A Novel Sodium-glucose Cotransporter Type 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

Niren K. Shah, Pharm.D.; Wasim E. Deeb, M.D.; Rushab Choksi, Pharm.D.; Benjamin J. Epstein, Pharm.D.


Pharmacotherapy. 2012;32(1):80-94. 

In This Article

Safety and Tolerability

The clinical trial experience with dapagliflozin has demonstrated a favorable safety profile (Table 3). In phase III clinical trials, the rate of hypoglycemia with dapaglifozin was similar to that with placebo, and no major hypoglycemic events were reported.[49,50] This is consistent with the mechanism of action of dapagliflozin, which promotes glucosuria in a glucose-dependent fashion while sparing insulin secretion and function. Overall, there was an increased frequency of genital infections in both men and women treated with dapagliflozin (2–13% of patients) compared with placebo (0–5%) and metformin (2%).[48,49,51] The frequency of UTI varied largely (4.6–12.5% with dapagliflozin, 4–8% with placebo, and 9% with metformin) and was more marked in female subjects.[48,49,51] No deaths were related to the use of dapagliflozin. The most common adverse events (≥ 5% of patients) were UTIs, genital infections, back pain, influenza, upper respiratory tract infections, cough, nasopharyngitis, diarrhea, hypertension, and headache.[51] The overall occurrence of adverse events was similar among patients treated with dapagliflozin (63.1–68.6%) and those treated with placebo (60%) and was generally consistent when dapagliflozin was given as monotherapy or add-on therapy.[49]

There were no relevant changes in renal function or serum electrolyte levels in phase II or III studies. Compared with placebo, dapagliflozin produces a significant increase in glucose excretion ranging from 20.4–53.3 g/day, but this is to be expected given the mechanism of SGLT2 inhibitors. No apparent changes were noted in renal tubular markers (N-acetyl-β-d-glucosaminidase and β2-microglubulin), concentrations of serum creatinine, magnesium, sodium, potassium, phosphate, chloride, oxalate, citrate, or albumin, urinary calcium, total protein, or osmolality.[38]

An osmotic-diuretic effect was noted after 12 weeks of therapy (107–470-ml increase),[48] but such an effect does not appear to result in significant hypotension or orthostatic hypotension.[49] Furthermore, clinical trials demonstrated that dapagliflozin reduces mean seated systolic blood pressure (−2.1 mm Hg to −5.1 mm Hg) and diastolic blood pressure (−1.7 mm Hg to −2.8 mm Hg). Increases in hematocrit (1.5–3.0%) were likely due to hemoconcentration and glucose-induced osmotic diuresis, and appeared to be a dose-related effect.[38,54] Serum uric acid levels decreased after 24 weeks of therapy, with reductions ranging from 0.35−0.54 mg/dl and also appeared to be dose related. Reductions in serum uric acid levels have been consistent across trials and have been suggested to arise from inhibition of sodium-coupled uric acid reabsorption in the renal proximal tubule.[56] No changes in fasting lipid profiles were seen, with the exception of increased high-density lipoprotein cholesterol (HDL) values (+1.8–4.4%) and decreased triglyceride values (−2.4% to −6.2%).[38]

Ongoing clinical trials, including long-term studies and studies in vulnerable populations (e.g., patients with established cardiovascular disease), will help to fully characterize the safety profile of dapagliflozin and give insight into why serious adverse events were more common in a recent trial.[53]


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