Novel therapies for type 2 diabetes on the horizon

ADA 71st Scientific Sessions

SAN DIEGO — Research into new compounds and biological pathways offers exciting opportunities for the future of type 2 diabetes management.

Presenters here discussed the potential therapeutic efficacy of several compounds, including sodium-glucose cotransporter (SGLT) inhibitors, bile acid sequestrants and peroxisome proliferator-activated receptor (PPAR) agonists.

“There are hundreds of targets that are being pursued as pharmacological technologies [for type 2 diabetes],” Charles F. Burant, MD, PhD, professor at the University of Michigan Medical School, said at the symposium.

Promise of SGLT1, SGLT2

Ernest M. Wright, DSc, professor of physiology at UCLA, discussed SGLT1 and SGLT2 inhibitors. These proteins work by driving the uphill transport of sugar into cells down the sodium gradient across cell membranes. An SGLT1 inhibitor, Wright noted, would block the intestinal absorption of glucose, while an SGLT2 inhibitor blocks reabsorption of glucose in the kidney.

“We may be able to control blood glucose levels by either interfering with normal dietary absorption or increasing the excretion of glucose in the kidney with the appropriate inhibitor,” Wright said at a symposium. He noted that phlorizin appears effective in this capacity, but this drug produces gastrointestinal adverse effects and is rapidly metabolized.

Currently, manufacturers are only working on one SGLT1 inhibitor — DSP-3235 — which is in phase 1 clinical trials. SGLT2 inhibitors appear more promising and are the major focus of pharmacological development. There are several in phase 3 trials, including dapagliflozin (Bristol-Myers Squibb, AstraZeneca), which will be the focus of an FDA advisory committee meeting on July 19.

“So far, there are no remarkable adverse effects, but we have to be wary of side effects due to inhibition of SGLT2 at other sites in the body, such as the heart,” Wright said.

Bile acid sequestrants

Researchers are also analyzing the potential use of bile acid sequestrants — resins that bind bile acids to the liver — as a treatment option for type 2 diabetes, according to David J. Mangelsdorf, MD, PhD, professor of pharmacology at the University of Texas Southwest Medical Center.

Presently, bile acid sequestrants are approved to lower LDL, but studies indicate potential glycemic improvements. The effects of bile acid sequestrants on blood glucose levels are due in part to activation of the TGR5 pathway and their ability to robustly suppress hepatic glycogenolysis, Mangelsdorf explained.

Bile acid sequestrants also dramatically reduce liver fat, although the mechanisms through which this occurs are unclear. Studies in mice and rats are promising, yet further research is needed, he said.

Problems with PPARs

Jorge Plutzky, MD, director of the Vascular Disease Prevention Program at Brigham and Women’s Hospital and faculty member at Harvard Medical School, highlighted the potential of novel PPAR agonists.

Plutzky noted that preclinical and even early human data have generated excitement because they show the impact of PPAR on insulin sensitivity, inflammation and atherosclerosis. However, PPARs have been associated with potential adverse events, such as increased cardiovascular risk, fluid retention, increased body weight, bone fractures and bladder cancer.

Both PPAR-alpha and PPAR-gamma favorably affect lipids and adipose tissue and inflammation. A dual agonist might combine these effects and offer an appealing therapeutic alternative, according to Plutzky. Aleglitazar is a dual PPAR agonist under study in a large CV trial. Other selective PPAR agonists and novel strategies to generate PPAR effects, such as CDK5 protein inhibitors, are being pursued.

“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.”

Next-generation treatments

In an overview, Burant highlighted several treatments in development. One topic of discussion was fatty acid elongases, which have been targeted for study due to the association of long-chain fatty acids and their end products with toxicity related to overconsumption of food. Researchers hypothesize that inhibiting this elongation may have an effect on metabolism.

Burant also described 1-beta HSD1 as an area of study. Inhibition of 1-beta HSD1 may preclude of the enzyme’s effects on changes in the liver and metabolism and may mediate insulin resistance.

G-protein-coupled receptor 40 (GPR40) and G protein-coupled receptor 119 (GPR119) are two agonists with different signaling pathways in the beta cell, and both are being explored as potential treatments for type 2 diabetes. GPR40 stimulates the intestinal hormone, and studies indicate it may decrease blood glucose. Research also suggests a positive secretory effect in a glucose-dependent manner in GPR119.

Burant said exploring new therapies is important, but cautioned against abandoning lifestyle changes too quickly.

“There are lots of targets for pharmacological therapy. Some are theoretical and don’t work, or at least don’t work as well as we think they should,” he said. “There is no perfect drug. There is no perfect target. Expecting that there is one is unreasonable.” – by Melissa Foster

For more information:

• Rosenstock J. Novel therapies for type 2 diabetes – Today and tomorrow. Presented at: American Diabetes Association’s 71st Scientific Sessions; June 24-28, 2011; San Diego, Calif.

Disclosure: Dr. Burant is a board or advisory panel member for Animas Corporation, Biodel, Inc., GluMetrics, Inc., GlySens, Inc, Medtronic and receives research support from Abbott Diabetes Care. Dr. Mangelsdorf is a board or advisory panel member for Daiichi-Sankyo. Dr. Plutzky is a consultant for Abbott Laboratories, Amylin, AstraZeneca, Bristol Myers Squibb, Novo Nordisk, Orexigen, Pfizer and Takeda. Dr. Wright is a board or advisory panel member for Boehringer Ingelheim and a consultant for Merck Sharpe & Dohme Limited.

Multiple potentially promising targets with novel mechanisms of action are being investigated for treating diabetes. Of these, only the SGLT2 inhibitors - namely, dapagliflozin and canagliflozin - have undergone phase 3 trials. The FDA is currently reviewing the application for dapagliflozin.

The number of classes of diabetes medications currently on the market has rapidly increased. If the most recent ADA Scientific Sessions are any barometer, the number of targets and medications will likely continue to follow this upward trend. It will be interesting to see where the novel agents which are approved will fit in therapeutic regimens.

– Edward C. Chao, DO
Endocrine Today Editorial Board member

Disclosure: Dr. Chao reports no relevant financial disclosures.

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