New Agents Hold Promise in Diabetes Treatment

Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors and bile acid sequestrants hold promise for the treatment of type 2 diabetes. Both were among the agents highlighted in the symposium, “Novel Therapies for Type 2 Diabetes -- Today and Tomorrow,” at the American Diabetes annual meeting in San Diego

SGLT-2 inhibitors, eight of which are in clinical trials, are the first class of drugs to target renal glucose reabsorption for treating diabetes, said Ernest M. Wright, PhD, DSc, of UCLA. By increasing the urinary excretion of glucose, SGLT2 inhibition reduces blood glucose levels.

“Reabsorption of glucose in the kidney is not essential for life,” as illustrated by the benign nature of familial renal glycosuria, Wright siad. However, this novel class of therapies may have a downside. “So far, there are no remarkable adverse effects, but since SGL2 expression occurs throughout the body, we need to be curious about off target sites,” he said.

Among the SGLT2 compounds in development for blood glucose control are dapagliflozin.

Researchers presented results of a 104-week phase 3 study of dapagliflozin. Sustained reductions in blood glucose levels as well as body weight characterized study patients taking dapagliflozin added to metformin. In contrast, patients taking glipizide added to metformin gained weight Change from baseline in HbA1c in patients receiving glipizide plus metformin was 0.02 percent , compared to -0.48 percent for those treated with dapagliflozin (dap) 2.5 mg plus metformin (met); -0.58 percent for patients on dap 5 mg plus met; and -0.78 percent for those on dapa10 mg plus met. However, genital infections or urinary tract infections were more common in patients taking dap added to met.

David J. Mangelsdorf, PhD, of University of Texas Southwestern Medical Center at Dallas spoke about bile acid sequestrants (BASs) during the symposium on novel therapies.

The potential of bile acid sequestrants to improve blood glucose levels is not news. The agent’s impact on glucose as well as cholesterol homeostasis was noted almost two decades ago. “We now know that this is a general feature of bile acid sequestrants,” said David J. Mangelsdorf, PhD, of University of Texas Southwestern Medical Center at Dallas.

The introduction of HMG-CoA reductase inhibitors, or statins, has reduced the clinical use of BASs in tackling hyperlipidemia. However, these agents may play a role n type 2 diabetes therapy.

BASs absorb bile acids (BAs) in the intestine and inhibit enterohepatic circulation of BAs by preventing their reabsorption, resulting in increased excretion of BAs in the stool. In order to produce more BAs to compensate for the stool loss, the liver converts cholesterol into BAs, thereby lowering blood levels of cholesterol. BASs promote glucose homeostasis by suppressing glycogenolysis through the glucagon-like peptide 1 (GLP-1), a potent anti-hyperglycemic hormone that induces glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. When plasma glucose concentration is in the normal fasting range, GLP-1 no longer stimulates insulin, and hypoglycemia does not occur.

Thus far, colesevelam hydrochloride is the only BAS with FDA approval for both glycemic and lipid management. Colesevelam’s use is limited by its ability to increase triglyceride levels in patients with type 2 diabetes.

The symposium also included presentations on peroxisome proliferator-activated receptor (PPAR) agonists. Several PPAR-γ agonists are already approved for the treatment of type 2 diabetes: thiazolidinediones and the insulin-sensitizing drugs rosiglitazone and pioglitazone.

The scientific—and pharmaceutical—community’s interest in PPARs as drug targets is based on their effects on insulin sensitivity, atherosclerosis, and inflammation, said Jorge Plutzky, MD, of Harvard Medical School. Studies have shown that activating PPAR-γ may help prevent diabetic nephropathy by blocking the effects of glucose and renin-angiotensin-aldosterone system (RAAS) in triggering podocyte apoptosis.

Researchers’ interest in the PPARS, however, is accompanied by substantial caution owing to the side-effects associated with the agents. They include bone fractures, fluid retention, weight gain as well as bladder cancer and cardiovascular risk.

“We face the issue of separating PPARs as a target from the issues seen with various PPAR-targeting drugs, but biologic studies continue to underscore the importance of the target itself,” said Plutzky.

Charles F. Burant, MD, PhD, of the University of Michigan Medical concluded the symposium by highlighting fatty acid elongases, 1-beta HSD1 inhibitors, and G-protein-coupled receptors.

While there are numerous targets for diabetes drug development, “there is no perfect drug,” he said. “There is no perfect target. Expecting that there is one is unreasonable.”

September 2011 (Vol. 3, Number 9)