapy when added to metformin or as triple therapy when added to metformin and sulfonylurea.

Thus, the study excluded the recently reported Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) of the SGLT2 inhibitor empagliflozin (Jardiance, Lilly/Boehringer Ingelheim); the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial of the GLP-1 receptor agonist liraglutide (Victoza, Novo Nordisk); and the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial of the GLP-1 receptor agonist lixisenatide (Lyxumia, Sanofi).

Two of these large cardiovascular safety outcomes trials did show the mortality benefits of glucose-lowering agents, most recently the LEADER trial, reported at the American Diabetes Association (ADA) 2016 Scientific Sessions, and EMPA-REG, presented at the European Association for the Study of Diabetes (EASD) 2015 Meeting. An FDA advisory committee recently narrowly recommended a new labeling claim, that of reduced cardiovascular mortality, for empagliflozin.

300 Clinical Trials, 1.4 Million Patient-Months of Treatment

The researchers identified 301 clinical trials that met the study criteria. The primary end point was cardiovascular mortality and secondary end points were all-cause mortality, myocardial infarction (MI), stroke, HbA1c, treatment failure (lack of efficacy or need for rescue treatment), serious adverse events, hypoglycemia, and body weight.

Patients had a mean HbA1c of 8.2% to 8.4% and had had diabetes for a median of 5.7 years. They were followed for a median of 6 months.

There were no significant differences between any drug class (as monotherapy, dual therapy, or triple therapy) and the odds of cardiovascular or all-cause mortality. However, there were few or no cardiovascular deaths in most of the available studies.

There was also no evidence of differences in associations between glucose-lowering drugs alone or in combination with the odds of serious adverse events, MI, or stroke.

Reductions in HbA1c were larger with monotherapy than placebo, and metformin was associated with moderately lower HbA1c than sulfonylurea (standardized mean difference [SMD] 0.18), thiazolidinedione (0.16), DPP-4 inhibitor (0.33), and α-glucosidase inhibitor (0.35).

Importantly, sulfonylurea and basal insulin were associated with a 10% higher risk of hypoglycemia compared with metformin.

When added to metformin, the different drugs were associated with similar HbA1c, but SGLT2 inhibitors were associated with the lowest odds of hypoglycemia (OR, 0.12).

When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60).

"A central finding in this meta-analysis was that 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 coexisting treatment prolonged life expectancy or prevented cardiovascular disease," Dr Palmer and colleagues write.

In contrast, the EMPA-REG OUTCOME trial demonstrated reductions in cardiovascular and all-cause mortality with empagliflozin added to existing care among type 2 diabetes patients at high cardiovascular risk, while liraglutide added to standard care in the LEADER trial reduced cardiovascular and all-cause death among a similar population of patients.

Future Studies Needed

Although the "EMPA-REG OUTCOME and LEADER trials show benefit for SGLT2 inhibitors and GLP-1 receptor agonists against placebo...we have limited information that one drug is better than another," Drs Palmer and Strippoli explain.

Trial outcomes are often surrogate measures of effect (HbA1c) rather than important clinical outcomes such as mortality, they add, and "the vast majority of trials in this field are industry-led, short duration, and principally done to measure interim outcomes."

Future studies are needed to compare outcomes with these newer SGLT2 inhibitors and GLP-1 receptor agonists vs metformin as monotherapy or added to metformin as dual therapy.

Dr Palmer reported receiving a research grant from the Royal Society of New Zealand and Amgen Dompé. Dr Strippoli reported receiving a research grant from Agenzia Italiana del Farmaco during the study and receiving personal or consultancy fees from Servier Laboratories. Disclosures for the coauthors are listed in the article.

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JAMA. 2016;316:313-324. Abstract

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