Sodium glucose co-transporter 2 (SGLT2) inhibitors

• 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

SGLT2 inhibitors in chronic kidney disease (CKD)

• a review (13 trials; n=90,409; 82.7% with diabetes) found SGLT2 inhibitors reduced risk of kidney disease progression (RR 0.63; 95% CI 0.58-0.69), acute kidney injury (0.77, 0.70-0.84) and cardiovascular death or hospitalisation for heart failure (0.77, 0.74-0.81) vs placebo (3)

SGLT2 inhibitors in cardiovascular disease (4):

• in both RCTs (randomised clinical trials) and cohort studies, SGLT2 inhibitors reduced MI (myocardial infarction) incidence
  • cardioprotective effects of SGLT2 inhibitors were observed in patients with and without a history of CVD
    

Consult the Summary of Product Characteristics before prescribing this drug.

Reference:

• 1) Clar C et al.Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012 Oct 18;2(5).
• 2) Kim Y, Babu A. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes Diabetes Metab Syndr Obes. 2012; 5: 313-327.
• 3) The Nuffield Department of Population Health Renal Studies Group and SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet November 6th 2022 https://doi.org/10.1016/S0140-6736(22)02074-8
• (4) Huang X, Dannya E, Liu X, Yu Y, Tian P, Li Z. Effect of sodium-glucose cotransporter-2 inhibitors on myocardial infarction incidence: A systematic review and meta-analysis of randomized controlled trials and cohort studies. Diabetes Obes Metab. 2023; 1-10. doi:10.1111/dom.15405 (https://doi.org/10.1111/dom.15405)