Patient considerations in the management of type 2 diabetes – critical appraisal of dapagliflozin

Figures & data

Table 1 Phase III clinical trials of dapagliflozin as monotherapy or add-on therapy

Study	Methods	A1c reduction (% adjusted mean change from baseline)a	Other statistically significantb findings
Dapagliflozin monotherapy^Citation29	24-week, placebo-controlled RCT485 treatment-naïve patients	AM 2.5 mg: not statistically significant AM 5 mg: −0.77% (P<0.0005) AM 10 mg: −0.89% (P<0.0001) Placebo: −0.23% PM doses had similar reductions (−0.79% to −0.83%) (extrapolated data) Patients with baseline A1c ≥10% had mean change in A1c of −2.88% (for 5 mg) and −2.66% (for 10 mg) (extrapolated data)	FPG reductions AM 2.5 mg: −15.2 mg/dL AM 5 mg: −24.1 mg/dL AM 10 mg: −28.8 mg/dL PM dose reductions (−26 to −30 mg/dL) (extrapolated data) Patients with baseline A1c ≥10% had FPG reductions of −77 to −84 mg/dL (extrapolated data)
Dapagliflozin monotherapy^Citation30	24-week, double-blind, placebo-controlled RCT 282 treatment-naïve patients	5 mg: −0.82% 2.5 mg: −0.72% 1 mg: −0.68% Placebo: 0.02% (P<0.0001, for all doses)	FPG reductions 1 mg: −11 mg/dL 2.5 mg: −22 mg/dL 5 mg: −28 mg/dL OGTT reductions (with all doses): −33 to −52 mg/dL
Dapagliflozin + metformin vs placebo + metformin^Citation31,Citation32	24-week, double-blind, placebo-controlled RCT Extension study to 102 weeks 546 patients inadequately controlled on metformin monotherapy (≥1,500 mg/day)	2.5 mg: −0.65% (P=0.0008) 5 mg: −0.67% (P<0.0001) 10 mg: −0.82% (P<0.0001) Placebo: −0.31% At 102 weeks, reductions were maintained: −0.48% to −0.78%	FPG reductions: 5 mg: −26 mg/dL 10 mg: −24 mg/dL
Dapagliflozin + metformin vs placebo + metformin^Citation33	24-week double-blind, placebo-controlled RCT 182 patients inadequately controlled on metformin	10 mg: −0.39% Placebo: −0.10% (P<0.0001)	FPG reductions: 10 mg: −15 mg/dL
Dapagliflozin + glimepiride vs placebo + glimepiride^Citation34	24 week double-blind, placebo-controlled RCT 597 patients inadequately controlled on SU (≥ half the maximum recommended dose)	2.5 mg: −0.58% 5 mg: −0.63% 10 mg: −0.82% Placebo: −0.13% P<0.0001, for all doses Hypoglycemic episodes were more frequent in the dapagliflozin arm (6.9%–7.9% vs 4.8% placebo)	FPG reductions 5 mg: −21 mg/dL 10 mg: −28 mg/dL OGTT reductions (−32 to −35 mg/dL) were statistically significant for 5 mg and 10 mg
Dapagliflozin + insulin vs placebo + insulin^Citation35	24-week, placebo-controlled RCT with blinded oral administration 808 patients inadequately controlled on insulin (≥30 units/day) Mean daily insulin dose was 77.1 units/day, with 17% using basal insulin and 83% using sliding-scale	2.5 mg: −0.79% 5 mg: −0.89% 10 mg: −0.96% Placebo: −0.39% P<0.0001, for all doses After 48 weeks, A1c reduction was maintained with all doses (−0.79% to −1.01%) (P<0.001) Hypoglycemic episodes were 53.6% for dapagliflozin 10 mg vs 51.8% with placebo	FPG reductions: 2.5 mg: −12 mg/dL 5 mg: −20 mg/dL 10 mg: −20 mg/dL At 48 weeks, FPG reduction was −12 to −17 mg/dL Patients continued usual daily dose of insulin with titrations, and up to two existing oral antidiabetic drugs (>50%on existing orals, mostly metformin)
Dapagliflozin + pioglitazone vs placebo + pioglitazone^Citation36	24 week, placebo-controlled RCT 480 patients inadequately controlled on pioglitazone 30–45 mg/day	5 mg: −0.82% (P=0.0007)(br)10 mg: −0.97% (P<0.00001)(br)Placebo: −0.42%(br)After 48 weeks, A1c reductions were maintained (−0.95% to −1.21%).(br)However, statistical tests were not performed	FPG reductions:(br)5 mg: −24.9 mg/dL(br) 10 mg: −29.6 mg/dL
Dapagliflozin + sitagliptin vs placebo + sitagliptin^Citation37	24-week, placebo-controlled RCT 451 patients inadequately controlled on sitagliptin 100 mg/day ± metformin ≥1,500 mg/day	Without metformin: 10 mg: −0.5% Placebo: −0.1% (P<0.0001) With metformin: 10 mg: −0.4% Placebo: 0.0% (P<0.0001) Patients with baseline A1c ≥8% had mean change in A1c of −0.8% compared to 0.0% (P<0.0001)	FPG reductions (combined ±metformin) 10 mg: −24.1 mg/dL Placebo: 3.8 mg/dL

Notes:

a Versus placebo;

b statistical significance at P<0.05.

Abbreviations: A_1c, hemoglobin A_1c; RCT, randomized controlled trial; AM, morning; PM, evening; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; vs, versus; SU, sulfonylureas.

Table 2 Comparison of dapagliflozin and canagliflozin

	Dapagliflozin^Citation14	Canagliflozin^Citation51
Approved indication	Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes	Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
Starting dose	5 mg once-daily in the morning	100 mg once-daily
Dose titration	May increase to 10 mg for additional glycemic control	May increase to 300 mg with an eGFR ≥60 mL/min/1.73 m^2, for additional glycemic control
A1c reduction	Monotherapy: −0.8% (5 mg) and −0.9% (10 mg) With metformin: −0.7% (5 mg) and −0.8% (10 mg) With glimepiride: −0.6% (5 mg) and −0.8% (10 mg) With pioglitzone: −0.8% (5 mg) and −1.0% (10 mg) With sitagliptin: NS (5 mg) and −0.45% (10 mg)	Monotherapy: −0.77% (100 mg) and −1.03% (300 mg) With metformin: −0.79% (100 mg) and −0.94% (300 mg) With sulfonylurea: −0.70% (100 mg) and −0.79% (300 mg)
Administration	With or without food	Before the first meal of the day
Contraindications	Hypersensitivity, severe renal impairment, end stage renal disease, on dialysis	Hypersensitivity, severe renal impairment, end stage renal disease, on dialysis
Warning and precautions	Hypotension, increased serum creatinine, decrease in eGFR, hypoglycemia with insulin and insulin secretagogues, genital mycotic infections, increase in LDL, bladder cancer	Hypotension, increased serum creatinine, decrease in eGFR, hyperkalemia, hypoglycemia with insulin and insulin secretagogues, genital mycotic infections, increase in LDL
Common side effects (5% or greater incidence)	Female genital mycotic infections, nasopharyngitis, urinary tract infections	Female genital mycotic infections, urinary tract infections, increased urination
Drug interactions (avoid use)	None reported	Pimozide
Drug interactions (monitor concomitant use)	May increase effect of hypoglycemia agents and hypotensive agents	Digoxin (increased AUC and Cmax) UGT enzyme inducers* (decrease AUC of canagliflozin)
Renal impairment	Do not initiate if eGFR <60 mL/min/1.73 m^2 Discontinue if eGFR is persistently <60 mL/min/1.73 m^2	Do not initiate if eGFR <45 mL/min/1.73 m^2 Discontinue if eGFR falls below 45 mL/min/1.73 m^2 100 mg daily is maximum dose with eGFR 45–60 mL/min/1.73 m^2
Hepatic impairment	Assess risk: benefit with severe hepatic impairment	Not recommended with severe hepatic impairment
Special populations	Pregnancy category: C Breastfeeding: unknown excretion in breast milk Pediatrics: not studied Geriatrics: higher incidence of ADRs; similar A1c reduction compared to those <65 years old	Pregnancy category: C Breastfeeding: unknown excretion in breast milk Pediatrics: not studied Geriatrics: higher incidence of ADRs; less A1c reduction compared to those <65 years old
How supplied	5 mg and 10 mg tablets	100 mg and 300 mg tablets

Note:

* Rifampin, phenytoin, phenobarbital, ritonavir.

Abbreviations: eGFR, estimated glomerular filtration rate; NS, not studied; LDL, low-density lipoprotein; AUC, area under the curve; C_max, peak drug concentration; UGT, UDP-glucuronosyltransferase; ADRs, adverse drug reactions.

FerranniniERamosSJSalsaliATangWListJFDapagliflozin in monotherapy in type 2 diabetes patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trialDiabetes Care201033102217222420566676

 PubMed Web of Science ®Google Scholar

BaileyCJIqbalNT’joenCListJFDapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose rangeDiabetes Obes Metab2012141095195922776824

 PubMed Web of Science ®Google Scholar

BaileyCJGrossJLPietersABastienAListJFEffect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomized, double-blind, placebo-controlled trialLancet201037597332223223320609968

 PubMed Web of Science ®Google Scholar

BaileyCJGrossJLHennickenDDapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trialBMC Med2013114323425012

 PubMed Web of Science ®Google Scholar

BolinderJLjunggrenOKullbergJEffects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metforminJ Clin Endocrinol Metab20129731020103122238392

 PubMed Web of Science ®Google Scholar

StrojekKYoonKHHrubaVEffect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trialDiabetes Obes Metab2011131092893821672123

 PubMed Web of Science ®Google Scholar

WildingJPWooVSolerNLong-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulinAnn Intern Med2012156640541522431673

 PubMed Web of Science ®Google Scholar

RosenstockJVicoMWeiLSalsaliAListJFEffects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapyDiabetes Care20123571473147822446170

 PubMed Web of Science ®Google Scholar

JabbourSAHardyESuggJParikhSDapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24 week, multicenter, randomized, double-blind, placebo-controlled studyDiabetes Care1152014 [Epub ahead of print.]

 Web of Science ®Google Scholar

Farxiga [package insert]Princeton, NJBristol-Myers Squibb2014

 Google Scholar

Invokana [package insert]Titusville, NJJanssen Pharmaceuticals2014

 Google Scholar