Chicago, IL—The new drug class of sodium glucose cotransporter (SGLT)-2 inhibitors was the subject of several poster presentations at the 2013 American Diabetes Association annual meeting. In addition to lowering blood glucose levels in a series of phase 3 clinical trials, these agents show weight-loss benefits as well.
The long-term effect of SGLT-2 inhibitors on the urinary tract is unknown; over the short-term, the rate of genital infection has been increased with this class of agents. Below are some of the key studies that were presented at the meeting.
In a pooled analysis of 4 randomized, placebo-controlled phase 3 clinical trials, the effects of 24 weeks of therapy with empagliflozin were evaluated in 2477 patients with type 2 diabetes.
At a poster presented by Thomas Hach, MD, Senior Medical Director at Boehringer Ingelheim Pharma, Ingelheim, Germany, and colleagues, treatment with empagliflozin resulted in significant reductions in hemoglobin (Hb) A1c and weight versus placebo.
Those randomized to empagliflozin versus to placebo experienced an increased frequency of genital infections but not urinary tract infections (UTIs).
Compared with placebo, HbA1c levels declined by 0.62% in patients assigned to 10 mg daily of empagliflozin (P <.001), and by 0.68% in patients assigned to 25 mg daily (P <.001).
Among patients with a baseline HbA1c level ≥7.0%, significantly more who were assigned to empagliflozin at either dosage achieved an HbA1c <7.0% at week 24 compared with placebo (37.2%, 25 mg empagliflozin; 31.3%, 10 mg empagliflozin; 10.5%, placebo; P <.001 for both vs placebo).
Compared with placebo, body weight declined by 1.81 kg in patients randomized to 10 mg of empagliflozin and by 2.01 kg in those randomized to 25 mg of empagliflozin (P <.001 for both). Reductions in systolic or diastolic blood pressure, as well as uric acid levels also were reported in patients receiving empagliflozin.
A safety analysis of the same 4 pooled studies revealed that the incidence of UTI with empagliflozin was comparable with placebo (9.3% and 7.5% for 10 mg and 25 mg, respectively vs 8.2% with placebo). The safety data were presented by Gabriel Kim, MD, Clinical Project Lead at Boehringer Ingelheim, Ingelheim, Germany, and colleagues. Of the reported UTI episodes, most were mild in intensity, Dr Kim indicated.
There were more genital infections with empagliflozin compared with placebo—4.2% with empagliflozin 10 mg and 3.6% with empagliflozin 25 mg compared with 0.7% with placebo.
Results of a late-breaking abstract were reported for the selective SGLT-2 inhibitor dapagliflozin, showing that dapagliflozin reduced hyperglycemia in an insulin-independent way by raising the urinary glucose excretion in patients with type 2 diabetes, according to 4-year data presented by Stefano Del Prato, MD, Professor of Endocrinology at the University of Pisa, Italy.
Among patients whose disease was inadequately controlled with metformin, those who received dapagliflozin had greater durability of HbA1c reduction over 4 years compared with the patients receiving glipizide. Dapagliflozin was compared with glipizide in a randomized, double-blind trial as add-on therapy in 801 patients who had inadequate glycemic control with metformin.
At 52 weeks, the change in HbA1c with dapagliflozin was inferior to that with glipizide, but from week 52 to week 208, the rise in HbA1c was significantly lower with dapagliflozin compared with glipizide; the difference in HbA1c levels between the 2 treatment arms was significant at 208 weeks—a 0.30% difference in favor of dapagliflozin.
Weight loss was sustained and stable with dapagliflozin, reaching a 3.65-kg loss at study’s end, whereas patients receiving glipizide showed a gain of 0.73 kg.
Approximately 13.5% of the patients in the dapagliflozin group had evidence of a UTI, and 14.3% had evidence of a genital infection.
Canagliflozin First SGLT-2 Inhibitor Approved by FDA
In 2013, canagliflozin (Invokana) became the first SGLT-2 inhibitor to receive US Food and Drug Administration (FDA) approval for the treatment of patients with type 2 diabetes. In patients with impaired renal function, canagliflozin reduced levels of HbA1c, an effect that was more pronounced with higher levels of estimated glomerular filtration rate (eGFR), said Gary Meininger, MD, Franchise Medical Leader, Janssen Research and Development, Raritan, NJ.
According to Mary H. Parks, MD, Director, Division of Metabolism and Endocrinology Products at the FDA’s Center for Drug Evaluation and Research, “Invokana is the first diabetes treatment approved in a new class of drugs known as sodium-glucose cotransporter 2 inhibitors….We continue to advance innovation with the approval of new drug classes that provide additional treatment options for chronic conditions.
Dr Meininger presented a pooled analysis of canagliflozin compared with placebo in patients with inadequately controlled type 2 diabetes and stage 3 chronic kidney disease (CKD) who were enrolled in 4 randomized, double-blind, placebo-controlled phase 3 clinical trials. The options for glycemic control in patients with advanced CKD are limited, said Dr Meininger.
Canagliflozin received FDA approval as an adjunct treatment to diet and exercise to improve glycemic control in adult patients with type 2 diabetes. The FDA-approved dosage is limited to 100 mg once daily in patients with moderate renal impairment with eGFR from 45 mL/min/1.73 m2 to <60 mL/min/1.73 m2, and the drug is not indicated for the treatment of patients with eGFR <45 mL/min/1.73 m2.
The pooled analysis included 1085 patients with type 2 diabetes and stage 3 CKD (eGFRs between ≥30 mL/min/1.73 m2 and <60 mL/min/1.73 m2) who were randomized to canagliflozin 100 mg or 300 mg, or to placebo, for 18 to 26 weeks.
In the overall study population, the mean change from baseline to efficacy assessment in HbA1c was –0.14% in the placebo group, –0.52% in the group assigned to canagliflozin 100 mg (P <.001 vs placebo), and –0.62% in the group assigned to canagliflozin 300 mg (P <.001 vs placebo). When assessed by baseline eGFR, a greater reduction in HbA1c with canagliflozin was observed in patients with eGFR ≥45 mL/min/1.73 m2 than in those with eGFR <45 mL/min/1.73 m2.
Weight loss in the canagliflozin groups was also greater than in the placebo groups (–2.0% with 100 mg, –2.4% with 300 mg, –0.5% with placebo). The weight-loss effect was greater in patients with eGFR ≥45 mL/min/1.73 m2 than in those with eGFR <45 mL/min/1.73 m2.
Adverse Events with Canagliflozin
Adverse events related to reduced intravascular volume were more common in the canagliflozin groups (5.0% and 8.5% in the 100-mg and 300-mg groups, respectively) compared with placebo (2.6%), said Dr Meininger. The percentage of these events was greater in patients with eGFR <45 mL/min/1.73 m2 relative to placebo than in those with eGFR ≥45 mL/min/1.73 m2. Also, renal-related adverse events occurred more frequently with canagliflozin compared with placebo, and the rates were higher in all 3 groups with eGFR <45 mL/min/1.73 m2.
Low Rates of Hypoglycemia with All SGLT-2 Inhibitors
All of the SGLT-2 inhibitors are associated with low rates of hypoglycemia. The rate of hypoglycemic events was 10-fold less with dapagliflozin versus placebo.
The rates of confirmed hypoglycemic adverse events were between 4.0% and 5.2% with empagliflozin.
In the study of patients with stage 3 CKD, the rate of documented hypoglycemic events was between 2.4% and 8.1% with canagliflozin in patients not receiving insulin or a sulfonylurea.