Dapagliflozin for the treatment of type 2 diabetes: a review of the literature

Figures & data

Table 1 Some factors to consider while managing patients with diabetes

Factors	Considerations
Age	Licensed indications (eg, dapagliflozin licensed for use in patients 18–75 years of age)
Weight	Weight-neutral or promotion of weight loss in overweight/obese patients
Pregnancy	Contraindications exist for most oral hypoglycemic agents
Renal/hepatic dysfunction	Metabolism of the drug and/or route of excretion
Ease of use	Frequency and timing of medication
Polypharmacy	This can lead to poor patient adherence^Citation12
Occupation	HGV drivers and the risk of hypoglycemia
Costs	Individual, national, or insurance costs can dictate medication choice
Side effects	Hypoglycemia, weight gain, gastrointestinal disturbance, edema, etc

Abbreviation: HGV, heavy goods vehicle.

Figure 1 Flow diagram of search process.

Figure 2 S1 segment of the promixal convoluted tubule of the nephron.

Notes: SGLT2 located on the luminal membrane of the S1 segment of the proximal convoluted tubule of the nephron actively transports glucose from the lumen into the cell against a concentration gradient. The glucose is then transported out through the basolateral side via GLUT2. Na⁺-K⁺ ATPase actively excretes sodium from the cell in exchange for potassium.
Abbreviations: SGLT, sodium glucose cotransporter; GLUT, glucose cotransporter; ATPase, adenosine triphosphatase.

Figure 3 Chemical structure of dapagliflozin.

Table 2 Meta-analyses of dapagliflozin

Study	Year published	RCTs included, n	Theme of the meta-analysis	Summary
Musso et al^Citation75	2012	13	Efficacy and safety of dapagliflozin	– ↓ HbA1c (−0.52%, 95% CI −0.46% to −0.57%; P<0.00001) – ↓ FPG (−18.28 mg/dL [1.01 mmol/L], 95% CI −20.66 [1.15 mmol/L] to −15.89 [0.88 mmol/L]; P<0.00001) – ↓ BMI (−1.17%, 95% CI −1.41 to −0.92; P<0.00001) – ↓ SBP (−4.08 mmHg, 95% CI −4.91 to −3.24) – ↓ DBP (−1.16 mmHg, 95% CI −1.67 to −0.66) – ↓ Serum uric acid (−41.50 μmol/L, 95% CI −47.22 to −35.79) – ↑ Risk genital infections (OR 3.57, 95% CI 2.59–4.93) – ↑ Risk of UTIs (OR 1.34, 95% CI 1.05–1.71) – ↑ Hypoglycemia (mild) when added to insulin (OR 1.27, 95% CI 1.05–1.53)
Vasilakou et al^Citation76	2013	–a	Efficacy and safety of SGLT2 inhibitors	– ↓ HbA1c (−0.59%, 95% CI −0.67% to −0.50% versus placebo) – ↓ BW (−1.92 kg, 95% CI −2.23% to −1.60%; P<0.00001 versus placebo) – ↓ SBP/DBP – ↓ CV events (OR 0.73, 95% CI 0.46–1.16) – ↑Genital infections (OR 3.48, 95% CI 2.33–5.20 versus placebo; OR 4.81, 95% CI 2.97–7.81 versus active agent) – ↑ UTIs (OR 1.43, 95% CI 1.05–1.94 versus placebo; OR 1.69, 95% CI 1.19–2.40 versus active agent) – ↑ Hypoglycemia (OR 1.20, 95% CI 0.88–1.64 versus placebo; OR 0.49, 957% CI 0.18–1.39 versus active agent) – ↑ Hypotension
Goring et al^Citation74	2014	6	Adding dapagliflozin versus other OHAs to metformin monotherapy (1-year data)	– Similar efficacy – Similar or reduced hypoglycemic episodes – Added benefit of weight reduction (versus DPP-4 inhibitors, −2.74 kg, 95% CI −5.35 to −0.10); versus SUs, −4.67 kg, 95% CI −7.03 to −2.35)
Sun et al^Citation72	2014	12	Synergism of dapagliflozin in combination with other OHAs	– ↓ HbA1c (−0.52%, 95% CI −0.60% to −0.45%; P<0.001) – ↓ FPG (−1.13 mmol/L, 95% CI −1.33 to −0.93; P<0.001) – ↓ BW (−2.10 kg; 95% CI −2.32 to −1.88; P<0.001)
Zhang et al^Citation73	2014	10	Efficacy and safety of dapagliflozin	– ↓ HbA1c (−0.53%, 95% CI −0.58% to −0.47%; P<0.00001) – ↓ FPG (−1.06 mmol/L, 95% CI −1.20 to −0.92; P<0.00001) – ↓ BW (−1.63 kg, 95% CI −1.83 to −1.43; P<0.00001) – No hypoglycemia as monotherapy – ↑ Hypoglycemia (RR 1.16, 95% CI 1.05–1.29; P=0.005) when added to a hypoglycemic agent – ↑ Risk of UTIs (RR 1.33, 95% CI 1.10–1.60; P=0.004) – ↑ Risk of genital infections (RR 3.23, 95% CI 2.50–4.18; P=0.00001)

Note:

a Several studies used.

Abbreviations: BMI, body mass index; BW, body weight; CI, confidence interval; DBP, diastolic blood pressure; DPP, dipeptidyl peptidase; FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; OHAs, oral hypoglycemic agents; OR, odds ratio; RCTs, randomized controlled trials; RR, relative reduction; SBP, systolic blood pressure; SGLT, sodium glucose cotransporter; SUs, sulfonylureas; UTIs, urinary tract infections.

Table 3 Differentiating features between dapa-/empa-/canagliflozin

Drug	Age of patient (years)	Renal impairment (eGFR: mL/min/1.73 m^2)	Severe hepatic impairment	Side effects
Dapagliflozin	≥65: volume depletion should be taken into account ≥75: not recommended	<60: not recommended	Start at 5 mg OD; if tolerated, can use 10 mg OD	–
Empagliflozin	≥75: volume depletion should be taken into account >85: not recommended	<60: do not initiate; if eGFR falls to this level, maintain or reduce to 10 mg OD when already ona <45: do not use, and stop when already on	Do not use	–
Canagliflozin	≥65: volume depletion should be taken into account	<60: do not initiate; if eGFR falls to this level, maintain or reduce to 100 mg OD when already on <45: do not use, and stop when already on	Do not use	Vulvovaginal candidiasis appears to have a higher incidenceb compared to dapagliflozin and empagliflozin)

Notes:

a Safety data in chronic kidney disease 3A (45–59 mL/min/1.73 m²) is available for both canagliflozin¹¹⁴ and empagliflozin¹¹⁵

b described as “very common” (>1/10 frequency) in canagliflozin versus “common” (≥1/100 to <1/10) in dapagliflozin and empagliflozin (based on information available in the summary of product characteristics for each drug).

Abbreviations: eGFR, estimated glomerular filtration rate; OD, once daily.

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Barnett AH Mithal A Manassie J Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial Lancet Diabetes Endocrinol 2014 2 5 369 384 24795251

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