Incretin-Based Diabetes Therapies Seen as 'Modestly Effective' Option

BOSTON, July 10 -- Incretin-based therapies offer an alternative to hypoglycemic agents for type 2 diabetes with little if any weight gain, a meta-analysis showed.

However, only three of the 29 trials reviewed followed patients beyond one month of treatment, said Anastassios G. Pittas, M.D., of the Tufts-New England Medical Center here, and colleagues.

And in even short-term trials there was an increase in certain infections (RR 1.2 for nasopharyngitis and 1.5 for urinary tract infection) and headache with incretin therapies, they reported in the July 11 issue of the Journal of the American Medical Association.

"Careful postmarketing surveillance for adverse effects ? and continued evaluation in longer-term studies and in clinical practice are required to determine the role of this new class among current pharmacotherapies for type 2 diabetes," the authors wrote.

Incretin therapies use intestinal peptides released in the presence of glucose or nutrients in the gut to boost glucose-stimulated insulin secretion. The incretin effect is composed primarily of 2 peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide 1 (GLP-1). Incretins are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP4), resulting in a very short half-life (minutes).

They entered the market in April 2005 with FDA approval of exenatide (Byetta), an injectable glucagon-like peptide 1 (GLP-1) receptor analogue. Sitagliptin (Januvia), an oral dipeptidyl peptidase 4 (DPP4) inhibitor, followed with approval in October 2006.

Others are in late-stage development, including the DPP4 inhibitor vildagliptin (Galvus) and the GLP-1 analogue liraglutide, the researchers said.

To clarify the overall safety and efficacy of these agents, the researchers conducted a systematic review and meta-analysis of 29 randomized controlled trials.

Trials had to be at least 12 weeks in duration and report hemoglobin A1c (HbA1c) data in nonpregnant adults with type 2 diabetes.

Eight published trials randomized a total of 3,139 patients to a GLP-1 analogue plus existing inadequate therapy or to control (placebo, metformin, or open-label insulin). One study used a long-acting formulation of a GLP-1 analogue in 45 patients.

Thirteen published trials with 4,780 patients compared a DPP4 inhibitor to placebo whether monotherapy or add-on therapy. Another four trials with 3,053 patients compared a DPP4 inhibitor with a hypoglycemic agent-glipizide (Glucotrol), metformin, or a thiazolidenedione. Three DPP4 studies were used only for certain meta-analyses.

Pharmaceutical companies funded all of the studies.

The dropout rate was high (about 20%), primarily because of glycemic control issues with placebo and gastrointestinal side effects with exenatide, the researchers said.

Among the GLP-1 analogue findings, the investigators reported:

• HbA1c decline from baseline was significantly better with GLP-1 agents overall than with placebo (weighted mean difference ?0.97%, 95% confidence interval ?1.13% to ?0.81%).
• HbA1c levels were no different with exenatide than with insulin in open-label noninferiority studies (weighted mean difference -0.06%, 95% CI -0.22% to 0.10%).
• HbA1c efficacy was similar with liraglutide and either open-label glimepiride (Amaryl) or metformin.
• Patients were more likely to reach HbA1c below 7% on exenatide than placebo (risk ratio 4.2, 95% CI, 3.2 to 5.5) but not compared with insulin (RR 1.1, 95% CI 0.8 to 1.5).
• GLP-1 analogues reduced fasting plasma glucose significantly more than placebo (weighted mean difference ?27 mg/dL, 95% CI ?33 to ?21 mg/dL).
• Fasting plasma glucose was not reduced more by exenatide than insulin in open-label studies (weighted mean difference 13 mg/dL, 95% CI ?16 to 41 mg/dL).

Among the DPP4 inhibitor findings, the researchers found:

• DPP4 inhibitors lowered HbA1c significantly more than placebo overall (weighted mean difference ?0.74%, 95% CI ?0.85% to ?0.62%) whether as monotherapy or add-on therapy.
• Sitagliptin and vildagliptin appeared to reduce HbA1c similarly versus placebo (?0.74% versus ?0.73%).
• DPP4 inhibitors were less effective than other hypoglycemic agents at reducing HbA1c (weighted mean difference 0.21%, 95%CI 0.02% to 0.39%).
• Patients on DPP4 inhibitors achieved HbA1c below 7% more often than those on placebo (RR 2.5%, 95% CI 2.1 to 2.8).
• DPP4 inhibitors reduced fasting plasma glucose more than placebo (weighted mean difference ?18 mg/dL, 95% CI ?22 to ?14 mg/dL).
• Sitagliptin reduced fasting plasma glucose more than vildagliptin (weighted mean difference ?22 versus ?12 mg/dL).

For both types of incretin therapy, "the modest effectiveness may, at least in part, be also attributed to participants' relatively low baseline HbA1c (about 8%)," Dr. Pittas and colleagues wrote.

The GLP-1 analogues appeared to promote weight loss (weighted mean difference ?2.37 kg versus control, 95% CI ?3.95 to ?0.78).

The DPP4 inhibitors appeared "weight neutral," according to the authors, although they showed a small weight gain versus placebo over 30 days (weighted mean difference 0.5 kg, 95% CI, 0.3 to 0.7 kg).

Hypoglycemia was relatively rare with both classes, but they did show other notable short-term side effects.

GLP-1 analogues increased gastrointestinal side effects (RR 2.9 for nausea and 3.2 for vomiting).

DPP4 inhibitors increased risk of headache (RR 1.4) and infection (RR 1.2 for nasopharyngitis and 1.5 for urinary tract infection), which reinforces concerns about long-term effects of these agents on immune function, the researchers said.

"Although the relative risk we measured was small, its implications in clinical practice are significant" because so many patients have diabetes, the researchers said.

The urinary tract infection risk with DPP4 agents has the potential to increase incidence by 1 million cases per year, they added, "placing a significant burden on the individual patient and the health care system."

"Individuals with mild diabetes, suggesting an adequate pancreatic cell reserve, who are at risk of hypoglycemic sequelae and in need of weight loss may benefit from this new class," they concluded, though long-term efficacy and safety remain unknown.