Dapagliflozin is a sodium glucose co-transporter inhibitor under review for FDA approval for the treatment of type 2 diabetes mellitus. Despite the availability of many antidiabetic agents in the United States, type 2 diabetes remains inadequately controlled in many patients.
Dapagliflozin is a sodium glucose co-transporter inhibitor under review for FDA approval for the treatment of type 2 diabetes mellitus. Despite the availability of many antidiabetic agents in the United States, type 2 diabetes remains inadequately controlled in many patients. Type 2 diabetes patients are at risk for complications such as retinopathy, nephropathy, neuropathy, and accelerated cardiovascular disease. Moreover, many of the currently marketed antidiabetic agents in the United States have been associated with treatment-limiting side effects. Therefore, efficacious alternative agents without these side effects are needed for the management of patients with this devastating chronic condition. Phase 3 trials have established the efficacy of dapagliflozin dosages of 5 to 10 mg once daily in treatment-naïve type 2 diabetes patients. Dosages of dapagliflozin ranging from 2.5 to 10 mg once daily have been shown to be efficacious in type 2 diabetes patients already on metformin or glimepiride. Pharmacokinetic studies of dapagliflozin have shown a low propensity for drug interactions. The most common adverse effects reported in phase 3 trials were signs and symptoms suggestive of genital and urinary tract infections. Unresolved issues with dapagliflozin treatment include risks of breast cancer, bladder cancer, and liver dysfunction in type 2 diabetes mellitus patients. (Formulary. 2011; 46:412-431.)
Diabetes mellitus is a group of complex metabolic disorders characterized by defective insulin secretion and/or insufficient action of insulin (insulin resistance).1 Poor glycemic control contributes to micro- and macrovascular complications such as retinopathy, nephropathy, neuropathy, and accelerated cardiovascular disease.2
In the UK Prospective Diabetes Study, approximately half of the study population required combination therapy within 3 years of diagnosis, with the percentage increasing to 75% by the ninth year of disease.4
Type 2 diabetes is caused by nonmodifiable factors such as advanced age, ethnicity, and genetics, but also by modifiable factors such as sedentary lifestyle, weight/body mass index (BMI), and central adiposity.1 Before type 2 diabetes is fully manifested, there is a several-year period of insulin resistance and impaired glucose tolerance (IGT). During this time, in order to maintain fasting glucose within normal range, endogenous insulin secretion in IGT may be increased. Two-hour postprandial blood glucose elevations to 140 to 199 mg/dL occur as endogenous insulin secretion is decreased, ultimately leading to type 2 diabetes. It has been postulated that people with defective β-cell function in the presence of insulin resistance at the level of muscle, fat, and liver may be predisposed to developing type 2 diabetes. Gluco- and lipotoxicity contribute to the deterioration of β-cell function.1 In addition to impaired insulin action and secretion, nonsuppressible glucagon secretion has been exhibited by type 2 diabetes patients after meals.1 Glucagon-like peptide 1 (GLP-1) is an incretin that L cells of the intestine secrete upon eating. GLP-1 regulates gastric emptying, enhances glucose-dependent insulin secretion, and reduces glucagon secretion postprandially. It promotes satiety and decreases appetite, producing noticeable weight loss.1
The 2011 American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus includes one of the following: (1) hemoglobin A1c ≥6.5%; (2) fasting plasma glucose ≥126 mg/dL, with fasting defined as no caloric intake for at least 8 hours; (3) 2-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test, with the glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water; (4) classic symptoms of hyperglycemia and a random plasma glucose ≥200 mg/dL; or (5) in the absence of unequivocal hyperglycemia, results confirmed by repeat testing.5
Initial treatment involves diabetes self-management education, medical nutrition therapy, and physical exercise. Diabetes education generally includes information on disease progression, treatment options, nutrition, exercise, prescribed medications, self-monitoring of blood glucose, diabetes complications, psychosocial concerns, and individualized plans.1 Medical nutrition therapy usually targets weight loss through consuming fewer carbohydrates and saturated fat, along with ingesting more dietary fiber. Regarding exercise, diabetic patients should incorporate at least 150 minutes of moderate-intensity aerobic physical activity (50% to 70% of maximum heart rate) into their weekly schedule.5
The ADA "Standards of Medical Care in Diabetes-2011" guidelines recommend initiating metformin therapy concurrently with lifestyle modifications in newly diagnosed patients.5 Furthermore, in order to achieve and maintain glycemic control, timely augmentation of treatment with additional agents (including early initiation of insulin therapy) should occur on a continual basis. Pharmacologic agents from different classes should be added to existing therapy when patients fail to meet hemoglobin A1c targets.5 However, achieving and maintaining treatment goals can be challenging and problematic with the currently available treatment options.
Sulfonylureas increase the production of insulin from the pancreatic β-cells, but excessive insulin release may cause weight gain and hypoglycemia. Moreover, apoptosis of β-cells may contribute to a 20% primary failure rate and a secondary failure rate of 5% to 10% per year of treatment.1 Meglitinides act by binding to a different part of the sulfonylurea receptor than sulfonylurea drugs; these agents also cause weight gain and hypoglycemia, and appear to be less potent than the sulfonylurea drugs.1 Thiazolidinediones have been shown to preserve or improve β-cell secretory function in type 2 diabetes patients, but these drugs have also been shown to cause weight gain and to increase the risk of cardiovascular events. They are contraindicated in patients with heart failure.1 Since α-glucosidase inhibitors block the digestion of complex carbohydrates in the upper portion of the small intestine, they cause flatulence (due to higher glucose load in colon) and are contraindicated in patients with gastrointestinal diseases.1
GLP-1 (gut hormone) analogs lower hepatic glucose output through stimulation of glucose-dependent insulin secretion and inhibition of glucagon production. These agents can be used in combination with metformin, sulfonylureas, or thiazolidinediones, and have been shown to be associated with weight loss in type 2 patients. FDA has required the manufacturer of liraglutide to include a boxed warning about increased risk of medullary thyroid cancer in the prescribing information document. Another safety concern is the possible increased risk of pancreatitis seen in users of exenatide or liraglutide, which needs to be addressed in long-term safety studies.1
Dipeptidyl peptidase IV (DPP-IV) inhibitors are weight-neutral drugs that prevent the degradation of native GLP-1, thereby increasing the levels of this incretin (peptide hormones that modulate glucose metabolism). DPP-IV inhibitors can be administered as monotherapy or in combination with other oral agents such as metformin, but the long-term safety of this class of drugs has yet to be established.1 Pramlintide, an amylin analog, is thought to exert its action through suppression of inappropriate glucagon secretion after eating, and by increasing satiety. This agent has been shown to promote weight loss in morbidly obese type 2 diabetic patients and it serves as an adjunct to insulin therapy, with or without concurrent therapy with a sulfonylurea agent and/or metformin.1 Pramlintide users often experience gastrointestinal adverse effects (bloating, nausea, vomiting), and they have a heightened risk for hypoglycemia, as this agent is used in combination with insulin therapy. Colesevelam, a bile acid sequestrant used for the management of patients with dyslipidemia, has recently been FDA-approved for treatment of type 2 diabetes mellitus.1 This agent's beneficial effects may arise from delayed or altered intestinal absorption of glucose; constipation may occur in some patients taking colesevelam.
Because current type 2 diabetes therapies are often limited by their potential significant adverse effects, researchers have been looking for alternative agents without these side effects. Dapagliflozin, a sodium glucose co-transporter (SGLT) inhibitor, offers a novel approach to the treatment of type 2 diabetes mellitus, and is under investigation for the treatment of this condition. A new drug application (NDA) for dapagliflozin was submitted to FDA in December 2010 by Bristol-Myers Squibb and AstraZeneca.6 On July 19, 2011, an advisory committee voted 9 to 6 to reject the NDA for dapagliflozin because of concerns regarding breast cancer, bladder cancer, and liver dysfunction.7 FDA will make its final decision regarding the NDA on October 28, 2011.
CHEMISTRY AND PHARMACOLOGY
Dapagliflozin [(2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol] belongs to the SGLT inhibitor class of drugs.8 SGLTs are a family of proteins expressed in various human tissues including the central nervous system, intestinal epithelium, and renal tubules.9 Among SGLTs, which transport glucose, amino acids, vitamins, ions, and osmolytes across these tissue membranes, SGLT1 and SGLT2 mediate glucose reabsorption. Whereas SGLT1 is the major glucose transporter in the small intestine, SGLT2 is predominantly expressed on the surface of epithelial cells lining the S1 segment of the proximal convoluted tubule. SGLT2 is a 672-amino acid transporter believed to account for 90% of renal glucose reabsorption.9 Given its role in glucose transport within the kidney, SGLT2 has become an attractive therapeutic target in the management of type 2 diabetes mellitus.
In the proximal convoluted tubule of the kidney, SGLT2 binds sodium and glucose in tubule fluid, and sodium and glucose are translocated across the apical cell membrane by a process driven by the electrochemical gradient of sodium between the tubule and the cell.9 The average capacity of maximum glucose reabsorption of renal tubules is 375 mg/min. In nondiabetic individuals, the filtered glucose load does not surpass 375 mg/min, and the entire load of filtered glucose is reabsorbed into the systemic circulation. In diabetic individuals who experience a filtered glucose load in excess of 375 mg/min, reabsorption capacity is exceeded and the excess glucose is excreted in urine.9
SGLT2 inhibitors have been a focus of clinical research in the management of type 2 diabetes over the past 2 decades.9 To date, dapagliflozin is farther along in clinical development compared with other SGLT2 inhibitors, with numerous phase 2b and 3 studies completed in recent years. Other notable agents that have been studied in this drug class include sergliflozin, remogliflozin, and canagliflozin, which are at various stages of clinical development and study.9 SGLT2 inhibitors contain a similar chemical moiety to that of a natural SGLT2 inhibitor called O-glucoside phlorizin. Phlorizin was first isolated in 1835 from the root bark of the apple tree, and has been documented to be a potent but nonselective SGLT inhibitor that induces glucosuria and weight loss in humans following oral administration.2,9 However, it was not considered a suitable drug due to its poor metabolic stability. Rapid degradation by β-glycosidase in the gut, poor intestinal absorption, and resultant low bioavailability limited its therapeutic potential. Also, since phlorizin acts on SGLT1, which is mainly expressed in the gastrointestinal tract, this agent causes glucose and galactose malabsorption, along with gastrointestinal side effects such as diarrhea.2 Dapagliflozin has been shown to be selective for SGLT2 (1,200-fold over SGLT1), and because of its C-glucoside chemical structure, has improved metabolic stability in comparison to phlorizin.8
PHARMACOKINETICS OF DAPAGLIFLOZIN
Obermeier and associates conducted pharmacokinetic assessments of dapagliflozin in an in vitro and human trial that involved Caco-2 cell (continuous line of heterogeneous human epithelial colorectal adenocarcinoma cells) permeability studies, cytochrome P450 studies in human hepatocytes/human liver microsomes, and an open-label, nonrandomized, single-dose study in 6 healthy adult men.8 Caco-2 cell permeability studies were performed to assess the ability of dapagliflozin to inhibit P-glycoprotein (P-gp), along with determining if it is a substrate of P-gp. The basolateral to apical (B-to-A) permeability coefficient value was 227 nm/s (BA/AB ratio, 3.8) in the initial Caco-2 cell permeability analysis (absence of P-gp inhibitor). The BA/AB ratio declined to 1.2 in the presence of a P-gp inhibitor (B-to-A permeability coefficient, 188 nm/s; A-to-B permeability coefficient, 159 nm/s), indicating that dapagliflozin may be a substrate of P-gp. The ability of dapagliflozin to inhibit P-gp was determined by measuring the permeability of digoxin, a known P-gp substrate, across Caco-2 cell monolayers in the presence and absence of dapagliflozin (10 μM). This analysis revealed 10% inhibition of digoxin, a modest effect, compared with the 65% inhibition exerted by a known P-gp inhibitor, verapamil.
Dapagliflozin, at concentrations ranging from 0.2 to 20 μM, did not induce CYP (cytochrome P450) 1A2, CYP2B6, or CYP3A4 in human hepatocytes.8 Dapagliflozin did not inhibit the activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes, as shown by IC50 (half maximal inhibitory concentration) values that exceeded the highest concentration of dapagliflozin evaluated (45 μM). Administration of dapagliflozin 50 mg as a single dose to 6 adult men (in fasted state) revealed that maximal plasma concentrations (Cmax) occurred within 1 hour, and that the amount of unchanged dapagliflozin recovered in the urine was 1.6%. Additional pharmacokinetic parameters determined for dapagliflozin included half-life (t1/2), oral plasma clearance, and renal clearance. Consumption of a single dose of 50 mg yielded a half-life of 13.8 hours, oral plasma clearance of 4.9 mL/min/kg, and a renal clearance of 5.6 mL/min.8
Positive pharmacokinetic properties were observed in single ascending dose (SAD) and multiple ascending dose (MAD) studies of dapagliflozin in healthy individuals who were assigned to dapagliflozin 2.5 to 500 mg, and dapagliflozin 2.5 to 100 mg, respectively.10 For the SAD and MAD studies, subjects assigned to receive the lowest dose began the regimen first, and after the investigators confirmed safety and tolerability, subjects assigned to the next dose level started their regimen.
The double-blind, randomized, placebo-controlled, 2-period, sequential, SAD study included 64 healthy subjects, who underwent randomization to receive placebo or single oral doses of dapagliflozin 2.5, 5, 10, 20, 50, 100, 250, or 500 mg. During the first period, subjects fasted for 10 hours before receiving the study drug. Subjects who received dapagliflozin 250 mg during period 1 advanced to period 2, following a 7-day washout phase, and received a second dose of dapagliflozin 250 mg or matched placebo after consuming a high-fat breakfast. Subjects achieved Cmax within 2 hours and demonstrated dose-proportional elevations in area under the plasma concentration-time curves (AUC) with doses up to 100 mg. The AUC increased slightly greater than dose-proportionally with doses between 100 mg and 500 mg, whereas Cmax values increased marginally less than dose proportionally. Consumption of a high-fat breakfast delayed the time to maximal concentration (Tmax) by 2.5 hours, reduced Cmax by 39%, and decreased AUC8 by 7% compared to values yielded during fasting.
The double-blind, randomized, placebo-controlled, sequential, MAD study included 40 healthy subjects who underwent randomization to receive placebo or doses of dapagliflozin 2.5, 10, 20, 50, or 100 mg administered for 14 days.10 The pharmacokinetic patterns observed in the MAD study paralleled the results yielded in the SAD study, as Cmax and AUCmax increased dose-proportionally. Mean half-life ranged from 11.2 hours to 16.6 hours, and the mean day 14: day 1 AUC index for dapagliflozin ranged from 1.20 to 1.30 for all doses. Less than 3% of dapagliflozin and 0.2% of its metabolite appeared in urine, matching the results obtained by Obermeier. Pharmacodynamic analyses revealed that dapagliflozin doses of 20 mg and higher inhibited up to 50% of filtered glucose from being reabsorbed by the kidney, which translates to glucose excretion of up to 3 g/h.10
Kasichayanula et al conducted SAD and MAD pharmacokinetic studies in Japanese subjects, using a narrower dosing range of dapagliflozin (2.5 to 50 mg).11 SAD and MAD study subjects assigned to receive the lowest dose began the regimen first, and after the investigators confirmed safety and tolerability, subjects assigned to the next dose level started their regimen. Both studies featured a randomized, double-blind, placebo-controlled, sequential, ascending-dose study design. The SAD study included 32 healthy subjects who underwent randomization to receive placebo or single doses of dapagliflozin 2.5, 10, 20, or 50 mg after fasting for 10 hours. Healthy subjects displayed dose-proportional increases in Cmax and AUC, and required 1.0 to 1.3 hours to achieve Cmax. The amount of unchanged drug found in urine ranged from 0.8% to 1.1% of total dose, and the mean t1/2 ranged from 8.1 to 12.2 hours. The MAD study included 36 type 2 diabetes patients who underwent randomization to receive either placebo or 14 days of dapagliflozin 2.5, 10, or 20 mg. Multiple doses of dapagliflozin did not yield substantially different pharmacokinetic parameters from those seen in SAD study patients, indicating that this drug does not have a time-dependent pharmacokinetic profile. Dose-dependent urinary excretion of glucose occurred in this study of healthy and diabetic Japanese subjects. Dapagliflozin inhibited SGLT2 by 20% to 44% in diabetes subjects and by 16% to 50% in healthy subjects.
The effect of a high-fat meal (fat calories comprised 52% of caloric content) on AUC and Cmax of dapagliflozin revealed no clinically meaningful effect on systemic exposure in a healthy volunteer study conducted by Kasichayanula et al.12 Fourteen subjects ingested dapagliflozin 10 mg in the fasted (≥10 hours) and fed state, with a 4-day washout period between treatments. If 90% confidence intervals (CIs) for the fed:fasted ratios of geometric means did not deviate from the range of 0.80 to 1.25 for Cmax and AUC for dapagliflozin, an absence of food effect was concluded by study investigators. The 90% CIs for the ratios of the population geometric means of fed versus fasted state remained within the interval of 0.80 to 1.25 for AUC8 values of dapagliflozin and dapagliflozin-3-O-glucuronide. The 90% CIs for the ratios of the population geometric means of fed vs. fasted states fell below the prespecified lower limit of 0.80 for Cmax values of dapagliflozin and dapagliflozin-3-O-glucuronide, but the investigators concluded that the effect of such a decrease was not likely to be clinically meaningful.
The NDA for dapagliflozin included supporting data from 4 phase 3 clinical trials that included more than 2,500 patients.13–16 The safety and efficacy of this agent was evaluated for initial therapy as a once daily oral monotherapy regimen (2.5, 5, 10 mg/d), or as add-on therapy to patients with inadequate control on metformin or a sulfonylurea (glimepiride).13-16 Furthermore, phase-3 trial investigators assessed the comparative glycemic control achieved by patients who received placebo or a sulfonylurea agent as add-on therapy to metformin, compared with that achieved by patients receiving dapagliflozin as add-on therapy to metformin.14,16 With the exception of one phase 3 study that evaluated change in hemoglobin A1c at 52 weeks, all phase-3 trials had the same primary end point of change from baseline hemoglobin A1c at 24 weeks.16 In general, exclusion criteria included: (1) history of type 1 diabetes; (2) BMI >45 kg/m2; (3) serum creatinine ≥133 mmol/L (men) or ≥124 mmol/L (women); (4) urine albumin-to-creatinine ratio >200 mg/mmol; (5) aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal; (6) creatine kinase >3 times the upper limit of normal; (7) symptoms of poorly controlled diabetes (including marked polyuria/polydipsia with >10% weight loss within the 3-month period preceding study enrollment); (8) significant renal, hepatic, hematologic, oncologic, endocrine, psychiatric, or rheumatic diseases; (9) a cardiovascular event (including New York Heart Association class III/IV congestive heart failure) within 6 months of enrollment; and (10) severe uncontrolled blood pressure (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg).
The role of dapagliflozin as monotherapy was explored in a parallel-group, double-blind, placebo-controlled phase 3 study of men and women aged 18 to 77 with type 2 diabetes.13 These subjects were treatment naive and experienced hyperglycemia that was inadequately controlled by diet and exercise alone. The main cohort consisted of individuals with a baseline A1c of 7.0% to 10.0% who received morning doses of placebo or once daily dapagliflozin (n=274). Four hundred eighty-five subjects underwent randomization to 1 of 7 treatment arms to receive once-daily placebo or dapagliflozin 2.5-, 5-, or 10-mg daily in the morning (main cohort) or in the evening (exploratory cohort). Seventy-three individuals with a higher A1c range of 10.1% to 12.0% underwent randomization to 1 of 2 treatment arms to receive 5- or 10-mg daily doses of dapagliflozin. The primary outcome measure of change from baseline A1c at week 24 pertained to the main cohort, not the exploratory cohorts. The ethnic background of study subjects was not reported, but patients had mean BMIs ranging from 32.3 to 33.6 kg/m2 and baseline A1c ranging from 7.84 to 8.01 in the main cohort. At 24 weeks, the 2.5-, 5-, and 10-mg doses of dapagliflozin reduced A1c by -0.58%, -0.77% (P=.0005 vs placebo), and -0.89% (P<.0001 vs placebo), respectively, in the main cohort. At week 24, the 5- and 10-mg doses of dapagliflozin reduced A1c by -2.88% and -2.66%, respectively, in the exploratory cohort of patients with an A1c >10%. However, decrements in mean body weight did not achieve statistical significance when comparing dapagliflozin-treated patients to placebo-treated patients. The diuretic effect of dapagliflozin also produced nonsignificant decreases in mean systolic and diastolic blood pressures, without inducing orthostatic hypotension.
A similar clinical trial compared the A1c-lowering effect of dapagliflozin with placebo, involving 546 type 2 diabetes patients on metformin (≥1,500 mg/d).14 This study differed from the one that compared the efficacy of dapagliflozin with that of placebo in treatment-naive patients by virtue of its choice of rescue medications for excessively elevated fasting plasma glucose concentrations (pioglitazone or acarbose vs metformin), along with lack of patients with A1c in excess of 10%. Ethnicity data were not included in this published report, and baseline A1c ranged from 7.92% to 8.17%. The patients in this study had an average duration of type 2 diabetes of approximately 6 years, and had mean BMIs ranging from 31.2 to 31.8 kg/m2. The results showed a significant reduction in mean A1c, with a decrease of -0.67% (95% CI, -0.81 to -0.53; P=.0002) in the dapagliflozin 2.5-mg group, -0.70% (95% CI, -0.85 to -0.56; P<.0001) in the 5-mg group, and -0.84% (95% CI, -0.98 to -0.70; P<.0001) in the 10-mg group, compared with -0.30% (95% CI, -0.44 to -0.16) in the placebo group. At 24 weeks, the 5- and 10-mg doses of dapagliflozin reduced A1c by -1.37% (95% CI, -1.74 to -1.00; P=.0068 vs. placebo) and by -1.32% (95% CI, -1.83 to -0.80; P=.0290 vs placebo), respectively, in the exploratory cohort of patients with hemoglobin A1c ≥9% (n=91). Compared with placebo-treated patients, 18.1% (95% CI, 9.9 to 26.3), 19.5% (95% CI, 11.2 to 27.9), and 22.1% (95% CI, 13.5 to 30.6) more patients assigned to dapagliflozin 2.5, 5, and 10 mg, respectively, experienced bodyweight reductions of 5% or more at week 24.
The combination of dapagliflozin with a sulfonylurea agent was tested in a phase 3 study that differed from other phase 3 studies by virtue of having additional exclusion criteria and good representation of Asian/Pacific patients (~30%).15 Additional exclusion criteria included: (1) history of diabetic ketoacidosis or hyperosmolar nonketotic coma; (2) use of insulin for more than 7 consecutive days during the 6 months prior to enrollment; (3) use of glimepiride doses in excess of 4 mg/d during the 8 weeks up to and including enrollment; (4) calculated creatinine clearance <50 mL/min; (5) hemoglobin ≤10 g/dL for men and ≤9.5 g/dL for women; (6) ingestion of systemic corticosteroids for >4 weeks within 3 months of enrollment; and (7) use of weight reduction drug within 30 days of enrollment. In this study, 597 type 2 diabetes patients inadequately controlled on glimepiride 4 mg/d monotherapy underwent randomization to 1 of 4 treatment groups: dapagliflozin 2.5, 5, or 10 mg daily, or placebo, while concurrently taking open-label glimepiride 4 mg daily for the duration of the study period. Like the 2 aforementioned trials, the primary outcome involved the mean change in A1c from baseline to week 24. Mean duration of diabetes ranged from 7.2 to 7.7 years, and the mean A1c of subjects ranged from 8.07% to 8.15%. The reductions in A1c were -0.13% for the placebo group and -0.58% (95% CI, -0.61 to -0.27; P<.0001), -0.63% (95% CI, -0.67 to -0.32; P<.0001), and -0.82% (95% CI, -0.86 to -0.51; P<.0001) for the dapagliflozin 2.5-, 5-, and 10-mg groups, respectively. In the corresponding order, this study also found the mean change in body weight to be -0.72 kg for placebo and -1.18 (95% CI, -1.08 to 0.15; P=.1410), -1.56 (95% CI, -1.47 to -0.21; P=.0091), and -2.26 kg (95% CI, -2.17 to -0.92; P<.0001) for dapagliflozin 2.5-, 5-, and 10-mg groups, respectively.
Nauck and associates assessed longer-term efficacy of dapagliflozin in a 52-week, double-blind, multicenter, active-controlled, noninferiority trial that included 814 patients with type 2 diabetes mellitus already on metformin monotherapy.16 Following randomization, patients either received add-on therapy with glipizide (up-titration from 5 mg/d to 20 mg/d) or dapagliflozin (up-titration from 2.5 mg/d to 10 mg/d). The study population consisted of subjects with a mean baseline A1c of 7.7%; at the end of the titration period, nearly 87% of dapagliflozin-treated patients required 10 mg/d and nearly 3 in 4 glipizide-treated patients required 20 mg/d. At week 52, the A1c adjusted mean change from baseline was -0.52% (95% CI, -0.60 to -0.44) for dapagliflozin, and glipizide-treated patients showed an adjusted mean change from baseline of -0.52% (95% CI, -0.60 to -0.44), which represented statistical noninferiority. Compared with glipizide-treated patients, 30.8% (95% CI, 26.0 to 35.7; P<.0001) more patients assigned to dapagliflozin experienced the secondary outcome of bodyweight reductions of 5% or more at week 52.
Until the release of information by the FDA advisory panel on dapagliflozin-associated breast cancer, bladder cancer, and liver dysfunction, the only adverse effects of concern involved urinary tract and genital infections.7,13–16 Phase 3 clinical trials of dapagliflozin showed that the most commonly reported adverse effects associated with this agent included signs/symptoms suggestive of genital infection (8.9%; 155/1,748), signs/symptoms suggestive of urinary tract infection (7.8%; 137/1,748), nasopharyngitis (7.1%; 95/1,339), headache (6.9%; 90/1,298), upper respiratory tract infection (4.3%; 54/1,265), back pain (3.9%; 50/1,265), and diarrhea (3.7%; 65/1,748).13–16 Study investigators stated that type 2 diabetes patients have an inherently higher risk of experiencing fungal genital infections and urinary tract infections compared with the general population.16 Longer-term studies will need to address the risk of genital and urinary tract infections in patients receiving dapagliflozin therapy. The New York Times reported that 0.4% of women who received dapagliflozin in clinical trials developed breast cancer, compared with 0.1% of patients who did not receive this agent.7 In addition, a 6-fold higher rate of bladder cancer was seen in men who received dapagliflozin (0.3%) compared with men who did not receive this agent (0.05%). One patient experienced liver dysfunction (laboratory values not specified) temporally associated with dapagliflozin therapy in the 52-week phase 3 study of dapagliflozin.16 Liver function tests showed improvement within 10 days of discontinuing dapagliflozin therapy and completely normalized within 6 months.
Dapagliflozin appears to have a low propensity for interacting with other drugs, given that it does not have strong inhibitory effects on P-gp, and it does not induce CYP1A2, CYP2B6, or CYP3A4 isoenzymes. Furthermore, this drug does not inhibit the activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 isoenzymes.8 An open-label, randomized, crossover study assessed pharmacokinetic interactions between dapagliflozin and metformin, pioglitazone, glimepiride, or sitagliptin in healthy subjects.17 This study demonstrated that co-administration of dapagliflozin with the 4 other antidiabetic agents did not result in Cmax or AUC values of dapagliflozin deviating from the predefined bioequivalence limits of 0.80 to 1.25. Similarly, except for slight deviations outside the 90% CI for the ratio of the geometric means for glimepiride AUC (upper limit, 1.29) and pioglitazone Cmax (lower limit, 0.75), dapagliflozin did not affect the Cmax or AUC values for the 4 co-administered antidiabetic agents.
DOSING AND ADMINISTRATION
Dapagliflozin dosages ranging from 2.5 mg/d to 10 mg/d have been evaluated in 4 published phase 3 trials.13–16 Dapagliflozin 2.5 mg/d did not lower the A1c of treatment-naïve type 2 diabetes patients by a significantly greater extent from baseline compared with placebo-treated patients in one phase 3 trial.13 However, when used as add-on therapy to metformin and glimepiride, dapagliflozin 2.5 mg/d lowered A1c by an additional -0.67% and -0.58%, respectively, which represented statistically significant reductions compared with placebo.14,15 The once-daily regimen of dapagliflozin 5 mg consistently resulted in reductions in A1c (-0.63% to -0.77%) that were significantly greater than reductions in placebo-treated patients, regardless of whether it was used as monotherapy or as add-on therapy to metformin or glimepiride.13–15 Similarly, the once-daily regimen of dapagliflozin 10 mg (used as add-on therapy to metformin or glimepiride) also showed consistent reductions in A1c (-0.82% to -0.89%) that were significantly greater than reductions in placebo-treated patients.13–15 Based on these data, 5 to 10 mg once a day would be a reasonable dosage range for type 2 diabetes patients receiving dapagliflozin as monotherapy. A wider dosage range from 2.5 to 10 mg once a day would be reasonable for type 2 diabetes patients receiving dapagliflozin as add-on therapy to metformin or glimepiride.
At present, there are numerous antidiabetic agents marketed in the United States. However, despite the vast array of medications with differing mechanisms of action, type 2 diabetes patients struggle to achieve and maintain targets of glycemic control established by the ADA. Due to the progressive nature of this disease, most patients will require combination therapy to maintain adequate glycemic control. Unfortunately, many of the available antidiabetic agents have treatment-limiting side effects. Insulin, sulfonylureas, and thiazolidinediones have been shown to be associated with weight gain in type 2 patients. Amylin analogs, bile acid sequestrants, and alpha-glucosidase inhibitors have been shown to cause undesirable gastrointestinal side effects. While GLP-1 analogs are associated with weight loss, serious adverse effects such as pancreatitis and medullary thyroid cancer need to be addressed in long-term safety studies.
Dapagliflozin, an SGLT inhibitor, has been studied in several phase 3 clinical trials and offers a novel approach to the management of type 2 diabetes mellitus.13–17 Phase 3 clinical trials have compared this agent's A1c-lowering effect to that of placebo and glipizide in type 2 patients already on metformin therapy. In addition, the A1c-lowering effect of dapagliflozin has been compared with placebo in phase 3 trials that have included treatment-naive patients and patients already taking glimepiride. Results indicate that once daily dapagliflozin 5 and 10 mg has superior efficacy in lowering A1c in treatment-naive type 2 diabetes patients compared with placebo. Dapagliflozin 2.5, 5, and 10 mg administered once daily shows superior efficacy in lowering A1c when used as add-on therapy to metformin or glimepiride compared with placebo.
Phase 3 clinical trials have also examined secondary or exploratory outcome measures such as reduction in body weight, A1c-lowering effect of dapagliflozin observed in type 2 diabetes patients with higher baseline A1c, and decrease in mean systolic/diastolic blood pressures. Dapagliflozin 2.5-, 5-, and 10-mg doses did not significantly lower body weight compared with placebo in treatment-naive patients, whereas a significantly higher proportion of patients receiving dapagliflozin 2.5, 5, and 10 mg as add-on therapy to metformin achieved bodyweight reductions of at least 5% compared with placebo and glipizide. Phase 3 clinical studies have included low numbers of patients with higher baseline A1c; add-on (to metformin) dapagliflozin 5- and 10-mg doses lowered A1c from baseline by -1.37% and -1.32%, respectively, in patients with baseline A1c ≥9%, a statistically significant reduction compared with placebo.14 In general, dapagliflozin therapy resulted in modest, nonsignificant decreases in mean systolic and diastolic blood pressures, without inducing orthostatic hypotension.
Issues that need to be addressed in longer-term clinical trials include the risk for genital and urinary tract infections, along with the risks of breast cancer, bladder cancer, and liver dysfunction. Until these safety issues are further evaluated in clinical trials, dapagliflozin's place on a formulary remains unclear.
Ms Lu and Ms Ta are pharmacy doctoral candidates at University of the Pacific School of Pharmacy, Stockton, Calif. Dr Song is an ambulatory care/mental health clinical supervisor and SCVH&HS PGY1 pharmacy residency coordinator, Department of Pharmacy Services, Santa Clara Valley Medical Center, San Jose, Calif.
Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.
In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, medical editor, University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn., and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, associate professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.
EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.
1. Nyenwe EA, Jerkins TW, Umpierrez GE, Kitabchi AE. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism. 2011;60:1–23.
2. Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors. Systematic review and meta-analysis of randomized trials. Ann Med. 2011 [Epub ahead of print]; DOI: 10.3109/07853890.2011.560181.
3. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.
4. Turner RC, Cull CA, Frighi V, Holman RR, for the UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;281:2005–2012.
5. American Diabetes Association. Standards of medical care in diabetes – 2011. Diabetes Care. 2011;(Suppl 1): S11–S61.
6. FDA accepts dapagliflozin NDA. Business Wire, March 8, 2011. Available at: http://www.drugs.com/nda/dapagliflozin_110308.html. Accessed August 28, 2011.
7. Pollock A. Diabetes drug dapagliflozin rejected by FDA panel. The New York Times, July 19, 2011. Available at: http://www.nytimes.com/2011/07/20/business/diabetes-drug-dapagliflozin-rejected-by-fda-panel.html. Accessed August 28, 2011.
8. Obermeier M, Yao M, Khanna A, et al. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab Dispos. 2010;38:405–414.
9. Neumiller JJ, White JR Jr., Campbell RK. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs. 2010;70:377–385.
10. Komoroski B, Vachharajani N, Boulton D, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009;85:520–526.
11. Kasichayanula S, Chang M, Hasegawa M, et al. Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus. Diabetes Obes Metab. 2011;13:357–365.
12. Kasichayanula S, Liu X, Zhang W, et al. Effect of a high-fat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects. Diabetes Obes Metab. 2011;13:770–773.
13. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33:2217–2224.
14. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:2223–2233.
15. Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomised, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011; Accepted Article; DOI: 10.1111/j.1463-1326.2011.01434.
16. Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;Published Ahead of Print; DOI: 10.2337/dc11-0606.
17. Kasichayanula S, Liu X, Shyu WC, et al. Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects. Diabetes Obes Metab. 2011;13:47–54.