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SGLT2 Inhibitors: Frequently Asked Questions

To date, management of diabetes has focussed on enhanced insulin secretion or sensitivity to the hormone. An emerging strategy enhances renal elimination of glucose from the body by blocking the SGLT2 transporter.

We summarize some of the most widely asked questions about this therapy below.

Only the content of this FAQ page has been validated by the FMOQ

FAQ #1: How do SGLT2 inhibitors affect A1C, body weight and BP?

FAQ1Tap/Click to enlargeA1C:

  • There are no head-to-head trials of SGLT2 inhibitors
  • Pooled clinical trial data shows an average reduction in A1C of 0.5-0.9% across the class
  • In addition, SGLT2 inhibitors are associated with marked reductions in A1C when baseline A1C is very high
  • Studies have shown SGLT2 inhibitors to be more effective than SUs and similar or better than DPP4 inhibitors with respect to A1C lowering
  • Also, the combination of DPP-4 inhibitor+ SGLT2 inhibitor was found to be more effective than either therapy alone.

A1C references (open)A1C references (close)

  1. Blonde L et al. ADA Annual Meeting 2013. Abstract 1110-P.
  2. DeFronzo R et al. Diabetes Care 2015; 38(3): 384-393.
  3. FDA Advisory Committee Meeting. Dec. 12, 2013.
  4. Ferrannini E et al. Diabetes Care 2010;33:2217-2224.
  5. Haring H et al. Diabetes Care 2014;37:1650-1659.
  6. Haring H et al. Diabetes Care 2013;36:3396-3404.
  7. Jabbour S et al. Diabetes Care 2014;37:740-750.
  8. Lavalle-González FJ,  et al. Diabetologia 2013; 56:2582-92.
  9. Leiter L et al. Diabetes Care 2015 36(3):355-64.
  10. Liakos A et al. Diabetes, Obesity & Metabolism. 2014;16:984-983.
  11. Nauck M et al. Diabetes, Obesity & Metabolism 2014; 16:1111-1120.
  12. Ridderstrale M et al. Lancet Diabetes Endocrinol. 2014;2:691-700.
  13. Roden M et al. Lancet Diabetes Endocrinol 2013;1:208-219.
  14. Rosenstock J et al. Diabetes Care 2015; 38(3):376-83.
  15. Stenlof K et al. Diabetes, Obesity & Metabolism 2013; 15(4):372-82.

Body weight:

  • Data from pooled clinical trials demonstrated placebo-corrected weight reduction ranges from 1.4 to 3.7 kg with the various SGLT2 inhibitors
  • The benefits on weight are not surprising given the mechanism of action of SGLT2 inhibitors, which leads to glycosuria in turn leading to caloric loss in the urine
  • How much weight loss can patients expect?
    • A modest weight loss is expected for most patients, in the order of 2-3 kg
    • 2/3 of the lost weight is fat
  • Over what time frame?
    • Most studies report the weight loss at 12- or 24-weeks
  • Is it sustainable?
    • Weight loss appears to be sustained over time

Body weight references (open)Body weight references (close)

  1. Blonde L et al. ADA Annual Meeting 2013. Abstract 1110-P
  2. McCulloch DK. Management of persistent hyperglycemia in type 2 diabetes mellitus. Uptodate – Accessed May 28, 2015.
  3. FDA Advisory Committee (click to access)
  4. FDA Advisory Committee Meeting. Dec. 12, 2013 (click to access)
  5. Liakos A et al. Diabetes, Obesity & Metabolism. 2014; 16:984-983.

Blood pressure:

  • SGLT2 inhibitors can be expected to result in a reduction in systolic BP in the order of 1-5 mmHg from baseline and to a lesser extent on diastolic BP
  • BP reduction is due to weight loss and osmotic diuresis, with the diuretic effect leading to a reduction in systolic BP
  • Reduction in BP may be more pronounced in patients with high blood glucose concentrations
  • The decrease in blood pressure is greater if SBP is >140 mmHg

Blood pressure references (open)

  1. Blonde L et al. ADA Annual Meeting 2013. Abstract 1110-P
  2. FDA Advisory Committee Meeting. Dec. 12, 2013.
  3. Hach T et al. Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension 2012, Barcelona, Spain.
  4. Liakos A et al. Diabetes, Obesity & Metabolism. 2014;16:984-983.
  5. Woo V et al. Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension 2012, Barcelona, Spain.

FAQ #2: What side effects should I warn patients about?

FAQ1Tap/Click to enlarge

  • Risk of hypoglycemia
    • Low incidence, usually in combination with other agents
  • Genital mycotic infections (10-15% of females) and urinary tract infections (small but significant increase)
  • Osmotic diuresis and volume-related adverse effects
  • Lipid and cardiovascular effects
    • Hypotension due to intravascular volume depletion, orthostatic hypotension
    • Patients with renal impairment, elderly, patients on other antihypertensive agents, those with low SBP
  • FDA & Health Canada: Ketoacidosis warning (may occur without hyperglycemia)
    • Watch for signs and symptoms: Shortness of breath, nausea, vomiting, abdominal pain, confusion, unusual fatigue
    • ‘Sick day’ management if fever, vomiting or diarrhea leads to reduced food and fluid intake

References (open)References (close)

  1. Liakos A et al. Diabetes, Obesity & Metabolism. 2014;16:984-983
  2. Respective product monographs as per July 2015

FAQ #3: What patients should I NOT consider for SGLT2i?

  • Do not initiate if eGFR < 60 mL/min/1.73 m2
  • Caution in patients prone to hypotension or volume depletion,
    e.g., on antihypertensive agents or loop diuretics, in the elderly
  • Canagliflozin not recommended for patients on loop diuretics
  • Stop SGLT2 inhibitors during acute illnesses causing volume depletion
  • Caution if history of recurrent mycotic or urinary tract infections
  • SGLT2 inhibitors should not be used during pregnancy

References (open)References (close)

Respective product monographs as per July 2015

FAQ #4: What classes of medications can I combine with SGLT2i?

FAQ1Tap/Click to enlarge

While there are differences within the class, SGLT2 inhibitors therapies are uniformly approved as second-line therapies; as add-on to metformin when metformin alone fails to provide adequate glycemic control.

Download this slide as PDF (FAQ4_Download.pdf, 268.09 Kb)

FAQ #5: What are the similarities and differences between the medications in this class?


FAQ5Tap/Click to enlargeEfficacy and impact on weight:

  • No Head-to-Head trials in diabetic patients
  • NICE Network meta-analysis
    • Add on to Metformin
      • Mean % A1C change: All comparators were similar
      • Mean weight change: All comparators were similar with the exception of superiority of Canagliflozin 300 mg
    • Add on to Insulin
      • For both mean % A1C change and weight change, all comparators were similar 

FAQ #6: Should one be concerned about using SGLT2 inhibitors in patients with underlying kidney disease?

FAQ1Tap/Click to enlarge

  • SGLT2 inhibitors reduce A1C in patients with renal disease but less so than in patients with normal renal function
  • In general, SGLT2 inhibitors are safe in patients with renal dysfunction but are associated with more volume-mediated side effects
  • Product monograph recommendation for SGLT2 inhibitor use in renal impairment:
    • Canagliflozin: Do not initiate if eGFR < 60 ml/min. If eGFR persistently falls below 60 ml/min, dose should be 100 mg. Discontinue if eGFR is persistently < 45 ml/min.
    • Dapagliflozin: Do not initiate if eGFR < 60 ml/min. Discontinue when eGFR is < 60 ml/min.
    • Empagliflozin: Do not initiate if eGFR is < 60 ml/min.  Discontinue if eGFR falls below 45 ml/min. If eGFR is 45-60 ml/min, close monitoring of renal function is recommended.
  • There is ongoing research that long-term use of these medications might have a protective effect on the kidney, despite short term, mild reductions in eGFR
  • Bottom-line: Use of SGLT2 inhibitor class will usually be limited to patients with eGFR >60 mL/min/1.73m2

References (open)References (close)

  1. Barnett A et al. Lancet Diabetes Endocrinol. 2014; 2(5):369-84
  2. FDA Advisory Committee
  3. Gilbert et al. ADA Annual Meeting 2014; Abstract 1034-P
  4. Kohan D et al. ASN Annual Meeting 2011. Abstract TH-PO524.
  5. Kohan D et al. Kidney International 2013.
  6. Mithal A et al. EASD Annual Meeting 2013; Abstract 952.
  7. Respective Product Monographs as per July 2015.
  8. Woo V et al ADA Annual Meeting 2013; Abstract 73-LB.
  9. Yale JF et al. Diabetes Obes Metab 2014;16:1016-1027.
  10. Yale JF et al. Diabetes Obes Metab 2013;15:463-473.
Antihyperglycemic Agents and Renal Function.pdf (EN-renal function table alone.pdf, n/a)

FAQ #7: Can I use SGLT2 inhibitors with ACEi and ARBs? Loop diuretics? Is hyperkalemia an issue?


  • The use of ACEi/ARB and loop diuretics is not contraindicated when using SGLT2 inhibitors
  • No concern with SGLT2 inhibitors and ACEi/ARB with intact kidney function
  • For Canagliflozin: If eGFR is 45-60 mL/min/1.73m2, monitor potassium if patient is predisposed to hyperkalemia due to medications or other conditions
  • Exercise caution when prescribing SGLT2 inhibitors with these drugs, particularly with reduced GFR and in the elderly
  • Check creatinine and potassium after initiating
  • Reinforce “sick day” management
  • Non-loop diuretics not of concern 

References (open)References (close)

  1. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37 (suppl 1):S1-S212.
  2. Respective Product Monographs as of July 2015

Practical Tips & Take Home Messages


  • Relative A1C lowering of SGLT2i êê to êêê
  • Monotherapy: Can be used as adjunct to diet and exercise in patients
    who are intolerant of metformin
  • In Combination: Can be used in combination with metformin or SU,
    or with metformin and either SU or pioglitazone, or in combination with insulin (with or without metformin)
  • Elderly, CKD patients, and those on ACEi/ARBs or loop diuretics have higher incidence of adverse reactions related to reduced intravascular volume
  • CANA and EMPA contraindicated in patients with eGFR < 45 mL/min/1.73 m2 and DAPA with eGFR < 60 ml/min/1.73 m2 due to poor efficacy with reduced renal function
  • Most patients experience some weight loss, mostly due to loss of fat,
    which appears to be sustainable
  • Weight loss and osmotic diuresis may provide a reduction in BP
  • Incidence of hypoglycemic events are low and usually associated
    with a background of insulin or SU
  • Mycotic infections and UTIs may occur at a greater frequency (in women)
    but are usually mild to moderate, easily treated and usually do not recur

Practical tools to download and/or print

For healthcare provider tools and resources visit the Canadian Diabetes Association’s Clinical Practice Guidelines Website at: http://guidelines.diabetes.ca/

For the 2015 Interim Update to the CDA Guidelines http://guidelines.diabetes.ca/2015update

Or, please try these useful references below

Attachments

SGLTi: All in One handout (EN-Spotlight_handouts_All-In-One_v4.pdf, 1015.27 Kb)