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Emerging Options for the Treatment of Type 2 Diabetes Mellitus

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 71st Scientific Sessions of the American Diabetes Association

San Diego, California / June 24-28, 2011

Chief Medical Editor: Dr. Léna Coïc, Montreal, Québec

Over the past decade, improvements in glycemic control have translated into reductions in neuropathic and microvascular complications, including lower incidences of diabetic retinopathy and lower extremity amputation, in patients with type 2 diabetes mellitus (T2DM).

The preferred first-line pharmacologic therapy for controlling glycemia cited in most consensus guidelines and treatment algorithms remains metformin, but as beta cell function and insulin sensitivity decline and T2DM progresses, metformin alone often fails to maintain glycemic control.

The current therapeutic landscape includes no fewer than 9 classes of agents for the treatment of T2DM, each with its own set of benefits and risks. Hypoglycemia, weight gain, edema/heart failure, excess cardiovascular (CV) risk and pancreatitis are some of the risks/side effects associated with currently available drug classes. Consequently, newer agents that are safe and well-tolerated are needed, and “CV profiles will be key,” confirmed Dr. Silvio E. Inzucchi, Director, Yale Diabetes Center, New Haven, Connecticut, who added that CV risk reduction is an unmet need in T2DM therapy. “With more antihyperglycemic agents on the horizon, T2DM will remain an increasingly complex—and interesting—disease to treat,” Dr. Inzucchi told ADA delegates.

The sodium-glucose co-transporter type 2 (SGLT2) inhibitors represent a new class of agents under investigation for the treatment of T2DM, with a unique mechanism of action. The novel SGLT2 inhibitor dapagliflozin reduces hyperglycemia by inhibiting renal glucose reabsorption and increasing urinary glucose excretion. As its mode of action is focused on the kidney, the agent is less effective in renally compromised patients. Other agents in this class under investigation include canagliflozin, remogliflozin and sergliflozin.

“This is an entirely new approach to the treatment of diabetes: to remove the excess blood glucose by increasing the elimination of glucose in the urine,” explained Dr. Clifford Bailey, Professor of Clinical Science, Aston University, Birmingham, UK, here at the ADA. “The key advantage here is that the mechanism is not dependent on either the amount of insulin secreted or the action of insulin, whereas most other treatments are dependent on one or the other of those 2 issues, which are major pathogenic issues in type 2 diabetes.”

Durable Effect in Controlling Glycemia, Low Risk of Hypoglycemia

A 78-week extension of a 24-week, randomized-controlled study in patients with T2DM showed that the SGLT2 inhibitor dapagliflozin had durable efficacy in controlling blood glucose as add-on therapy to metformin with a low risk of hypoglycemia. Furthermore, it reduced body weight over the 102 weeks, reported Dr. Bailey, the lead investigator of this study.

The trial included 546 patients with T2DM inadequately controlled on metformin alone who were randomized to placebo or 1 of 3 dosages of the SGLT2 inhibitor (2.5, 5 or 10 mg/day) in addition to metformine. Those who completed the 24-week study were eligible to continue on their originally assigned blinded treatment for an additional 78 weeks (total of 102 weeks).

The 10-mg dose achieved a 0.78% lowering of hemoglobin (Hb) A<sub>1c</sub> from baseline after 102 weeks, with the 2.5-mg and 5-mg doses achieving HbA1c reductions of 0.48% and 0.58%, respectively. “There was a concomitant reduction of fasting plasma glucose (FPG) and at the same time there was also a reduction of body weight,” Dr. Bailey informed delegates.

The adjusted mean change in FPG from baseline to week 102 was a reduction of 19.3 mg/dL (1.07 mmol/L) to 24.5 mg/dL (1.36 mmol/L) in the add-on groups compared with a reduction of 10.4 mg/dL (0.58 mmol/L) in the placebo/metformin group. Over the 102 weeks, body weight decreased by 1.10 to 1.74 kg in the dapagliflozin/metformin groups whereas it increased by 1.36 kg in those assigned to placebo/metformin. The percentage of patients with at least 1 hypoglycemia event ranged from 3.6% to 5.2% with the SGLT2 inhibitor in a dose-dependent manner and 5.8% with placebo. No serious hypoglycemic event was reported in any group.

“There was a small but what I consider manageable increase in genital and urinary tract infections… but only 1 individual in this trial of 546 discontinued because of a recurrent urinary tract issue and 1 discontinued because of genital infection,” Dr. Bailey reported. Events suggestive of genital infection occurred in 11.7% to 14.6% of patients in the SGLT2 inhibitor groups compared to 5.1% in the placebo group.

Sustained Reductions in Weight, BP

A second randomized study of the SGLT2 inhibitor as add-on therapy to metformin showed non-inferiority on the primary end point of HbA<sub>1c</sub> level compared with glipizide/metformin over 104 weeks, with sustained reductions in total body weight and blood pressure (BP) and a tenfold lower incidence of hypoglycemic events in dapagliflozin-treated patients, reported Dr. Michael Nauck, Head of the Diabetes Center, Bad Lauterberg, Germany.

The data released here at the ADA were from a 52-week extension of an initial 52-week trial reported in 2010 at the 46th European Association for the Study of Diabetes meeting in Stockholm. Some 801 patients with T2DM whose HbA<sub>1c</sub> levels were 6.5% to 10% despite metformin treatment were randomized to dapagliflozin added to metformin or glipizide added to metformin. The mean baseline HbA1c levels were 7.69% in the SGLT2 inhibitor group and 7.74% in the glipizide group. Both dapagliflozin and glipizide reduced HbA<sub>1c</sub> levels by 0.52% from baseline to 52 weeks.

Some 624 patients entered the extension study; of these, 445 completed the entire 104 weeks. “The initial HbA1c reduction at 52 weeks was sustained with dapagliflozin but this effect had attenuated with glipizide at 104 weeks,” noted Dr. Nauck. By 104 weeks, the SGLT2 inhibitor was associated with a 0.18% reduction in HbA<sub>1c</sub> compared with glipizide. Moreover, the weight reduction with dapagliflozin at 52 weeks and the weight gain with glipizide at 52 weeks were both sustained: -3.70 kg vs. +1.36 kg, respectively.

At 52 weeks, the change from baseline in systolic BP was 4.7 mm Hg lower in the dapagliflozin-treated patients compared with the glipizide-treated patients; the difference was 3.9 mm Hgin favour of the SGLT2 inhibitor at 104 weeks. The proportion of patients with hypoglycemia was 4.2% with add-on dapagliflozin vs. 45.8% with add-on glipizide, a tenfold reduction.

Signs, symptoms and other reports suggestive of genital infections were more common with dapagliflozin/ metformin (14.8%) than with glipizide/metformin (2.9%). The percentage of patients with signs, symptoms and other reports suggestive of urinary tract infection was greater for the former group (13.5% vs. 9.1%). Most occurred in the first year of treatment, were mild to moderate in intensity and responded to standard treatment.

Non-inferiority to Metformin as Initial Therapy

As initial therapy in T2DM, the combination of dapagliflozin and metformin performed better than either agent alone in lowering hyperglycemia, stated Dr. Robert R. Henry, Professor of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, here at the ADA.

In 2 randomized, double-blind, active-controlled trials, SGLT2 inhibitor monotherapy (5 or 10 mg) was compared with metformin monotherapy (titrated to 2000 mg/day) and the combination of either 5 or 10 mg dapagliflozin with metformin in 1236 patients with T2DM.

At week 24, the adjusted mean change from baseline in HbA<sub>1c</sub> was similar between metformin (-1.35% to -1.44%), the SGLT2 inhibitor at 5 mg (-1.19%) and at 10 mg (-1.45%; non-inferior to metformin). The combination of 5 mg and metformin reduced the mean HbA<sub>1c</sub> level from baseline by 2.05%; the 10-mg dose combined with metformin reduced mean HbA<sub>1c</sub> by 1.98% from baseline (P<0.0001 for either combination vs. monotherapy).

Diastolic BP was unchanged with metformin monotherapy but was reduced from baseline by 3.0 mm Hg and 1.9 mm Hg in the 5-mg and 10-mg groups, respectively. Systolic BP declined by at least 4.0 mm Hg with either SGLT2 inhibitor dosage, compared with reductions of less than 2.0 mm Hg in the metformin monotherapy groups. Events suggestive of genital infections or urinary tract infections were more common in the SGLT2 inhibitor groups.

In prespecified comparisons, dapagliflozin 10 mg was superior to metformin in reducing FPG and weight. “In principle, this treatment approach [SGLT2 inhibition] should be a very flexible add-on to other treatments at any stage in the natural course of the disease, provided that the patients have adequate renal function,” noted Dr. Bailey.

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