SGLT Inhibitors

SGLT-2 inhibitor: Sodium glucose cotransporter 2 inhibition increases the excretion of glucose in the urine. SGLT-2 is a glucose transporter in the kidney reponsible for 90% of glucose reabsorption. Inhibiting this transporter leads to increased renal excretion of glucose.

SGLT-1 inhibitor: SGLT-1 inhibition reduces dietary glucose absorption primarily in the small intestine and indirectly increases the release of incretins, like GLP-1, due to delivery of glucose to the more distal gut and colon. 

1. Therapeutic Considerations of SGLT Inhibitors

 All information from medication product monograph unless referenced below. 

A1c Lowering 0.5 - 1%1 
Hypoglycemia Risk Low 
Class Side Effects Genital and urinary tract infections (mainly fungal- Candida), dehydration, hypotension. Rare: acute kidney injury, DKA.  Some side effects are specific to individual brands - see below.
Vascular Protection Yes - empagliflozin and canagliflozin in those with established cardiovascular disease.  
Weight weight reduction
Cost, Blue Cross coverage;  strengths;  dosing frequency; indications

Click to visit this class in the Complete Diabetes Medications Table  

Combination Medications Visit combination meds on Complete Diabetes Medications Table
Advice for times of dehydration, vomiting, diarrhea Diabetes Canada advises this medication be stopped until symptoms are resolved. Adequate hydration should be promoted. Patients are to seek medical care if they have signs of DKA (nausea, vomiting, a lack of appetite, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue, or sleepiness).
Other
  • Associated with blood pressure reduction.
  • Health Canada and FDA investigations into DKA in type 2 diabetes. Important to be aware that DKA may occur without concurrent hyperglycemia. 
  • Renal benefit seen in empagaliflozin. Possible benefit in canagliflozin and dapagliflozin- studies are pending. 
  • Reminder- due to mechanism of action, urine will be positive for glucose. 
  • Glycosuria from hyperglycemia versus from SGLT-2 inhibitor: Hyperglycemia increases pressure within the glomerulus (filters of kidney), leading to hyperfiltration. Hyperfiltration is implicated in the loss of glomeruli and the subsequent decline in GFR. SGLT2 inhibitors are known to reduce glomerular pressure, resulting in less hyperfiltration and increased protection of renal function.

2. Dosing Considerations

 

  • Refer to Therapeutic Considerations for Renal Impairment, Diabetes Canada for specific brand dosing recommendations in renal impairment.
  • Tablet for all brands is taken once a day at any time with, or without food. 
  • Lower dose tablet is usually started for all brands and titrated up to maximum dose tablet based on overall glucose values and/or A1c level (if no renal impairment or other exceptions). 

3. Brand Considerations

 

Canagliflozin - Invokana®

  •  See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications.
  • Side effects in addition to those listed above: increased risk for toe amputations, increased risk for bone fracture (decreased bone density to hip in particular). 
  • The following are key points for consideration from the CANVAS program trials (CANVAS trial and CANVAS renal end-points trial).2 CANVAS participants had Type 2 Diabetes with history of cardiovascular disease or at high risk for cardiovascular disease. The objective was to assess the effect of canagliflozin (Invokana) – SGLT-2 inhibitor- on cardiovascular, renal and safety outcomes.
    Results:
    • Cardiovascular results:
      Significantly fewer participants in the canagliflozin group had a primary outcome event (the composite of death from cardiovascular causes, nonfatal myocardial infarction and nonfatal stroke) with 26.9 (canagliflozin group) vs. 31.5 (placebo group) participants with an event/1000 patient-years 14% relative risk reduction. Significantly fewer participants in the canagliflozin group had a lower risk of hospitalization for heart failure.
    • Renal results: Data supports a possible renal benefit: A reduction in albuminuria for those on canagliflozin. Those in the treatment group experienced the composite end point less than the placebo group (a sustained 40% reduction of eGFR, the need for renal-replacement therapy or death from renal causes). Further study is ongoing to confirm effects on kidney. The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial results are expected in 2019.
    • Adverse event: Those in treatment group experienced significantly higher risk of amputation and fracture.
      • Amputation: Rate of amputations was 6.3 (canagliflozin group) vs 3.4 (placebo group) per 1000 patient-years. Those with a previous amputation or peripheral vascular disease had the highest absolute risk.Treatment and placebo groups had similar levels of prior amputation and peripheral vascular disease as baseline characteristics. This is a new finding (not found in EMPA-REG) and mechanism is unknown.
      • Fracture: Rate of fractures was 15.4 (canagliflozin group) vs. 11.9 (placebo group) per 1000 patient-years.

        Prescribers will likely use caution when considering use of canagliflozin in individuals at high risk for amputation and/or fracture.
  • May be associated with hyperkalemia especially in those with renal impairment or on other medications that affect serum K. Serum K levels should be monitored while on therapy. 

 

Dapagliflozin- Forxiga®

  • See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications
  • Side effects in addition to those listed above: possible increased risk for bladder cancer (more trials needed but not recommended in those with bladder cancer or history of bladder cancer). 
  • Cardiovascular outcome data from Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) published by NEJM November 2018. Results summary: 
    • Participants: This study included patients over 40 years of age, with type 2 diabetes, A1c 6.5-12%, Cr Clearance of at 60ml or more/min. Patients had multiple risk factors for atherosclerotic cardiovascular disease, or established atherosclerotic cardiovascular disease. Followed for median of 4.2 years.

      Cardiovascular results: The results of this trial indicate that dapagliflozin did not result in lower rate of MACE (the composite of death from cardiovascular causes, nonfatal myocardial infarction and nonfatal stroke) than placebo. In secondary analysis, dapagliflozin did result in a lower rate of hospitalization for heart failure compared to placebo (4.9% for dapa, 5.8% for placebo), but no statistical difference in cardiovascular death in comparison to placebo was observed.

      Renal results: Beneficial effect on renal outcomes but requires further study.

      Adverse events: Unlike canagliflozin, there was no evidence for increased rate of amputations or fractures. As with other drugs in the SGLT-2 inhibitor class there was an increased risk for diabetic ketoacidosis (DKA) (0.3% for dapa and 0.1% for placebo) and genital infections (0.9% dapa and 0.1% placebo). 

 

Dapagliflozin + Metformin - Xigduo®

  • See Combination Medications in the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications
  • See Dapagliflozin above and Metformin on the Biguanide class page.

 

Dapagliflozin + Saxagliptin - QTERN®

  •  See Combination Medications in the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications
  • See Dapagliflozin above and Saxagliptin on the DPP-4 Inhibitor class page.

 

Empagliflozin - Jardiance®

  • See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications.
  • The following are key points from  “Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes” (or EMPA-REG OUTCOME) trial published in 20153
    The study included patients over the age of 18, with a BMI < 45, and eGFR > 30.
    In contrast to previous studies of hypoglycemic agents in patients with type 2 diabetes, the patients included in this trial already had established coronary artery disease.
    Results:
    • The primary outcome of the study was a composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke.The results showed that irrespective of the dose, empagliflozin lead to a 38% relative reduction in cardiovascular mortality, and a 32% relative reduction in all-cause mortality, compared to placebo. Reduction in the primary outcome was greatest for patients over the age of 65, Caucasians or Asians, and those with a baseline A1c < 8.5%. Notably, reduction in cardiovascular mortality was seen across all subgroups.
    • 35% reduction in hospitalizations for heart failure in those treated with empagliflozin.
  • Long-term renal effects also analyzed.4 In those patients with established cardiovascular disease and type 2 diabetes, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events compared to placebo. 

Ertugliflozin - Steglatro® 

  • See the Complete Diabetes Medication Table for: cost/month; Blue Cross coverage; available strengths; dosing frequency; Health Canada indications. 
  • Notes from product monograph below.
  • Steady state is reached after 4 to 6 days of once-daily dosing with ertugliflozin.
  • Renal: 
    • Contraindicated GFR < 45 mL/min. 
    • Should not be initiated if GFR ˂60.
    • Renal function must be assessed prior to initiation and periodically thereafter, with more frequent monitoring if GFR decreases to <60.
    • Cases of acute kidney injury have been observed with STEGLATRO™ in clinical trial. Patients with moderate renal impairment are more susceptible to these changes. Before initiating consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing in any setting of reduced oral intake (acute
      illness or fasting) or fluid losses (such as GI illness or excessive heat exposure)
  • Cardiovascular/Volume Depletion: Caution should be exercised in patients for whom an ertugliflozin-induced decrease in blood pressure could pose a risk. This includes patients:  with known cardiovascular disease, on anti-hypertensive therapy, on diuretics, who are elderly (≥65 years), ahve impaired renal function (GFR < 60), have low systolic blood pressure, or  have intercurrent conditions that may lead to volume depletion (such as gastrointestinal illness).
  • LDL: Dose-related increases in LDL-C are seen with STEGLATRO™ treatment. LDL-C levels should be monitored in patients and treated as appropriate.

Sotagliflozin - Zynquista®

  • Not yet approved by Health Canada (SGLT-1 and SGLT-2 inhibitors)
  • Indications are expected to be with type 1 diabetes first. (Consideration for type 2 diabetes requires completion of cardiovascular outcome trials.)

References

1.  Inzucchi SE, Bergenstal RM, Buse JB, det al. Management of hyperglycemia in type 2 diabetes: a patient-centred approach. Diabetes Care 2012; 35: 1364-79.  http://care.diabetesjournals.org/content/35/6/1364  (Accessed Feb 26, 2018). 

2.  Neal, B, et al. Canagliflozin and Cardiovascular and Renal events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657.

3. Zinman, B et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.

4.  Wanner, et.al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375:323-334.

5.  Expert Opin Ther Targets. 2016 September; 20(9): 1109–1125. doi:10.1517/14728222.2016.1168808 

6. Wiviott, S et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2018; 380: 347-357.