Blocking Glucose Reuptake for Diabetes

There is a new drug treatment strategy coming down the pipeline for diabetes, one that targets the kidney. These new drugs “should be available in three to four years,” according to Jaime Davidson, MD, Clinical Professor of Medicine, University of Texas Southwestern Medical Center in Dallas, who chaired “Revolutionary Approaches in the Treatment of Diabetes — Developments in Targeting the Kidney for Blood Pressure and Glucose Control,” a satellite session outlining the rationale for their use and their place in diabetes treatment.

The drugs promote urinary excretion of glucose by blocking the protein that promotes its reuptake in the kidney. These drugs are likely to be complementary to current therapies and may find use as either monotherapy or adjunct therapy, Dr. Davidson said.

Understanding the function of the kidney is critical to targeting kidney function for glycemic control, said Mark Molitch, MD, Professor of Medicine at Northwestern University Feinberg School of Medicine, Chicago. Of 144 g glucose filtered daily through the nondiabetic kidney, essentially none gets excreted. Ninety percent of the reabsorption is performed by the sodium glucose cotransporter SGLT2 in the proximal tubule. SGLT2 activity is even greater ii diabetes, because production of the protein is increased.

The kidney and diabetes are related in other ways, Molitch noted. “Diabetes is clearly the leading cause of end-stage kidney disease, not only in the United States but throughout the world. But, he noted, there may be some reason for optimism: Incidence of the disease in the US peaked in the late 1990s, and has since stabilized and may even be declining. “We really are making some headway in improving a lot of our patients,” he said.

Hypertension management in the context of diabetes has not lacked for drug treatments, or guidelines for therapy, according to George Bakris, MD, Professor of Medicine, University of Chicago Pritzker School of Medicine. He presented a comprehensive review of guidelines issued by several professional organizations, and discussed results from recent trials.

He summarized this plethora of data by saying that both angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective in improving hypertension, cardiovascular outcomes, and renal outcomes. However, they are only partially effective at inhibiting activity of the renin-angiotensin-aldosterone system, the pathway that controls blood pressure through its actions on the kidney. Combination therapy, he said, can reduce protein in the urine, but has not demonstrated benefit on either cardiovascular or chronic kidney disease outcomes. Neither is it yet clear what effects dual treatment has in patients with diabetes and kidney disease, but those data should be available in 2013.

“It is critical to control blood glucose early in our patients,” Davidson said. Cardiovascular benefits accrue when it is controlled within the first 15 years, but not after that. It should be targeted “from day one.”

SGLT2 inhibitors moving through trials may become part of this strategy, he said. There are currently at least 7 agents in active development, including dapagliflozin and remogliflozin. The latter drug had beneficial effects on 24-hour glucose, oral glucose tolerance, body weight, and blood pressure. Similarly, dapagliflozin improved 24-hour glucose, glycosylated hemoglobin, and body weight. An increase in urinary tract infections—a concern with elevated urinary glucose—was not seen in patients receiving the dose most likely to be marketed.

Davidson noted some education will be required for the patient and the general practitioner, since these drugs increase glucose in the urine, perhaps up to tenfold, contrary to the long-held goal in diabetes treatment of decreasing it.

He noted the drugs can be used in combination with other treatments; “they are complementary to everything we have today,” he said.

This satellite symposium was sponsored by Bristol-Myers Squibb and AstraZeneca and presented at the 19th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists.