Issue: June 2011
June 01, 2011
2 min read

Comparable glucose control achieved with third-line therapies

Issue: June 2011
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Researchers found no apparent difference in glycemic control between diabetes drug classes in patients with type 2 diabetes who are receiving metformin and a sulfonylurea and also require a third antihyperglycemic agent.

Jorge L. Gross, MD, PhD, and researchers for the Diabetes and Endocrinology Meta-analysis Group searched for randomized trials of at least 24 weeks in duration that evaluated the effects of adding a third antihyperglycemic drug to the treatment regimen of adults with uncontrolled type 2 diabetes (HbA1c >7%) who were already receiving metformin and a sulfonylurea. The studies evaluated alpha-glucosidase inhibitors (acarbose), dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, insulin and thiazolidinediones. Their search yielded 18 trials involving more than 4,500 participants (mean duration, 31 weeks).

“In order to analyze the efficacy of the third agent, it is recommendable to conduct randomized controlled trials comparing the different antihyperglycemic classes. At least 13 to 15 studies would be needed to have a complete analysis of the alternatives and it is very unlikely that these will be conducted,” Gross told Endocrine Today. “For this reason, we decided to perform a network meta-analysis.”

Compared with placebo, the mean change in HbA1c level was similar between the drug classes studied. Mean reductions ranged from 0.7% for acarbose to 1.08% for insulin. The overall reduction in HbA1c level with all drug classes was 0.96%.

However, weight gain was seen with insulin (mean, 2.84 kg) and TZDs (4.25 kg), whereas GLP-1 agonists were associated with weight loss (–1.63 kg). In addition, insulin was associated with twice the absolute number of severe hypoglycemic episodes vs. noninsulin therapies.

“The available limited evidence does not clearly identify a preferred antihyperglycemic drug class among drugs represented in clinical trials,” the researchers said.

Several limitations of the meta-analysis were noted, including the short-term length and quality of many trials included.

“Insulin is effective, but it is associated with hypoglycemia and weight gain. Therefore, the choice of the third agent should be individualized according to the characteristics of the patients and the undesirable effects of the medications,” Gross said. – by Katie Kalvaitis

For more information:

  • Gross JL. Ann Intern Med. 2011;154:672-679.

Disclosure: Dr. Gross reports board membership for Bristol-Myers Squibb, GlaxoSmithKline, Novo Nordisk, Sanofi-Aventis and Eli Lilly. He also reports payment for development of educational presentations from Bristol-Myers Squibb, Novo Nordisk and Eli Lilly.


Zachary Bloomgarden, MD
Zachary T. Bloomgarden, MD

The researchers have chosen what is unfortunately an infelicitous base combination, that of metformin plus sulfonylurea. They, not unexpectedly, find little difference in glycemic improvement among agents, with high likelihood of weight gain from insulin and TZDs and of hypoglycemia from insulin. Incretin-based therapy also proves to be associated with these adverse effects when administered in combination with metformin plus sulfonylureas. The explanation is at least in part the uncontrolled insulin secretory effect of sulfonylureas, although sulfonylurea receptors may be present on tissues other than the beta cell to exert off-target effects. We should recall that a number of studies, begining with UKPDS, have found adverse outcome in patients receiving metformin plus a sulfonylurea. Rather than concluding "there is no difference between any of the add-on treatments," we should take a step back, as it were, to realize that reassessment of the overall therapeutic approach is needed when a patient fails to achieve adequate control on these agents.

– Zachary T. Bloomgarden, MD
Endocrine Today Editorial Board member

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