Diabetes Pipeline: New Strategies Emerging for Glycemic Control

Web Exclusives - Pipeline
Wayne Kuznar

Several new classes of drugs in the pipeline to improve glycemic control, including a rapid-acting inhalable insulin using a new technology, were featured at the 2009 annual meeting of the American Diabetes Association (ADA).

Attacking the Kidney’s Sodium Glucose Cotransporter

Inhibitors of sodium glucose cotransporter (SGLT)-2 offer an alternate way to reduce fasting glucose and hemoglobin (Hb) A1c levels, independent of acting on insulin.

Dapagliflozin is an SGLT-2 inhibitor that is in phase 3 clinical trials. SLGT-2 inhibitors block the receptor in the proximal convoluted tubule in the kidney that is responsible for glucose reabsorption. Blocking this receptor increases urinary glucose excretion, thereby reducing fasting glucose levels and increasing urinary glucose secretion and urinary volume, leading to improvements in glucose levels and weight loss.

Dapagliflozin reduces fasting glucose levels in a dosedependent manner. At doses >2.5 mg, its effect on fasting glucose is greater than that of 1500 mg of metformin.

Results of a study presented at the ADA meeting demonstrated that dapagliflozin decreased HbA1c, fasting plasma glucose, and postprandial glucose levels, and resulted in weight loss when added to insulin and oral insulin sensitizers in insulin-resistant patients with type 2 diabetes.

Typical weight loss with SGLT-2 inhibitors is 2.5 kg to 3.4 kg. Because SGLT-2 inhibitors act independently of insulin, the risk of hypoglycemia is low.

New Human GLP-1 Analogs

Liraglutide is a human glucagon-like peptide (GLP)-1 analog currently under review by the Food and Drug Administration (FDA). Switching from twice-daily exenatide (Byetta) to the investigational once-daily liraglutide improved glycemic control in patients with type 2 diabetes on a background of metformin and/or a sulfonylurea.

“It seems that liraglutide lowers A1c a bit more [than exenatide], lowers fasting glucose a lot more, lowers postprandial glucose a little bit less, seems to have a modestly better effect on blood pressure and lipids, and is modestly better tolerated with regard to nausea and mild hypoglycemia,” said John Buse, MD, PhD, Professor and Chief of Endocrinology at the University of North Carolina, Chapel Hill.

Liraglutide was compared with exenatide in a 26-week randomized trial, Liraglutide Effect and Action in Diabetes 6 (LEAD-6), which demonstrated liraglutide to be superior to exenatide in improving HbA1c levels and beta-cell function in patients with type 2 diabetes receiving background oral therapy.

According to data from a 14-week extension of LEAD-6, patients initially randomized to exenatide were switched to liraglutide, and those initially assigned to liraglutide continued receiving the drug. Among those who switched, mean HbA1c levels decreased by 0.3% (P <.001). After switching, treatment HbA1c levels were similar to those in the patients who continued taking liraglutide.

During the extension phase, the proportion of patients who reached HbA1c <7.0% increased from 43% to 57% among patients who switched from exenatide to liraglutide, and from 54% to 61% among those who remained on liraglutide.

Albiglutide is a long-acting GLP-1 receptor antagonist that was shown to consistently improve measures of glycemia in patients with type 2 diabetes. With a half-life of about 5 days, weekly dosing of albiglutide appears optimal, although biweekly dosing may offer a maintenance option.

New Form of Inhaled Insulin

Technosphere Insulin, an ultra-rapid-acting inhalable insulin powder, is composed of recombinant human insulin adsorbed onto Technosphere particles. When given at mealtime in combination with basal insulin in patients with type 2 diabetes, its glycemic efficacy is comparable with that of twice-daily premixed insulin analog 70/30, according to phase 3 data presented at the ADA meeting. There was less risk of weight gain and hypoglycemia with Technosphere Insulin.

The inhaled insulin is dissolved immediately on contact with the lung surface, and the insulin is rapidly absorbed into systemic circulation. Most of the glucose-lowering effect occurs in the first 3 hours. A new drug application has been filed with the FDA for the treatment of hyperglycemia.

In the study, mean weight gain was significantly less with Technosphere Insulin (0.9 kg vs 2.5 kg; P = .002). There were no differences in pulmonary function at week 52 between the 2 groups.

New DPP IV inhibitors

Linagliptin (BI 1356), a dipeptidyl peptidase 4 (DPP-IV) inhibitor, is currently being studied in 5 pivotal phase 3 clinical trials that include >4000 patients as an oral once-daily tablet for the treatment of type 2 diabetes. These trials are fully recruited and underway globally.

Data from a phase 2 clinical trial of linagliptin were presented at the meeting, showing that doses of 1 mg, 5 mg, and 10 mg of linagliptin achieved significant reductions that were clinically relevant in HbA1c levels when given as add-on therapy to patients with type 2 diabetes who are inadequately controlled with metformin.

Saxagliptin, another DPP-IV inhibitor, was recently approved by the FDA as a once-daily tablet for patients with inadequately controlled type 2 diabetes. When used in combination with metformin as initial therapy, saxagliptin produced reductions across all key measures of glucose control in treatment-naïve patients with type 2 diabetes whose blood glucose levels were inadequately controlled.

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Last modified: February 14, 2019
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