It was few months ago when I complained in another post about the fact that empagliflozin (Jardiance®) was the only SGLT inhibitor that has demonstrated some cardiovascular benefits but was not covered by our provincial drug plan. Well, the good news is that it is officially reimbursed by the Ontario Drug Benefit now.   And so…. it deserves another post to review its clinical benefits as well as some key prescribing information.

Clinical Evidence

n-eng-j-med-screenshot
EMPA-REG Outcome Study; N Engl J Med 373;22 Nov 26, 2015

This was a randomized, double-blind, placebo-controlled trial to assess the effect of once daily empagliflozin (at 10mg/day or 25mg/day) versus placebo on cardiovascular events in adults with Type 2 diabetes, particular those with high cardiovascular risk factors.

study-summary-slide

The key results are summarized below:

summary-of-results

For more detailed information about this clinical trial, click here.

Here are some of my thoughts:

  • The results speak for themselves, that it is clear the empagliflozin group has demonstrated its superiority to placebo on many counts:  the composite endpoint,  cardiovascular death, heart failure and all cause mortality.  All of these endpoints have important application in clinical practice.
  • Of note is that many results are presented as pooled analyses, instead of presenting separately in the two different treatment groups with different dosages of empagliflozin (10mg/day vs. 25mg/day).  Are the benefits observed dose-related?  I have reviewed some of the results slides presented by the different treatment arms. The result graphs of the two dosages either superimposed on one another, or the further reduction with higher dose of empagliflozin was minor and likely not significant.  Hence, I think the benefits we see with empagliflozin are related to the drug itself with little correlation to the dose.

lbct-2_inzucchi-final-cv-death-in-graph

  • The benefits appear to be noticeable within few months of starting the empagliflozin therapy.  For example, the reduction in cardiovascular death would be seen as early as 3 months (as the two graphs begin to diverge).
  • It is bewildering to see that the outcome for fatal or non-fatal stroke is worse among the empagliflozin group (HR = 1.18, p= 26 for fatal or non fatal stroke; HR = 1.24, p=0.16 for nonfatal stroke), although these results are not considered statistically significant. During the study, many patients (~ 83%) were concurrently treated with aspirin (82%), clopidogrel (~ 10%) or vitamin K antagonist (~ 5-6%).  It is unclear whether those individuals who has developed either fatal or non-fatal stroke were being anti-coagulated. The study team discussed that many of patients developed stroke after they have discontinued empagliflozin as the hazard ratios were different between their intent-to-treat and on-treatment analyses. I think there is more to the story that remains to be a mystery at this point.

empa-reg-outcome_stroke

  • Exactly how empagliflozin offers its cardiovascular protection is yet to be determined. But there are many speculations and proposed mechanisms:
    • Anti-hyperglycemic effect
    • Weight loss
    • BP reduction
    • Uricosuric effect
    • Inflammation
    • Glucoretic effect
    • Anti-arrhythmic effect
    • Increased cardiac β-hydroxybutyrate uptake
    • RAAS-mediated effect
    • Arterial stiffness
  • The trial was considered a success.  It is important to note that the results apply to patients with high cardiovascular risk factors.

Key Prescribing Information

  • Empagliflozin belongs to the newest class of anti-diabetic medication known as the SGLT-2 inhibitors (sodium glucose co-transporter inhibitors). They work by preventing the reabsorption of glucose in the kidney, thereby increasing the excretion of glucose and helping to lower the blood glucose.
  • In addition to its hypoglycemic effects, SGLT-2 inhibitors are also known to reduce weight, lower blood pressure.  SGLT-2 inhibitor on its own does not cause hypoglycemia; however when it is used in combination with insulin or other hypoglycemic agent, it may increase the overall risk of hypoglycemia.
  • Dose: Empagliflozin is indicated for Type 2 diabetes, starting dose is 10mg po daily, may increase up to 25mg po daily.
  • According to Lexicomp, no dosage adjustment is necessary for eGFR ≥45 mL/minute/1.73 m2.  However it is recommended not to initiate therapy once eGFR is below 45mL/min/1.73m² and its use is contraindicated if eGFR is below 30mL/min/1.73m² or on ESRD, dialysis.
  • The most common adverse effect is the increased risk of urinary tract infection and yeast infection, given it encourages glucose output renally.  Two other important side effects include diabetic ketoacidosis and possibly reduction in bone mineral density as well as an increase in the risk for bone fractures.

Place in Practice

The clinical evidence established so far apply only to type 2 diabetics with high cardiovascular risk factors. As an add on agent, it definitely offers additional glycemic control with its bonus effect on weight control and blood pressure.

However, the question is that, should the result of such trial calls for an evaluation of our current approach to Type 2 diabetes?

If the safety profile is better established with time and real life experience, should empagliflozin replaces metformin as first line agent for Type 2 diabetes? What about those individuals with Type 2 diabetics currently on insulin or other agents that have not been shown to offer cardiovascular benefits? Should they be considered empagliflozin?  I suspect these questions will remain unanswered at this point.

I still want to wait for the results from the CANVAS and the DECLARE-TIMI58 studies which are designed to evaluate the cardiovascular benefits of canagliflozin and dabagliflozin respectively.  When these results are available, we will have a better sense whether these benefits seen with empagliflozin are agent-specific or a class effect of SGLT-2 inhibitors.

The paradigm shift in the management of type 2 diabetes has begun with the impressive results from the EMPA-REG Outcome study. It will be interesting to see how it unfolds with time and more clinical experience with the use of empaliflozin in real life setting.

 

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