Drugs for Diabetes: Part 8 SGLT2 Inhibitors
Drugs for Diabetes: Part 8 SGLT2 Inhibitors
Monotherapy Two published studies have evaluated the use of dapagliflozin as monotherapy for type 2 diabetes. In a phase IIb study, List et al. randomised 389 drug-naïve obese patients with poorly controlled type 2 diabetes to treatment with one of five doses of dapagliflozin, extended-release metformin or placebo for 12 weeks. At week 12, the dapagliflozin group achieved a mean reduction in HbA1c ranging from 0.55 to 0.90%. This was compared with patients in the metformin group who had a mean reduction in HbA1c of 0.73% and the placebo group who had a mean reduction in HbA1c of 0.18%.
Ferrannini et al. randomised 485 drug-naïve obese patients with poorly controlled type 2 diabetes to 24 weeks' treatment with either placebo or dapagliflozin 2.5 mg, 5 mg or 10 mg once daily. Metformin was added in at 12 weeks to the maximum tolerated dose in those patients who remained poorly controlled at that stage. Overall, a mean reduction in HbA1c ranging from 0.58 to 0.89% was observed in the dapagliflozin group compared with 0.23% in the placebo group. The reduction was statistically significant in the 5 and 10 mg dapagliflozin arms (p=0.0005 and p<0.0001, respectively). No major episodes of hypoglycaemia were observed. Signs and symptoms of urinary and genital tract infection were more frequent in the dapagliflozin arms. All resolved with standard treatment and rarely led to discontinuation. Further phase III trials of dapagliflozin and canagliflozin monotherapy are ongoing.
Combination Therapy In a phase III multi-centre, double-blind, parallel-group, placebo-controlled trial, Bailey et al. randomised 546 adults with type 2 diabetes mellitus already receiving metformin (≥1,500 mg/day) with inadequate glycaemic control (HbA1c 7–10%) to treatment with one of three doses of dapagliflozin (2.5, 5 or 10 mg) or placebo. At 24 weeks, mean HbA1c decreased by 0.30% in the placebo group compared with 0.67% (p=0.0002) in the dapagliflozin 2.5 mg group, 0.70% (p<0.0001) in the dapagliflozin 5 mg group and 0.84% (p<0.0001) in the dapagliflozin 10 mg group. Rates of hypoglycaemia were similar between the dapagliflozin and placebo groups (2–4% vs. 3%). A higher incidence of genital infection was recorded in the dapagliflozin groups (8–13%) compared with the placebo group (5%). Seventeen patients had serious adverse events (four in each of the dapagliflozin groups and five in the placebo group).
In a phase IIb multi-centre, double-blind, three-arm, parallel-group, placebo-controlled study, Wilding et al. randomised 71 patients receiving high-dose insulin plus insulin sensitisers to treatment with either placebo, 10 mg dapagliflozin or 20 mg dapagliflozin. All oral antidiabetic agents were continued, but baseline insulin doses were reduced by 50%. At week 12, HbA1c levels in the dapagliflozin 10 mg and 20 mg groups fell by 0.70% and 0.78%, respectively, when compared with placebo. Further phase III trials of combination therapy for both dapagliflozin and canagliflozin are ongoing.
In addition to improvements in glycaemic control, dapagliflozin therapy is also associated with beneficial reductions in total body weight. The glycosuria induced by dapagliflozin monotherapy is associated with a net calorie loss of approximately 200–300 kilocalories per day. List et al. noted that 12 weeks' monotherapy with dapagliflozin was associated with weight loss of 2.5–3.4 kg compared with weight loss of 1.2 kg and 1.7 kg in the placebo and metformin arms. Bailey et al. observed a 2.2–2.9 kg weight loss over 24 weeks in the dapagliflozin group compared with 0.9 kg weight loss in the placebo arm. Wilding et al. also noted a mean weight loss of 4.5 kg and 4.3 kg in the dapagliflozin 10 mg and 20 mg groups versus 1.9 kg in the placebo group. Ferrannini et al., however, did not find a statistically significant difference in weight at 24 weeks between the dapagliflozin group and placebo. The authors attributed this to a large placebo effect due to greater impact of diet and exercise counselling on motivated, newly diagnosed patients in a clinical trial setting. Glycosuria consistent with a loss of 200–300 kilocalories was observed in the treatment group, consistent with other studies.
The long-term benefit of tight blood pressure control in patients with type 2 diabetes is well established. In the UK Prospective Diabetes Study (UKPDS) patients assigned to the tight blood pressure arm had a relative risk reduction of 24% for any diabetes-related end point, 32% for diabetes-related death, 44% for stroke and 37% for microvascular disease. Dapagliflozin, as monotherapy or as an addition to metformin therapy over periods of 12–24 weeks in doses of 2.5–10 mg per day, has been noted to reduce blood pressure. This is possibly mediated through net sodium loss. Doses of 10 mg/day reduced mean systolic blood pressure in the groups studied by 3–5 mmHg and diastolic blood pressure by approximately 2 mmHg with no apparent change in heart rate or increase in syncopal episodes. This small decrease in blood pressure may convey additional cardiovascular benefit in addition to the effects of improvement in glycaemic control and reduced weight.
The cardiovascular effects of long-term SGLT2 inhibition remain unknown. The Food and Drugs Administration (FDA) requires evidence that new treatments for diabetes do not increase cardiovascular risk. For dapagliflozin these data are being obtained from the study programme, which includes two ongoing phase III studies evaluating the safety and efficacy of dapagliflozin therapy in patients with type 2 diabetes and established cardiovascular disease and/or hypertension. Both of these are expected to complete in December 2011. Cardiovascular safety data for canagliflozin is being obtained from a large, dedicated phase III study: CANagliflozin cardiovascular Assessment Study (CANVAS). This will evaluate the use of canagliflozin or placebo in the treatment of around 5,000 patients with type 2 diabetes with a history of, or high risk for, cardiovascular disease. The primary end point for this study will be the incidence of major cardiovascular events including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The study is expected to run for four years and to complete in April 2013. If the safety parameters are met and the drug obtains a licence it is the intention to expand this into a study of possible cardiovascular benefits in 20,000 patients.
Trials of Safety and Efficacy
Evidence for Improved Glycaemic Control/Microvascular Benefit
Monotherapy Two published studies have evaluated the use of dapagliflozin as monotherapy for type 2 diabetes. In a phase IIb study, List et al. randomised 389 drug-naïve obese patients with poorly controlled type 2 diabetes to treatment with one of five doses of dapagliflozin, extended-release metformin or placebo for 12 weeks. At week 12, the dapagliflozin group achieved a mean reduction in HbA1c ranging from 0.55 to 0.90%. This was compared with patients in the metformin group who had a mean reduction in HbA1c of 0.73% and the placebo group who had a mean reduction in HbA1c of 0.18%.
Ferrannini et al. randomised 485 drug-naïve obese patients with poorly controlled type 2 diabetes to 24 weeks' treatment with either placebo or dapagliflozin 2.5 mg, 5 mg or 10 mg once daily. Metformin was added in at 12 weeks to the maximum tolerated dose in those patients who remained poorly controlled at that stage. Overall, a mean reduction in HbA1c ranging from 0.58 to 0.89% was observed in the dapagliflozin group compared with 0.23% in the placebo group. The reduction was statistically significant in the 5 and 10 mg dapagliflozin arms (p=0.0005 and p<0.0001, respectively). No major episodes of hypoglycaemia were observed. Signs and symptoms of urinary and genital tract infection were more frequent in the dapagliflozin arms. All resolved with standard treatment and rarely led to discontinuation. Further phase III trials of dapagliflozin and canagliflozin monotherapy are ongoing.
Combination Therapy In a phase III multi-centre, double-blind, parallel-group, placebo-controlled trial, Bailey et al. randomised 546 adults with type 2 diabetes mellitus already receiving metformin (≥1,500 mg/day) with inadequate glycaemic control (HbA1c 7–10%) to treatment with one of three doses of dapagliflozin (2.5, 5 or 10 mg) or placebo. At 24 weeks, mean HbA1c decreased by 0.30% in the placebo group compared with 0.67% (p=0.0002) in the dapagliflozin 2.5 mg group, 0.70% (p<0.0001) in the dapagliflozin 5 mg group and 0.84% (p<0.0001) in the dapagliflozin 10 mg group. Rates of hypoglycaemia were similar between the dapagliflozin and placebo groups (2–4% vs. 3%). A higher incidence of genital infection was recorded in the dapagliflozin groups (8–13%) compared with the placebo group (5%). Seventeen patients had serious adverse events (four in each of the dapagliflozin groups and five in the placebo group).
In a phase IIb multi-centre, double-blind, three-arm, parallel-group, placebo-controlled study, Wilding et al. randomised 71 patients receiving high-dose insulin plus insulin sensitisers to treatment with either placebo, 10 mg dapagliflozin or 20 mg dapagliflozin. All oral antidiabetic agents were continued, but baseline insulin doses were reduced by 50%. At week 12, HbA1c levels in the dapagliflozin 10 mg and 20 mg groups fell by 0.70% and 0.78%, respectively, when compared with placebo. Further phase III trials of combination therapy for both dapagliflozin and canagliflozin are ongoing.
Effects on Weight
In addition to improvements in glycaemic control, dapagliflozin therapy is also associated with beneficial reductions in total body weight. The glycosuria induced by dapagliflozin monotherapy is associated with a net calorie loss of approximately 200–300 kilocalories per day. List et al. noted that 12 weeks' monotherapy with dapagliflozin was associated with weight loss of 2.5–3.4 kg compared with weight loss of 1.2 kg and 1.7 kg in the placebo and metformin arms. Bailey et al. observed a 2.2–2.9 kg weight loss over 24 weeks in the dapagliflozin group compared with 0.9 kg weight loss in the placebo arm. Wilding et al. also noted a mean weight loss of 4.5 kg and 4.3 kg in the dapagliflozin 10 mg and 20 mg groups versus 1.9 kg in the placebo group. Ferrannini et al., however, did not find a statistically significant difference in weight at 24 weeks between the dapagliflozin group and placebo. The authors attributed this to a large placebo effect due to greater impact of diet and exercise counselling on motivated, newly diagnosed patients in a clinical trial setting. Glycosuria consistent with a loss of 200–300 kilocalories was observed in the treatment group, consistent with other studies.
Effects on Blood Pressure
The long-term benefit of tight blood pressure control in patients with type 2 diabetes is well established. In the UK Prospective Diabetes Study (UKPDS) patients assigned to the tight blood pressure arm had a relative risk reduction of 24% for any diabetes-related end point, 32% for diabetes-related death, 44% for stroke and 37% for microvascular disease. Dapagliflozin, as monotherapy or as an addition to metformin therapy over periods of 12–24 weeks in doses of 2.5–10 mg per day, has been noted to reduce blood pressure. This is possibly mediated through net sodium loss. Doses of 10 mg/day reduced mean systolic blood pressure in the groups studied by 3–5 mmHg and diastolic blood pressure by approximately 2 mmHg with no apparent change in heart rate or increase in syncopal episodes. This small decrease in blood pressure may convey additional cardiovascular benefit in addition to the effects of improvement in glycaemic control and reduced weight.
Evidence for Cardiovascular Safety and Benefit
The cardiovascular effects of long-term SGLT2 inhibition remain unknown. The Food and Drugs Administration (FDA) requires evidence that new treatments for diabetes do not increase cardiovascular risk. For dapagliflozin these data are being obtained from the study programme, which includes two ongoing phase III studies evaluating the safety and efficacy of dapagliflozin therapy in patients with type 2 diabetes and established cardiovascular disease and/or hypertension. Both of these are expected to complete in December 2011. Cardiovascular safety data for canagliflozin is being obtained from a large, dedicated phase III study: CANagliflozin cardiovascular Assessment Study (CANVAS). This will evaluate the use of canagliflozin or placebo in the treatment of around 5,000 patients with type 2 diabetes with a history of, or high risk for, cardiovascular disease. The primary end point for this study will be the incidence of major cardiovascular events including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The study is expected to run for four years and to complete in April 2013. If the safety parameters are met and the drug obtains a licence it is the intention to expand this into a study of possible cardiovascular benefits in 20,000 patients.
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