sodium glucose co-transporter 2 (SGLT2) inhibitors

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  • glucose filtration by the kidney and the role of sodium glucose co-transporter 2 (SGLT2)
    • glucose is normally filtered in the kidney and is reabsorbed in the proximal tubules
      • glycosuria occurs when the renal threshold of glucose (blood glucose of approximately 10 mmol/l (160-180 mg/dl) has been reached
        • at this threshold the proximal tubule cannot reabsorb all of the filtered glucose, resulting in glycosuria
      • in total, 98% of the urinary glucose is transported across the membrane of the proximal tubule by SGLT2
      • a naturally occurring mutation in the SLC5A2 gene, resulting in a defective SGLT2 protein, produces significant glycosuria
        • individuals who have this mutation have not been seen to have significant problems related to the glycosuria, such as urinary tract infections (UTIs) (1)
        • a therapeutic option in type 2 diabetics is to mimic the effect of the SLC5A2 mutation and prevent the reabsorption of renal-filtered glucose back into the circulation, thereby reducing hyperglycaemia, without the side effects of weight gain or hypoglycaemia

  • SGLT2 inhibitor drugs:
    • SGLT2 inhibitor drugs (dapagliflozin, canagliflozin, empagliflozin, ertugliflozin)

    • SGLT2 inhibitors correct a novel pathophysiological defect, have an insulin-independent action, are efficacious with glycosylated hemoglobin reduction ranging from 0.5% to 1.5%, promote weight loss, have a low incidence of hypoglycemia, complement the action of other antidiabetic agents, and can be used at any stage of diabetes (2)

    • a systematic review of these dapagliflozin and canagliflozin drugs being used as second or third line drugs has been undertaken (1)
      • Seven trials were reviewed.
        • dapagliflozin 10 mg reduced HbA1c by -0.54% (weighted mean differences (WMD), 95% CI -0.67 to -0.40) compared to placebo, but there was no difference compared to glipizide
        • canagliflozin reduced HbA1c slightly more than sitagliptin (up to -0.21% vs sitagliptin)
        • both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD -1.81 kg (95% CI -2.04 to -1.57), canagliflozin up to -2.3 kg compared to placebo)
      • the study authors concluded that dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed

    • adverse effects (2):
      • generally well tolerated
      • however, due to side effects, such as repeated urinary tract and genital infections, increased hematocrit, and decreased blood pressure, appropriate patient selection for drug initiation and close monitoring after initiation will be important
        • genital infections
          • an increase in genital infections in the dapagliflozin groups compared with controls in almost all the studies, with the incidence increasing with higher doses of dapagliflozin
            • reported incidence varied from 3% to 13% versus 0% to 5% in the placebo group
            • when dapagliflozin monotherapy was compared with metformin monotherapy, the incidence of genital infections was 2%-7% versus 2%, respectively
        • UTIs
          • reported urinary tract infection rates were 1%-12.9% in the dapagliflozin groups versus 0%-6.2% in controls and 9% on metformin monotherapy

    • the Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended approval of dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products, including insulin, and as a monotherapy for metformin-intolerant patients (2)

Consult the Summary of Product Characteristics before prescribing this drug.

Notes:

  • use in renal impairment
    • efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment. Forxiga (dapagliflozin) is not recommended for use in patients with moderate to severe renal impairment (patients with creatinine clearance [CrCl] < 60 ml/min or estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2

  • recommended dose is 10 mg dapagliflozin once daily for monotherapy and add-on combination therapy with other glucose-lowering medicinal products including insulin. When dapagliflozin is used in combination with insulin or an insulin secretagogue, such as a sulphonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycaemia

Reference:

Last edited 05/2019 and last reviewed 07/2021

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