Table 2 summarizes the clinical efficacy of dapagliflozin. The safety and efficacy of dapagliflozin was evaluated in a multicenter, prospective, 12-week, randomized, parallel-group, double-blind, placebo-controlled, clinical trial. A total of 389 treatment-naïve patients with type 2 diabetes, aged 18–79 years, with an A1C of 7–10% were randomly assigned to dapagliflozin 2.5, 5, 10, 20, or 50 mg once/day, metformin extended-release 750 mg/day force-titrated at week 2 to 1500 mg/day, or placebo. Patient inclusion criteria were fasting C-peptide greater than 1.0 ng/ml, body mass index (BMI) of 40 kg/m2 or less, glomerular filtration rate greater than 60 ml/minute/1.73 m2, and urine microalbumin:creatinine ratio of 300 mg/g or less. The primary outcome was a comparison of the mean A1C reduction from baseline for each dapagliflozin group versus placebo after 12 weeks of therapy. Secondary outcomes included changes from baseline in fasting plasma glucose (FPG) level, total body weight, and urinary glucose excretion.
Baseline demographics were similar for all patient subgroups. A total of 41 patients discontinued the trial; the most common cause was withdrawal of consent. The number of patients who discontinued because of adverse events was one for dapagliflozin 2.5 mg, zero for dapagliflozin 5 mg, three for dapagliflozin 10 mg, two for dapagliflozin 20 mg, two for dapagliflozin 50 mg, one for placebo, and one for metformin. At week 12, the change in mean A1C value from baseline was −0.55% to −0.90% for all dapagliflozin groups, −0.18% for placebo, and −0.73% for metformin (p<0.05 for all dapagliflozin groups vs placebo). Mean changes from baseline in FPG level were −16 to −31 mg/dl for all dapagliflozin groups, −6 mg/dl for placebo, and −18 mg/dl for metformin (p<0.05 for all dapagliflozin groups vs placebo). As anticipated, all dapagliflozin groups displayed an increase in urinary glucose excretion (p<0.001 for all dapagliflozin groups vs placebo). Mean changes in total body weight were −2.5% to −3.4% for dapagliflozin, −1.2% for placebo, and −1.7% for metformin.
Overall, dapagliflozin was well tolerated, with no deaths or serious adverse events reported. Hypoglycemia occurred in 6–10% of patients assigned to dapagliflozin, 4% assigned to placebo, and 9% assigned to metformin. Infections of the urinary tract (cystitis and urinary tract infections [UTIs]) were observed in 5–12%, 6%, and 9% of patients taking dapagliflozin, placebo, and metformin, respectively. Signs and symptoms suggestive of genital infections, but not UTIs, were reported in 2–7% of patients taking dapagliflozin, 0% taking placebo, and 2% taking metformin.
This trial demonstrated that dapagliflozin, across many dosing schemes, is effective in reducing total body weight, A1C, and FPG values. Furthermore, the adverse-effect profile of dapagliflozin was acceptable compared with those of metformin or placebo. Compared with metformin, dapagliflozin demonstrated a comparable safety and efficacy profile. Future trials need to be conducted in a similar manner and must address some of the limitations of this study such as a suboptimal metformin dose, short duration, and small sample size.
The safety and efficacy of dapagliflozin in treatment-naïve patients with type 2 diabetes who were inadequately controlled with diet and exercise alone were explored in an additional study. This 24-week, randomized, parallel-group, double-blind, placebo-controlled, phase III study assessed patients with an A1C of 7–10%, BMI less than 45 kg/m2, and a fasting C-peptide level of 1 ng/ml or greater. Patients were unable to participate if they had impaired renal or hepatic function, a cardiovascular event within 6 months, heart failure (New York Heart Association classes III–IV), or elevated blood pressure (systolic >180 mm Hg or diastolic >110 mm Hg). Patients were equally and randomly assigned to placebo or dapagliflozin 2.5, 5, or 10 mg once/day. The primary outcome of this study was a change from baseline in A1C at week 24. Additional outcomes included changes from baseline in FPG level and total body weight.
In total, 485 patients were randomly assigned to treatment. Patient demographics were similar in all study groups. The number of patients who discontinued because of adverse events was 1 (1.3%), 2 (3.1%), 3 (4.7%), and 5 (7.1%) in the placebo, dapagliflozin 2.5-mg, dapagliflozin 5-mg, and dapagliflozin 10-mg groups, respectively. Changes in A1C ranged from −0.58% to −0.89% with dapagliflozin compared with −0.23% with placebo; the reduction in A1C afforded by dapagliflozin therapy was statistically significant for the 5- and 10-mg dose groups. Dapagliflozin 5- and 10-mg doses were also associated with significant reductions in FPG compared with placebo (−15 to −29 mg/dl vs 4.1 mg/dl, respectively). Although all dapagliflozin groups had reductions in total body weight (−3.3 kg to −3.8 kg) compared with placebo (−2.2 kg), the difference in these changes was not statistically significant. Furthermore, this trial also demonstrated large A1C reductions in an additional cohort of 74 patients with baseline A1C values ranging from 10.1–12% who were treated with dapagliflozin (−2.88% and −2.66% in the dapagliflozin 5- and 10-mg groups, respectively).
Dapagliflozin was generally safe in patients with type 2 diabetes, with no discontinuations due to hypoglycemia. Consistent with other trials, dapagliflozin-treated patients experienced a higher frequency of adverse events that were suggestive for possible genital infections (7.7–12.9% with dapagliflozin vs 1.3% with placebo) and UTIs (4.6–12.5% with dapagliflozin vs 4.0% with placebo). Mean seated blood pressure values declined with dapagliflozin therapy (systolic −2.3 mm Hg to −4.6 mm Hg; diastolic −1.7 mm Hg to −2.8 mm Hg) with no notable increases in orthostatic hypotension, although these reductions were not statistically significantly different from baseline. The reduction in blood pressure observed in dapaglifozin studies has been ascribed to the drug's mild osmotic-diuretic effect. Increments in fractional renal glucose loss were directly related to reductions in body weight (r=−0.13, p=0.008).
The authors were able to conclude that treatment-naïve patients randomly assigned to dapagliflozin experienced reductions in A1C, FPG, total body weight, and blood pressure. It is encouraging to note that the reduction in total body weight did not plateau by the end of the study, indicating that the full potential of dapagliflozin may not have been realized and underscoring the importance of longer term studies with extended follow-up. This was also the first study to explore the efficacy of dapagliflozin in patients with an A1C greater than 10%. The findings signify that numerically greater reductions are expected in patients who have a higher baseline A1C.
Dapagliflozin With Oral Antidiabetic Drugs The efficacy of dapagliflozin in addition to metformin was first evaluated in a double-blind, placebo-controlled, randomized, parallel-group, multiple-dose, phase IIa study. Inclusion criteria were age 18–70 years, treatment-naïve or receiving a stable metformin dose, BMI less than 42 kg/m2, FPG level of 240 mg/dl or less, A1C of 6–10%, and normal renal function. Patients were not allowed to participate if they had a history of cardiovascular, renal, hepatic, neurologic, or gastrointestinal disease. Those receiving a stable dose of metformin (>4 wks) before randomization were given dapagliflozin as add-on therapy. A total of 47 patients (19 men, 28 women) were randomly assigned in a ratio of 1:1:1:2 to placebo or dapaglliflozin 5, 25, or 100 mg once/day, respectively. Baseline demographics were well balanced. Eighteen patients continued taking their maintenance dose of metformin (six, five, and seven patients in the 5-, 25-, and 100-mg dapagliflozin groups, respectively).
On day 13, treatment with dapagliflozin resulted in dose-dependent reductions in FPG of −11.7% (p<0.05), −13.3% (p<0.05), and −21.8% (p<0.0001) in the 5-, 25-, and 100-mg groups, respectively. After an oral glucose tolerance test (OGTT), dapagliflozin was associated with a reduction in glucose excursion on day 2 (range −9.6% to −13.7%, p<0.001) and on day 13 (range −17.6% to −22.6%, p<0.001). Increases in urinary glucose excretion were also dose dependent, resulting in losses of 36.6, 70.1, and 69.9 g/day after 2 weeks of therapy with the 5-, 25-, and 100-mg doses of dapagliflozin, respectively.
Dapagliflozin, either alone or in combination with metformin, was well tolerated with no deaths, serious adverse events, or withdrawals reported over 14 days. Two episodes of hypoglycemia were reported with dapagliflozin use; however, these were mild and self-limiting. Two female patients experienced vulvovaginal mycotic infections that were mild in nature and resolved with miconazole therapy. This study was the first to show that dapagliflozin, with or without metformin, results in clinically significant dose-dependent increases in glucosuria and improvements in FPG and OGTT results. It was noted that on day 14, a similar level of SGLT2 inhibition resulted in lower cumulative amounts of glucose excretion, indicating that the amount of glucose filtered by the glomeruli might diminish over time as plasma glucose levels stabilize. However, because of the short duration of this trial, long-term estimates are unable to be calculated from the results of this study.
In the first large-scale phase III clinical trial, the safety and efficacy of dapagliflozin in patients with type 2 diabetes who demonstrated inadequate control with metformin monotherapy were investigated. This study was a 24-week, multicenter, double-blind, parallel-group, placebo-controlled trial in which 546 patients were randomly assigned to receive dapagliflozin 2.5, 5, or 10 mg once/day or matching placebo in a 1:1:1:1 ratio. Patients were eligible to participate if they were aged 18–77 years and met the following criteria: A1C of 7–10%, C-peptide concentration greater than 0.34 nmol/L (1.0 ng/ml), BMI less than 45 kg/m2, and were taking a stable dose of metformin (≥ 1500 mg/day) for at least 8 weeks before enrollment. Patients continued taking metformin during the trial. Those who had impaired renal or hepatic function, a cardiovascular event within the past 6 months, heart failure (New York Heart Association classes III–IV), or elevated blood pressure (systolic > 180 mm Hg or diastolic > 110 mm Hg) were not permitted to participate. The predefined primary end point was a change from baseline in A1C at week 24. Predefined secondary end points included a change in FPG level (assessed at wk 1 and wk 24) and total body weight.
A total of 483 patients (88%) completed the trial. The primary reason for discontinuation was withdrawal of consent (17 patients) or loss to follow-up (18 patients). Baseline demographics were well matched in each treatment group for age, sex, BMI, A1C, FPG level, blood pressure, and baseline metformin dose (1792–1861 mg). After 24 weeks of therapy, mean change from baseline in A1C was significantly reduced in the dapagliflozin 2.5-, 5-, and 10-mg groups (−0.67%, −0.70%, and −0.84%, respectively) compared with placebo (−0.30%, p<0.0005). At week 1, FPG level was significantly reduced in the dapagliflozin 5- and 10-mg groups compared with placebo. By week 24, however, reductions in FPG were statistically significant in all dapagliflozin dosing groups (−18 mg/dl to −23 mg/dl) compared with placebo (−6 mg/dl). Mean total body weight decreased in a similar fashion, with reductions in mean total body weight ranging from 2.2−2.9 kg with dapagliflozin versus 0.9 kg with placebo (p<0.0001 for all dapagliflozin groups vs placebo). The authors suggested that dapagliflozin may induce weight loss partly through a mild osmotic diuresis.
Although dapagliflozin was generally well tolerated, a larger proportion of patients experienced signs and symptoms suggestive of genital infections compared with the placebo group (8–13% vs 5%). The percentage of patients experiencing a UTI was 4–8% with dapagliflozin and 8% with placebo. Dapagliflozin was not associated with an increased risk of hypoglycemia compared with placebo. This trial was the largest to date showing that dapagliflozin is safe and effective when added to metformin. Several findings from this study (i.e., small increases in hematocrit and small decreases in uric acid level and blood pressure) indicate that dapagliflozin may harbor ancillary or pleiotropic properties that could confer long-term benefits not yet fully appreciated in shorter clinical trials. Furthermore, this is the first trial to demonstrate a greater reduction in A1C in patients with a higher baseline A1C value.
A 52-week, multicenter, randomized, parallel-group, double-blind, active-controlled phase III study assessed the noninferiority of dapagliflozin compared with glipizide in patients inadequately controlled with at least 1500 mg/day of metformin. In total, 814 patients with type 2 diabetes aged 18 years or older with an A1C of 6.5–10% were randomly assigned to either dapagliflozin, starting at 2.5 mg/day, plus metformin, or glipizide, starting at 5 mg/day, plus metformin. Dose titration up to dapagliflozin 10 mg/day or glipizide 20 mg/day was allowed as necessary up to week 18. Noninferiority was defined as a difference in change in A1C of less than 0.35% for the comparison of dapagliflozin and glipizide. Secondary end points included the change from baseline in body weight and self-reported hypoglycemia events at week 52. These results have been published only in abstract form.
After 52 weeks of therapy, both the dapagliflozin-based regimen and glipizide-based regimen reduced A1C levels by 0.52% (difference in adjusted mean change from baseline for dapagliflozin added to metformin vs glipizide added to metformin was 0.00%, 95% confidence interval [CI] −0.11–11, indicating noninferiority). Patients treated with the dapagliflozin-based regimen had significantly greater reductions in mean total body weight compared with those treated with a glipizide-based regimen (−3.22 vs + 1.44 kg, p<0.0001 for the comparison between groups). A significant difference was noted between the percentage of patients who experienced a hypoglycemic event in the dapagliflozin-based groups (3.5%) versus those in the glipizide-based groups (40.8%, p<0.0001). No baseline demographics were presented for this unpublished study at the time of writing.
Discontinuations due to an adverse event were 9.1% for the dapagliflozin-based regimen versus 5.9% for the glipizide-based regimen. Signs and symptoms suggestive of UTIs were more frequent in patients taking a dapagliflozin-based regimen (10.8%) compared with the glipizide-based regimen (6.4%). Similarly, genital infections were more frequent with the dapagliflozin-based regimen (12.3%) than the glipizide-based regimen (2.7%). The dapagliflozin-based regimen was associated with reductions in both systolic and diastolic blood pressure (4.3 mm Hg and 1.6 mm Hg, respectively), whereas the glipizide-based regimen was not (+0.8 mm Hg and +0.4 mm Hg, respectively).
This was the first study conducted to assess the noninferiority of dapagliflozin versus other agents in the antidiabetic drug arena. The results of this study indicate that dapagliflozin compares favorably with glipizide in patients who are inadequately treated with metformin, with a lower frequency of hypoglycemia but increased occurrence of UTI and genital infections.
The efficacy of dapagliflozin added to glimepiride in patients with type 2 diabetes was studied in a 24-week, multicenter, international, randomized, parallel-group, double-blind, placebo-controlled, phase III clinical trial. This study randomly assigned 597 patients aged 18 years or older with an A1C of 7–10% to one of four treatment groups: dapagliflozin 2.5, 5, or 10 mg/day plus glimepiride, or placebo plus glimepiride. To be eligible, patients had to be receiving at least half the recommended maximal dose of glimepiride. The primary end point of this study assessed the change from baseline in A1C at week 24. Additional end points included change from baseline in total body weight, OGTT, and FPG. The results from this study have been presented in abstract form and are unavailable in a peer-reviewed format; thus, no baseline demographics have been reported yet.
Reductions in A1C levels ranged from −0.58% to −0.82% with dapagliflozin compared with −0.13% with placebo when either was added to glimepiride (p<0.0001 for all dapagliflozin groups vs placebo). A dose-dependent reduction in total body weight was also noted, ranging from −1.18 kg to −2.26 kg with dapagliflozin compared with −0.72 kg with placebo (p>0.05, p<0.01, p<0.0001 for dapagliflozin 2.5, 5, and 10 mg, respectively, vs placebo). The change in OGTT results from baseline was −37.5, −32.0, −34.9 mg/dl in the dapagliflozin 2.5-, 5-, and 10-mg groups, respectively, compared with −6.0 mg/dl in the glimepiride group. Patients in the dapagliflozin 5- and 10-mg groups had significant reductions in FPG (−21.2 and −28.5 mg/dl, respectively) compared with those in the placebo group (−2.0 mg/dl, p<0.0001 for both dapagliflozin groups vs placebo). Patients in the dapagliflozin 2.5-mg group had a reduction in FPG of −16.8 mg/dl.
More patients allocated to dapagliflozin experienced the following adverse events compared with placebo: back pain (1.9–4.6% vs 2.7%), upper respiratory tract infection (3.2–4.6% vs 2.7%), and bronchitis (1.3–3.3% vs 0.7%). The rates of UTI were similar among all groups: 3.9%, 6.9%, and 5.3% of patients in the dapagliflozin 2.5-, 5-, and 10-mg groups, respectively, compared with 6.2% of patients taking placebo. Genital infections were reported more frequently in patients taking dapagliflozin (3.9–6.6%) than in those taking placebo (0.7%). Serious adverse events were also more common with dapagliflozin (6.0–7.1%) than with placebo (4.8%). There appeared to be an increased risk for hypoglycemia when dapagliflozin was added to glimepiride (6.9–7.9%) compared with placebo plus glimepiride (4.8%). Mean reductions in seated systolic and diastolic blood pressure in the dapagliflozin groups and placebo group were −4.0 mm Hg to −5.0 mm Hg and −1.1 mm Hg to −2.8 mm Hg, respectively.
This trial was the first to demonstrate that dapagliflozin produces significant reductions in A1C in patients with type 2 diabetes when added to glimepiride. The frequency of adverse events was similar between both treatment groups, although the rates of gential infection and hypoglycemia were numerically higher in patients taking dapagliflozin plus glimepiride. Trials that are longer in duration would be helpful to assess whether the reductions in A1C, FPG, OGTT, and blood pressure with dapagliflozin added to glimepiride result in a favorable risk-benefit profile compared with other strategies.
Dapagliflozin With Insulin, With or Without Oral Antidiabetic Drugs The safety and efficacy of dapagliflozin added to insulin and OADs have been evaluated in a 12-week, randomized, single- and double-blind, three-arm parallel group, placebo-controlled trial. A total of 71 patients were randomly and equally assigned to placebo or dapagliflozin 10 mg/day or 20 mg/day, in addition to their previous OAD(s) and 50% of their current daily insulin dose. Down-titration of insulin doses occurred when patients were at risk for hypoglycemic events (plasma glucose level <54 mg/dl), and up-titration occurred when patients experienced elevated FPG values (>240 mg/dl at wks 4 and 6, >220 mg/dl at wk 8, and >200 mg/dl at wk 10). No dosage adjustments were allowed with dapagliflozin or OAD(s).
Inclusion criteria were type 2 diabetes, age 18–75 years, BMI of 45 kg/m2 or less, A1C of 7.5–10%, stable insulin sensitizer dose for 6 weeks or longer (metformin ≥ 1000 mg/day and/or pioglitazone ≥ 30 mg/day or rosiglitazone 4 mg/day), stable insulin dose for 12 weeks or longer, fasting C-peptide level of 0.8 ng/ml or greater, serum creatinine level less than 1.5 mg/dl (men) and less than 1.4 mg/dl (women), urine microalbumin:creatinine ratio less than 300 mg/g, and total urinary protein less than 3 g/24 hours. Patients were excluded if they had type 1 diabetes mellitus or any severe cardiovascular, renal, or hepatic disease. The primary outcome was a change from baseline in A1C values at week 12. Additional outcomes included change from baseline in FPG, total daily dose of insulin, and total body weight.
Most patients were taking combination metformin and insulin (74.7%) before randomization, and participants tended to be male (59.3%) and Caucasian (94.4%). Other baseline demographics were well matched. At the end of 12 weeks, the difference in mean change from baseline in A1C was −0.70% and −0.78% for dapagliflozin 10 mg and 20 mg, respectively, versus placebo. Changes in FPG levels were 17.8 mg/dl for placebo, 2.4 mg/dl for dapagliflozin 10 mg, and −9.6 mg/dl for dapagliflozin 20 mg. Patients receiving dapagliflozin tended to have greater reductions in total body weight compared with those receiving placebo (−4.3 kg to −4.5 kg vs −1.9 kg). After the 50% dose reduction, changes in total daily dose of insulin were not different from baseline in any treatment group. Dapagliflozin reduced mean systolic blood pressure (−6.1 mm Hg to −7.2 mm Hg) and diastolic blood pressure (−1.2 mm Hg to −3.9 mm Hg) as well as mean serum uric acid levels (−0.30 mg/dl).
This study is the first to confirm the utility of combining dapagliflozin with insulin and other OADs in patients with type 2 diabetes. This initial trial experience with dapagliflozin added to insulin and OADs provides evidence of reductions in A1C and FPG with a favorable safety profile in patients not controlled with two therapies. Despite the short duration and small sample size, this trial represents the impetus for future long-term trials in this population.
Dapagliflozin was evaluated in a 48-week clinical trial in patients with type 2 diabetes who were inadequately controlled with insulin therapy (with or without up to two OADs). A total of 808 patients with an A1C of 7.5–10.5% and receiving a mean insulin dose of 30 or more international units/day for at least 8 weeks were randomly assigned to dapagliflozin 2.5, 5, or 10 mg/day or placebo. Baseline demographics were not reported at the time of this writing. Down-titration of insulin was permitted when patients were at risk for hypoglycemic events (defined as a plasma glucose ≤ 70 mg/dl on ≥ 2 occasions), and up-titration was permitted if patients had three or more fasting serum glucose levels over the past 7 days that were greater than 240 mg/dl during weeks 1–12, greater than 220 mg/dl during weeks 13–24, and greater than 180 mg/dl during weeks 25–48. The primary end point was a change from baseline in A1C values at week 48. Additional end points included a change from baseline in total body weight and total daily dose of insulin at 48 weeks.
At 48 weeks, changes in A1C from baseline were −0.74% (95% CI −0.48% to −0.13%), −0.94% (95% CI −0.69% to −0.33%), and −0.93% (95% CI −0.67% to −0.32%) in the dapagliflozin 2.5-, 5-, and 10-mg groups, respectively. Placebo was associated with a −0.43% change in A1C from baseline at 48 weeks. Patients taking dapagliflozin had dose-dependent reductions in total body weight ranging from 0.83 kg to 1.45 kg, whereas placebo increased total body weight by 0.85 kg. Placebo-treated patients tended to require more up-titration of insulin throughout the study, requiring a mean increase of 10.54 IU/day. Conversely, total daily dose of insulin did not change from baseline in patients taking dapagliflozin (ranging from −0.92–0.30 IU/day), suggesting that dapagliflozin afforded patients an insulin-sparing effect. Similar to other trials, mean seated systolic blood pressure decreased from baseline with dapagliflozin (−3.8 mm Hg to −5.4 mm Hg), as well as mean seated diastolic blood pressure (−2.3 mm Hg to −3.1 mm Hg). Slight reductions in serum uric acid levels were also observed during the trial.
Dapagliflozin was generally well tolerated, and adverse events were reported in similar proportions of placebo-treated patients (73.1%) and dapagliflozin-treated patients (72.2–75.7%). More patients had a hypoglycemic event with dapagliflozin (53.6–60.4%) than with placebo (51.8%). A larger number of patients experienced genital infections in the dapagliflozin groups (13–21 patients) compared with placebo (five patients). Urinary tract infection was also reported more frequently in the dapagliflozin groups (11–16 patients) than with placebo (eight patients).
This was the second trial that assessed the efficacy and safety of adding dapagliflozin to an inadequate insulin regimen with or without OADs. Dapagliflozin produced sustained reductions in plasma glucose levels after 48 weeks of treatment and demonstrated its ability to reduce the total daily dose of insulin in patients already taking insulin. The reduction in total daily dose of insulin may likely be due to the sustained plasma glucose lowering and reduction in weight. Although it was already shown that dapagliflozin produces reductions in both A1C and total body weight in another trial, this study provided evidence that dapagliflozin's effects are durable and persisted over 48 weeks. However, future trials will need to assess the long-term safety and tolerability of dapagliflozin in conjunction with insulin and other OADs.
Pharmacotherapy. 2012;32(1):80-94. © 2012 Pharmacotherapy Publications