13 Jul, 17 | by sghosal
The recent publication of CANVAS PROGRAM (1) raised more questions than expected. The SGLT-2 inhibitor group of molecules were basking in the glory of EMPA-REG trial (2) and its cardio-vascular & renal benefits when CANVAS PROGRAM came as a rude shock.
EMPA-REG Summary (2):
- This was the first cardiovascular outcomes trial which demonstrated a statistically significant reduction in cardiovascular death (38% relative risk reduction), hospitalisation due to heart failure (35% relative risk reduction) & all-cause mortality (32% relative risk reduction).
- Clinically these values translated into 22 lesser CV deaths, 25 overall deaths & 14 lesser hospitalisation due to heart failure for every 1000 patients treated with empagliflozin for 3 years.
- The results were so impressive (a persuasive P value of <0.001) that a class I indication for reduction of these end points was suggested by FDA.
- In December 2016, FDA awarded empagliflozin a new indication (apart from glucose lowering), i.e. lowering CV deaths in type 2 diabetic patients with CV disease (3).
CANVAS PROGRAM (1):
With the developments mentioned above there were a lot of expectations from the CANVAS PROGRAM. EMPA-REG trial documented CV benefits in those with established CV disease. Could the same benefits be translated to those without established CVD (the majority of the patient population we see in clinical practice)? CANVAS PROGRAM was supposed to answer this vital question in addition to assessing CV outcomes in those with established CVD.
What was the clinical impact of CANVAS PROGRAM?
- The only end points in which canagliflozin came out with flying colours were MACE & hospitalisation due to heart failure.
- MACE benefits in only those with established CVD (mimicking EMPA REG trial).
- No reduction in all cause mortality.
- No reduction in CV deaths.
- Significant increase in rates of fractures & lower limb amputations.
To summarise treating patients with canagliflozin results in:
- 23 fewer MACE (? clinical implication: in the absence of any superiority of the individual end points), 16 fewer hospitalisation due to heart failure, at the cost of 15 more amputations per 1000 patients treated for 5 years (1).
Where does that leave us with?
- In a desperate bid to save the molecule there is an effort to generalise the amputation risk aspect.
- There is no escaping the fact that the amputation & fracture related issue was haunting canagliflozin well before the CANVAS PROGRAM was published (indicated by the black box warnings).
- What was brought out in the forefront was an EMEA observation of imbalances in the amputation rates in females in the EMPA REG trial (4). Although the EMEA statements were contradictory, they wanted to scrutinise the entire empagliflozin & dapagliflozin data before painting this entire class of molecules with the same brush.
- In July 19th 2017, the entire empagliflozin databank from phase 2 & 3 & EMPA REG were analysed and there was no signal of either increased amputation nor fracture risk (5).
- Similarly the entire dapagliflozin polled phase 2 & 3 data did not indicate any adverse signals related to amputation & fracture (6).
So where do we stand as of now?
- Empagliflozin remains the gold standard therapy for all type 2 diabetes patients with established CVD with a very reassuring safety profile.
- Dapagliflozin has also documented its CV safety in polled phase 2 & 3 trials. Further clarifications will be available after publication oF DECLARE TIMI 58 results.
- Canagliflozin has MACE benefits but not any CV or all-cause mortality benefits and at the cost of increased serious adverse effects.
- The first motto of a physician is “do no harm”.
- It seems to be a safe practice strategy as of now to stick to empagliflozin & dapagliflozin until further clarifications on canagliflozin becomes available.
(1). Neal B. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. NEJM. June 12, 2017DOI: 10.1056/NEJMoa1611925.
(2). Zinman B. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373:2117-28.
(3).FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. [Online] Available at: https:/www.fda.gov/newsevents/newsroom/pressannouncements/ucm531517.htm [Accessed on: 13th July 2017].
(4).SGLT2 inhibitors: information on potential risk of toe amputation to be included in prescribing information. [Online] Available at:www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors_(previously_Canagliflozin)/human_referral_prac_000059.jsp&mid=WC0b01ac05805c516f [Accessed on: 13th July 2017].
(5). Kohler S. Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes: Pooled Analysis of Phase I–III Clinical Trials. Adv Ther 2017, DOI 10.1007/s12325-017-0573-0.
(6). FDA briefing document: NDA 202293 Dapagliflozin. [Online]www.fda.gov/downloads/AdvisoryCommittees/UCM378076.pdf [Accessed on: 13th July 2017].