Bustling Pipeline for Diabetes and Its Metabolic Consequences

July/August 2008, Vol 1, No 6
Wayne Kuznar

A number of drugs in late stages of development were featured at the 2008 annual meeting of the American Diabetes Association.
 

SGLT-2 Inhibitors


Sodium glucose contransporter type 2 (SGLT-2) inhibitors, which reduce glucose levels by increasing kidney excretion of glucose, is a novel class designed to treat hyperglycemia.

Dapagliflozin is the first SGLT-2 inhibitor in a phase 3 clinical trial. In patients with type 2 diabetes, dapagliflozin reduces fasting glucose levels by about 20 mg/dL versus placebo and improves oral glucose tolerance. By 12 weeks, hemoglobin (Hb)A1C levels decline by 0.7% to 0.9% (from a baseline of 7.1% to 8.0%). Patients using dapagliflozin have lost an average of 2.5 to 3.5 kg of body weight.

Potential side effects of dapagliflozin include polyuria, recurrent urinary tract infections, salt wasting/dehydration, and electrolyte imbalance/depletion.
 

Exenatide


A long-acting once-weekly formulation of exenatide was found in an open-label, 30-week phase 3 trial to significantly improve HbA1C and fasting plasma glucose from baseline. More patients using once-weekly exenatide achieved an HbA1C of )7% than patients using exenatide twice daily (67% vs 61%; P = .004).

A second study showed that twice-daily exenatide was effective as monotherapy in reducing HbA1C and causing weight loss. A new drug application (NDA) has been submitted for twice-weekly exenatide as stand-alone therapy (it is currently only indicated for use with oral antidiabetic agents).
 

Liraglutide


Liraglutide, a once-daily human glucagon-like peptide-1 analog, significantly reduced HbA1C levels in a 26-week phase 3 trial of 1091 patients with type 2 diabetes previously treated with oral antidiabetic drugs. In contrast to the combination of metformin and glimepiride, liraglutide resulted in weight loss and few episodes of hypoglycemia.
 

More DPP-IV Inhibitors


Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-IV) inhibitor being developed as a once-daily oral treatment for type 2 diabetes. Several phase 3 trials of alogliptin as monotherapy and in combination with insulin, metformin, sulfonylureas, or pioglitazone showed improvements in glycemic control as monotherapy or as add-on therapy.

As monotherapy, alogliptin was superior to placebo in reducing HbA1C levels in a 12-week randomized, double-blind, dose-ranging study of 223 patients with type 2 diabetes. It was not associated with weight gain.

When added to insulin, alogliptin significantly improved glycemic control as early as week 4 in a 26-week randomized, placebo-controlled, double-blind phase 3 international trial of 390 patients with type 2 diabetes.

Saxagliptin is a reversible inhibitor of DPP-IV with dual routes of clearance that is being studied as oncedaily treatment. In a 24-week placebo-controlled phase 3 study of 401 patients with type 2 diabetes, saxagliptin monotherapy was associated with significant reductions in HbA1C, fasting plasma glucose, and postprandial glucose in treatment-naïve patients. An NDA for saxagliptin was submitted at the end of July.
 

New Fibrate for Mixed Dyslipidemia


When used in combination with rosuvastatin, an investigational fenofibric acid molecule (ABT-335), submitted for approval to the US Food and Drug Administration, treats mixed dyslipidemia in patients with type 2 diabetes better than rosuvastatin alone.

The combination of ABT-335 and rosuvastatin was evaluated in 276 patients with type 2 diabetes and mixed dyslipidemia.

ABT-335 plus 10 mg rosuvastatin increased high-density cholesterol by 21% compared with a 6.6% increase with 10 mg of rosuvastatin alone (P = .001) and decreased triglycerides by 44.7% compared with 37.1% with 10 mg rosuvastatin monotherapy. ABT-335 plus 20 mg rosuvastatin was also significantly superior to 20 mg rosuvastatin alone.

A fixed-dose combination of ABT-335 and rosuvastatin is in development, for which an NDA is expected to be submitted in 2009.

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