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#198 SGLT2 Inhibitors and Diabetics: Does sugar in the pee protect thee?


CLINICAL QUESTION
In patients with type 2 diabetes, do sodium-glucose co-transporter 2 (SGLT2) inhibitors affect mortality or cardiovascular disease (CVD)?

BOTTOM LINE
In diabetic patients at high-risk for CVD, empagliflozin reduces mortality for 1 in 39 patients at ~3 years (compared to placebo), while canagliflozin and empagliflozin both reduce CVD death, non-fatal myocardial infarction (MI), and stroke for ~1 in 60 patients. Both medications increased genital infections for ~1 in 6-22 and canagliflozin increased volume depletion (1 in 14-38) and amputations (1 in 96). Cost may limit use.  


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EVIDENCE
  • Two placebo-controlled, industry-funded, Randomized Controlled Trials (RCTs) of mostly males, long-standing type 2 diabetics in their 60s with A1cs ~8.1,2 Patients with GFR <30 ml/min were excluded. 
    • Empagliflozin 10 mg or 25 mg daily:1 7,020 patients with CVD mostly also on metformin, anti-hypertensives, statins, and ASA. At 3.1 years, empagliflozin significantly effected:  
      • CVD death, non-fatal MI, or stroke: 10.5% (empagliflozin) versus 12.1% (placebo), Number Needed to Treat (NNT)=63. 
      • Mortality: 5.7% versus 8.3%, NNT=39. 
      • Genital infections: 6.4% versus 1.8% (placebo), Number Needed to Harm (NNH)=22. 
      • No increase in fractures or volume depletion. 
      • Meta-analysis (57 RCTs, six regulatory submissions) had similar findings.3 
    • Canagliflozin 100 mg or 300 mg daily:2 10,142 patients from two different studies (with different enrollment and study lengths), with either CVD or ≥2 CVD risk factors. Concomitant medications unknown. Statistically significant outcomes from combined studies over 3.6 years, except where indicated: 
      • CVD death, non-fatal MI, or stroke: 2.7% (canagliflozin) versus 3.2% per year; NNT~61 over 3.6 years. 
      • Mortality: 1.7% (canagliflozin) versus 2% per year (approaches statistical significance). 
      • Genital infections: NNH=6 (female) to 12 (male). 
      • ‘Volume depletion’ (dry mouth/polydipsia to orthostatic hypotension/syncope): NNH=14-38. 
      • Amputation: NNH=96. 
      • Fractures: NNH=286. 
    • Neither RCT demonstrated significant increase in urinary tract infection, acute kidney injury, hypoglycemia, or diabetic ketoacidosis. 
Context: 
  • ~50% of diabetics die from CVD.4 
  • Both medications lower systolic blood pressure ~3-4 mmHg, A1c ~0.5%, and weight ~2kg.1,2 
  • CADTH recommends empagliflozin (after Metformin) for diabetics with CVD.5  
  • Post marketing warnings: Acute kidney injury with canagliflozin or dapagliflozin6 and fractures7 and amputations8 with canagliflozin. 
  • Cost ~$90 per month.9 
October 30, 2017

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Author(s):

  • Arden R. Barry BSc BScPharm PharmD
  • Kirsten Bester BSc
  • Michael R. Kolber BSc MD MSc CCFP

1. Zinman B, Wanner C, Lachin JM, et al. N Engl J Med. 2015; 373:2117-28.

2. Neal B, Perkovic V, Mahaffey KW, et al. N Engl J Med. 2017; 377(7):644-57.

3. Wu JHY, Foote C, Blomster J, et al. Lancet Diabetes Endocrinol. 2016; 4:411-9.

4. Bruno G, Biggeri A, Merletti F, et al. Diabetes Care. 2003; 26(8):2353-8.

5. Canadian Agency for Drugs and Technologies in Health (CADTH). May 2017. A Summary of the Therapeutic Review Project Second-Line Therapy for Type 2 Diabetes. Available at: https://www.cadth.ca/sites/default/files/pdf/second_line_therapy_for_type_2_diabetes_in_brief_e.pdf. Last accessed: September 4, 2017.

6. United States Food and Drug Administration June 2016 Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Available at: https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm. Last accessed: June 30 2017.

7. Health Canada. Health Canada – Health Product Info Watch August 2017. Available at: https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/health-product-infowatch/health-product-infowatch-august-2017.html. Last accessed: September 4, 2017.

8. Health Canada. Product Safety RA-64366 Issued Sept 6, 2017. Available at: http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2017/64366a-eng.php. Last accessed: September 7, 2017.

9. Kolber MR, Lee J, Allan GM, et al. Price Comparison of Commonly Prescribed Pharmaceuticals in Alberta 2017. Available at: https://www.acfp.ca/wp-content/uploads/2017/03/ACFPPricingDoc2017.pdf. Last accessed: September 7, 2017.

Authors do not have any conflicts of interest to declare.