ADA: New Class of Anti-Diabetic Agents Under Review by FDA

A novel category of oral antidiabetic agents that increase glucagon synthesis and improve beta cell function are showing “robust efficacy” and “placebo-like tolerability,” in the words of one investigator. The new drugs are the glucagon-like-peptide-1 (GLP-1) analogs and the dipeptidyl peptidase-4 (DPP-4) inhibitors, which increase endogenous GLP-1 levels. –

Results of a number of studies — with the DPP-4 inhibitors vildagliptin (Galvus; Novartis Pharmaceutical) and sitagliptin phosphate (Januvia; Merck) and the GLP-1 analog liraglutide (Novo Nordisk) – were presented at the ADA 66th Scientific Sessions..

INDs for Galvus and Januvia have been submitted to the FDA.

Dr. Ameet Nathwani of Novartis in Basel, Switzerland, presented findings of a six-month phase III study testing vildagliptin and pioglitazone in 592 treatment-naive type 2 diabetics who had baseline hemoglobin A1c levels between 7.5% and 11%. Patients were randomized to one of four treatment arms: vildagliptin 100 mg daily; pioglitazone 30 mg daily; vildagliptin 50 mg plus pioglitazone 15 mg daily; or vildagliptin 100 mg plus pioglitazone 30 mg daily.

The DPP-4 inhibitor had "a robust efficacy," Dr. Nathwani announced. Among the subgroup with baseline hemoglobin A1c levels of 9% or higher, combination therapy lowered A1c levels 2.8%. Vildagliptin had particularly potent effects in the elderly, with A1c levels reduced by 2.3% for a mean A1c level of 6.2%.

Patients in the high-dose combination arm had A1c levels reduced by 1.9% compared with 1.4% with high-dose pioglitazone alone. Two-thirds of patients in the trial achieved target A1c levels of 7% or below.

Vildagliptin had "placebo-like tolerability," Dr. Nathwani reported.

Dr. Nathwani also reported findings from a second trial involving 700 type 2 diabetics, which was a head-to-head comparison of vildagliptin 100 mg and rosiglitazone 8 mg daily. Both drugs showed equal efficacy, lowering hemoglobin A1c levels by 1.1%.
The incidence of edema was 2.5% with vildagliptin and 4.9% with rosiglitazone. There was no weight gain with the DPP-4 inhibitor compared with a 1.6 kg gain with rosiglitazone over the course of six months. For the subgroup of severely obese patients, those on the DPP-4 inhibitor lost 1 kg, for a difference of 2.8 kg between the groups after six months of treatment.
Dr. Nathwani told Diabetes In Control that the most effective treatment strategy would be a combination of a DPP-4 inhibitor and metformin or one of the thiazolidinediones. That would affect insulin secretion directly and indirectly.

Merck investigator Dr. Peter Stein reported similar results of several studies with sitagliptin. In patients with mildly to moderately elevated A1c levels (ranging from 7.5% to 8.1%), sitagliptin reduced A1c by 0.60% to 1.05%. Again, patients with the highest A1c levels at baseline had the greatest reductions, and the safety profile was similar to that of placebo.

Studies with Novo Nordisk’s liraglutide, reported by Dr. Tina Vilsboell of Genofte University Hospital in Copenhagen, Denmark, showed that the drug, an analog of the naturally occurring GLP-1, increased beta cell secretion of insulin in 165 patients with type 2 diabetes enrolled in a 14-week phase II trial.

In patients on liraglutide 1.25 mg or 1.9 mg daily, beta cell secretion of insulin was increased 97% and 114%, respectively, compared with placebo.

In a subgroup of 39 patients, Dr. Vilsboell and colleagues measured first phase insulin secretion, which is typically blunted in types 2 diabetes. The researchers found that liraglutide 1.25 mg and 1.9 mg increased first phase insulin secretion 107% and 124%, respectively.

Dr. Vilsboell added that body weight decreased linearly with liraglutide throughout the 14-week study. There was a 3 kg loss with active treatment. Dr. Vilsboell predicted that "longer studies would have probably led to more weight loss."

Dr. Vilsboell said in an interview ,"The DPP-4 inhibitors don’t appear to have much effect on weight. We don’t know why that is." .

Presented at the 66th annual Scientific Sessions of the American Diabetes Association

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