Cardio-renal protection with SGLT2i in T2DM patients
Date: 7 Oct 2021 (Thursday)
Time: 1-2pm (GMT +8)
Hosted by: Merck
Chairperson: Dr Sharifah Zahidah
Speakers:
- Dr Abel Soh, Endocrinologist, Mount Elizabeth Hospital
- Dr Daniel Wai, Endocrinologist, Mount Elizabeth Hospital
Introduction to T2DM and CVS and renal disease
- 5x increased risk of MI
- Up to 6x increased risk of stroke
- CVD is responsible for at least 50% of T2DM mortality
- Diabetic kidney disease (DKD)
- Associated with poor outcomes, longer LOS, more readmissions
- Untreated DM can lead to ESRD
- Almost 60% of T2DM patients have DKD
- Later stages of DKD in T2DM patients are associated with a higher probability of progression, than earlier stages of DKD
- Diabetes and HF
- Risk of hospitalisation for HF increases in later stages and T2DM: increasing from 4.3% at eGFR >90, to 30.5% at eGFR 15-30
- CVS mortality and all-cause mortality in T2DM patients with CKD
- Associated with an increased risk of CV mortality and all-cause mortality
- Afkarian M et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013 Feb;24(2):302-8
- Gansevoort RT et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013 Jul 27;382(9889):339-52
SGLT2 inhibitors introduction
ADA guidelines recommend use of SGLT2i for T2DM patients with DKD and CVD:
SGLT2 inhibition lowers renal glucose threshold (RTG)
- Usual RTG in healthy adults is 10-11mmol/L
- Without insulin, the blood glucose cannot go into the tubular cells
- Tubular cells reabsorb more glucose instead of excreting more glucose, resulting in increasing plasma glucose levels
- One good way to treat it is by giving SGLT2i –> lower the RTG. Even when blood glucose is in the normal range, the body can remove the glucose still. Can remove glucose in the blood well
CANVAS programme
An integrated analysis of CANVAS trial and CANVAS-R trial.
- Broad population of 10,142 patients with T2DM and either a history of CVD of 2 or more risk factors for CVD, following for 6.5 years
- Inclusion criteria are similar:
- T2DM patients
- HbA1c >7% to <10.5%
- eGFR >30
- Age >30 with history of prior CVD, OR >50 with 2 or more risk factors for CVD
Effects
- Placebo group: cannot use SLGT2i, but can use other kinds of treatment (insulin, GLP-1 agonist). Generally in the placebo group, it is very difficult to lower HbA1c, as it triggers the hunger issue, still have weight loss (could be due to it being a RCT effect)
- In the patient population that ceceive canagliflozin: still get more HbA1c reduction (0.58%), more weight loss (1.6kg), more BP loss (3.93mmHg)
- Key result: MACE outcome. Significant reduction of 14% (overall), 18% (patients with established CVD)
- eGFR over time: patients in placebo have steady drop, but in canagliflozin group had slow and steady improvement
- Albuminuria: placebo group steady progression, canagliflozin group have
- Long term outcomes: amputation risk is higher, fracture risk (p-value = 0.02) –> which led to FDA’s initial black box warning for canagliflozin
CREDENCE trial
Primarily a renal study, in patients with established renal disease. As compared to other trials:
- CANVAS: mean eGFR 76, median UACR 12
- DECLARE TIMI-58: mean eGFR 85, median UACR 13
- EMPA-REG OUTCOME: mean eGFR 74, median UACR 18
- CREDENCE: mean eGFR 56, median UACR 927
CREDENCE trial was an event-driven trial:
Primary outcome
- Composite of ESRD, doubling of sCr, renal, CV death
Secondary outcomes
- Composite of CV death or hospitalisation for HF
- 3-point MACE: composite of CV death, non-fatal MI, non-fatal stroke
- HF hospitalisation
- Renal composite outcome: ESRD, doubling of sCr, renal death
- CV death
- All-cause mortality
- CV composite: CV death, non-fatal MI, non-fatal stroke, HF hospitalisation, unstable angina hospitalisation
Results: primary outcome
- ESRD, double sCr, renal, CV death: 30% relative risk reduction (P = 0.0001, HR 0.70, 95% CI 0.59 – 0.82)
Results: intermediate outcomes
- Difference in HbA1c reduction vs placebo group: 0.25%.
- Less than CANVAS as the patient population is different. CREDENCE patient populations are in CKD, less urinary output
- Difference in BP: similar to CANVAS at 3.3mmHg
- Body weight: mean difference of 0.8kg vs placebo
- UACR: mean difference of 32% vs placebo
Results: secondary outcomes (renal)
- Renal composite outcome: ESRD, doubling of sCr, renal death: 34% relative risk reduction (P < 0.001, HR 0.66, 95% CI 0.53-0.81)
- ESRD: 32% relative risk reduction (P = 0.002, HR 0.68, 95% CI 0.54-0.86)
- Dialysis, kidney transplant, renal death (HR 0.72, 95% CI 0.54-0.97)
- Acute and long-term effects on eGFR: 60% reduction in rate of eGFR decline with canagliflozin
- Initial drop in eGFR due to the reduction in differential pressure between afferent and efferent, but very little drop after that
- Importance of starting SGLT2i early to stop the drop of eGFR
Results: secondary outcomes (cardiac)
- CV death, hospitalisation for HF: 31% relative risk reduction (P < 0.001, HR 0.69, 95% CI 0.57-0.83)
- Hospitalisation for HF: 39% relative risk reduction (P < 0.001, HR 0.61, 95% CI 0.47-0.80)
- MACE: 20% relative risk reduction (P = 0.01, HR 0.80, 95% CI 0.67-0.95)
- CV death: trend of lowered CV death but not statistically signification (P = 0.0502, HR 0.78, 95% CI 0.61-1.00)
Results: safety data
Forest Plots of selected AEs from CREDENCE: the reason why FDA removed black box warning of amputation risk
- Fracture: HR 0.98 [0.70-1.37]
- Amputation: HR 1.11 [0.79-1.56]
Safety summary between CANVAS and CREDENCE trials
- CANVAS
- Increased risk of amputation with patients with pre-existing lower limb issues
- Possible increase fracture risk
- Imbalance in male and female GMI, volume depletion, osmotic diuresis
- No DKA imbalance
- CREDENCE
- No imbalance was observed in serious AEs (including amputation and fractures)
- Imbalance in male GMIs and diabetic ketoacidosis was observed
Discussion
- Canagliflozin safely reduced renal and CV events in T2DM patients with nephropathy with consistent effects in patients with or without prior history of HF
- Greater reduction of CV death or HF hospitalisation, of HF hospitalisation alone in patients without prior history of HF
- Support the initiation of canagliflozin in patients with T2DM and nephropathy for CB and renal outcome benefit regardless of a prior history of HF
- Align with 2019 ESC guidelines that recommend SGLT2i initiation in patients with T2DM and proteinuria given elevated CV risks
Q&A
Q1: Are there any T2DM you would not give SGLT2i to?
Dr Daniel: Generally I follow the ADA guidelines. There is no fixed rule to say that we MUST use canagliflozin. Every doctor have different preferences. If a patient has past history of UTIs due to SGLT2i, or allergic reactions, I will be very careful about. Otherwise, I will push for my patients to be taking SGLT2i.
Other group may be if patient is prone to dehydration (e.g. tube feeding, loss of thirst sensation). Another group may be patients who already have amputation, to prevent the group of patient to be more worried.
Q2: The reduction in proteinuria seen in canagliflozin study: is it only for canagliflozin, or for other SGLT2i as well?
Dr Daniel: Most studies about 1/3. Only canagliflozin has the renal failure outcomes. Looking at ACEi and ARB using in combination, although more reduction of eGFR, but we get more hyperK and ARF. Other SGLT2i did not study renal outcomes as the primary outcome. Hence FDA only approve canagliflozin to reverse and slow down DKD.
Q3: For newly diagnosed T2DM, can we start SGLT2i straight away?
Dr Daniel: Certain times we may not even start metformin, if lactic acidosis or high sCr. But metformin still remains as the 1st recommended treatment due to its effects on obese patients and also evidence of use. Generally, I would not start 2 new medications straight away, but rather start with metformin as 1st line, and continue with lifestyle. Many times we can see good reduction initially as the pancreas is still 50% active.
On the other hand, if a patient is uncontrolled and/or longstanding DM, I will be more aggressive.
Q4: Currently there are multiple oral agents for T2DM. If the patient fails metformin mono-therapy, do we use SGLT2i as 2nd-line agents, in view of the favourable results of the trials?
Dr Daniel: As per the ADA and EASD guidelines, if there is a convincing co-morbidity (renal failure, heart failure, CVS), after metformin, SGLT2i should be favoured.
For patients who are only concerned about CVS, the more compelling agents may be using GLP-1 agonists.
For other agents (sulfonylureas, DPP-4 inhibitors): there are no compelling reasons to use them as there are no RCTs to support their use.
In primary setting without any co-morbidity, I can choose any agents.
Q5: Which SGLT2i is your most preferred choice and why?
Dr Daniel: Canagliflozin has proven to reduce the glucose in your blood the most. It is the only SGLT2i with solid renal and CVS RCT outcomes as well.
The other SGLT2i strengths are in patients with heart failure without diabetes. However for patients with diabetes, canagliflozin is probably the most proven agent to be used.
