• Diabetes Mellitus
• Hyperglycemia/Hypoglycemia
• Diabetes & Endocrinology Clinical Trials

• Diabetes Mellitus
• Endocrinology
• Diabetes & Metabolic Syndrome
• Hyperglycemia/Hypoglycemia
• Diabetes & Endocrinology Clinical Trials

Kaj Stenlöf, MD, PhD, Sahlgrenska University Hospital, Gothenburg, Sweden, presented the results of a double-blind phase 3 study of the sodium-glucose cotransporter 2 inhibitor canagliflozin in patients aged 55 to 80 years. The investigators found that the 100-mg and 300-mg doses of canagliflozin each improved glycemic control, reduced body weight, lowered blood pressure (BP), and were generally well tolerated in older patients with type 2 diabetes mellitus (T2DM) over 104 weeks. The adverse event (AE) profile was similar with that observed in a broad range of canagliflozin-treated patients.

Treatment of the older patients with T2DM can be complex given that these patients often have advanced T2DM, multiple comorbidities, and need combination therapy [Inzucchi SE et al. Diabetes Care. 2012]. In short-term trials, canagliflozin has demonstrated improvement in glycemic control and bodyweight [Lavalle-González FJ et al. Diabetologia. 2013; Schernthaner G et al. Diabetes Care. 2013; Stenlöf K et al. Diabetes Obes Metab. 2013; Wilding JP et al. Int J Clin Pract. 2013; Yale JF et al. Diabetes Obes Metab. 2013; Rosenstock J et al. Diabetes Care. 2012], as well as reductions in BP across a broad population of patients with T2DM, including older patients [Forst T et al. Diabetes Obes Metab. 2014; Bode B et al. Hosp Pract (1995). 2013].

According to Prof Stenlöf, the objectives of this trial were to evaluate the long-term efficacy and safety of canagliflozin, 100 mg and 300 mg, in older patients with T2DM whose HbA_1c values were inadequately controlled (7% to 10%) on their current treatment regimens. Among the 714 patients in the study, 74% were currently taking an antihyperglycemic agent (AHA) associated with hyperglycemia; 23% were on an AHA not associated with hyperglycemia; and 3% were taking no AHA. Patients were randomized to canagliflozin-100 mg, canagliflozin-300 mg, or placebo and followed for 104 weeks. During the trial, patients were continued on a stable AHA regimen, and progressively stricter glycemic rescue criteria were employed as the study progressed.

The mean age of the sample was 64 years; the mean HbA_1c level was 7.7%; and the mean body mass index was 32 kg/m². End points included the change from baseline in HbA_1c, fasting plasma glucose, percentage change in bodyweight, systolic B P, percentage change in low-density lipoprotein cholesterol (LDL-C), and percentage change in high-density lipoprotein cholesterol (HDL-C) at week 104. The overall safety and tolerability of the drug, including selective AEs, were also assessed. Statistical testing of canagliflozin compared with placebo was not prespecified and thus not conducted for the analyses of efficacy parameters; therefore, no P values were reported.

Over 104 weeks, changes in baseline for HbA_1c were +0.17% (placebo), −0.49% (canagliflozin, 100 mg), and −0.60% for (canagliflozin, 300 mg). Positive changes were also seen in HbA_1c, fasting plasma glucose, bodyweight, and systolic BP (−1.2 mm Hg and −3.0 mm Hg from baseline in the 100-mg and 300-mg treatment groups, respectively). The proportions of patients who achieved HbA_1c < 7.0% at week 104 were 20.3% (placebo), 35.8% (canagliflozin, 100 mg), and 41.9% (canagliflozin, 300 mg). Compared with that of placebo, body weight decreased in both the 100-mg group (−2.3%) and the 300-mg group (−3.2%). Small increases in LDL-C and HDL-C were observed in the 2 canagliflozin groups as compared with patients receiving placebo, although these increases plateaued after 26 weeks.

Canagliflozin was generally well tolerated over 104 weeks, but it was associated with an increased incidence of fungal infections of the genitourinary system and AEs related to osmotic diuresis when compared with placebo (Table 1). The majority of these AEs occurred during the first 26 weeks of treatment.

Volume-related AEs (eg, dehydration, dizziness, and presyncope) were more common in canagliflozin patients, occurred more frequently in the first 26 weeks, but were relatively infrequent (5.4% and 5.9% in the 100-mg and 300-mg treatment groups, respectively). The majority of fungal infections were treated with topical therapy. Incidence of documented hypoglycemia was higher with both canagliflozin doses than with placebo, but there were few severe hypoglycemia episodes in any of the treatment groups (Table 2).

In summary, canagliflozin, both 100 mg and 300 mg, improved glycemic control, reduced bodyweight, and lowered BP when compared with placebo over 104 weeks in older patients with T2DM whose HbA_1c values were inadequately controlled by their current regimens. The incidence of documented hypoglycemia was higher with both doses of canagliflozin than with placebo, although there were few severe episodes noted. Canagliflozin was generally well tolerated, with a safety profile in this study consistent with that seen in other phase 3 canagliflozin studies.

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