New agents for diabetes management

Plenty of information has been released recently about the sodium-glucose transporter-2 inhi-bitors, commonly known as SGLT2s, leading endocrinologists to ask, “What is all the excitement?”

These agents represent a potentially promising approach to treating diabetes because they have no effect on insulin secretion and insulin resistance. Instead, SGLT2 inhibitors block reabsorption of glucose by the kidneys.

At the American Diabetes Association 70th Scientific Sessions in June, nine abstracts were presented on canagliflozin and three were presented on dapagliflozin. To date, three clinical trials of the most studied SGLT2 inhibitor — dapagliflozin — have been published. Several SGLT2 inhibitors are currently being studied in phase 2 and 3 clinical trials for patients with type 2 diabetes.

Edward C. Chao

Discovery and development

A crucial evolutionary adaption to retain calories, renal glucose absorption by the kidney contributes to hyperglycemia, and is a crucial evolutionary adaption to retain calories. Paradoxically, patients with diabetes may have this process accentuated. Historically, glycosuria has been regarded as a sign of metabolic decompensation and adverse clinical consequences. Diminishing renal glucose reabsorption and elevating urinary glucose excretion as a strategy for treating diabetes, thus, represents a paradigm shift. SGLT is responsible for renal glucose reabsorption, with 90% mediated by SGLT2, a high-capacity, low-affinity carrier found mainly in the S1 segment of the proximal convoluted tubule. SGLT1 coordinates the remaining 10% of glucose reabsorption in the kidney; these co-transporters are situated in the S2 and S3 segment of the proximal convoluted tubule. The high plasma glucose levels that are the hallmark of uncontrolled type 2 diabetes exceed the maximum threshold of glucose reabsorption, thus leading to saturation of the SGLT receptors and, in turn, resulting in glycosuria.

The development of SGLT2 inhibitors extends to 1835, when phlorizin was first isolated. This compound, derived from the root bark of the apple tree, was an inhibitor of both SGLT2 and SGLT1. Phlorizin was not feasible for further development, due to being quickly degraded and because it had low bioavailability secondary to being poorly absorbed from the gastrointestinal tract. Other agents were tested, which provided more specificity, but were discontinued for reasons that were not entirely known, but likely included suboptimal safety and efficacy.

Promising, recent research

In one abstract presented at the ADA meeting, Wilding and colleagues examined dapagliflozin (AstraZeneca and Bristol-Myers Squibb); this agent has progressed the furthest in development among the SGLT2 inhibitors. For 48 weeks, 808 patients with type 2 diabetes who were suboptimally controlled on insulin were administered this SGLT2 inhibitor. HbA1c levels declined by –0.43% (standard error 0.07%) in the placebo group; –0.74% (0.06%) in the dapagliflozin 2.5 mg group; –0.94% (0.06%) in the dapagliflozin 5-mg group; and –0.93% (0.06%) in the dapagliflozin 10-mg group. Urinary tract infections were observed in 7.9% to 10.8% of patients assigned to dapagliflozin vs. 5.1% of patients assigned to placebo. Genital infections were also more common in the dapagliflozin group vs. placebo group (6.4% to 10.7% vs. 2.5%).

Canagliflozin (Johnson & Johnson) is another SGLT2 inhibitor that is in clinical trials and was presented at the ADA meeting. In a randomized, double blind, placebo-controlled study by Schwartz and colleagues, 29 people with type 2 diabetes suboptimally controlled on stable insulin doses were administered canagliflozin 100-mg daily, 300-mg twice daily or placebo. The HbA1c decrease was –0.19% from a baseline level of 8.27% in the placebo group; –0.73% from 8.38% in the canagliflozin 100-mg daily group; and –0.92% from 8.42% in the canagliflozin 300 mg twice-daily group. Weight decreases ranged from –0.7 kg with canagliflozin at 100 mg per day to –1.2 kg with canagliflozin 300 mg twice daily.

In another study, Rosenstock and colleagues randomly assigned 451 patients with type 2 diabetes who were not optimally controlled on metformin to daily canagliflozin 50 mg, 100 mg, 200 mg or 300 mg; to twice-daily canagliflozin 300 mg; to daily sitagliptin 100 mg (Januvia, Merck); or to placebo. HbA1c declined between 0.45% and 0.73% in all patients assigned to canagliflozin compared with a 0.56% decrease in patients assigned to sitagliptin. Weight was reduced by 1.3% to 2.3% with canagliflozin. In addition, fasting plasma glucose changed from –16.2 mg/dL to –32.4 mg/dL vs. an increase of 0.4 mg/dL with sitagliptin. The overnight urine glucose-creatinine ratio ranged from 36.1 to 60.3 vs. –3/3 with sitagliptin. These changes were all statistically significant.

Also in the study, hypoglycemia was observed in up to 6% of the canagliflozin patients compared with 2% with placebo and 5% with sitagliptin. Urinary tract infections occurred in 3% to 9% of the canagliflozin groups, 6% of the placebo group and 2% of the sitagliptin group. The researchers noted no dose-response effect for hypoglycemia or urinary tract infection. Non-dose-dependent elevations in symptomatic genital infections were also observed: 3% to 8% with canagliflozin and 2% with placebo and sitagliptin.

Further exploration in trials

Further studies are needed to address safety issues associated with SGLT2 inhibitors, such as risks for hypoglycemia, electrolyte imbalance, urinary and genital infections and the inhibitors’ effect on bone metabolism. How to best use these medications to attain greater glycemic control while minimizing adverse effects also awaits further research.

Whether these agents will be best used for type 1 diabetes or type 2 diabetes will depend on studies that have examined use in both. The role of SGLT2 inhibitors in combination with oral agents must also be further explored in large trials of longer duration.

These are just some of the unanswered questions that remain. The data generated thus far appear to suggest that SGLT2 inhibitors represent a promising approach to tackling hyperglycemia.

Edward C. Chao, DO, is assistant clinical professor of medicine at University of California, San Diego, and staff physician at VA Medical Center, San Diego.

For more information:

• Rosenstock J. Canagliflozin, an inhibitor of sodium glucose co transporter 2 (SGLT2), improves glycemic control and lowers body weight in subjects with type 2 diabetes (T2D) on metformin.
• Schwartz S. Canagliflozin improves glycemic control in subjects with type 2 diabetes (T2D) not optimally controlled on stable doses of insulin.
• Wilding J. Sustained effectiveness of dapagliflozin over 48 weeks in patients with type 2 diabetes poorly controlled with insulin. All presented at: American Diabetes Association 70th Scientific Sessions; June 24-29, 2010; Orlando, Fla.