SGLT-2 inhibitors in heart failure blue book article AND the ADS/ANZCA joint statement

Question 1

Along with improving glycemic control in T2DM, what are some other approved indications for SGLT2 inhibitors?

Answer 1

Dapagliflozin (forxiga):

• Prevent hospitalisation for HF in those with T2DM & CVD or risk factors
• Improve symptom control & cardiovascular outcomes as adjunct therapy in HFrEF
• Prevent new or worsening nephropathy in T2DM & CVD or risk factors (NZ)
• Rx of CKD in adults (NZ)

Empagliflozin (jardiance):
-prevent CV death in those with T2DM & established CVD

Europe: as an adjunct to insulin for pts with T1DM who are overweight

Question 2

What are the benefits of SGLT2 inhibitors?

Answer 2

Improve HbA1c by 0.5-1%

• modest weight loss & BP reductions
• In pts with T2DM: reduce MACE, improve cardiovascular survival, improve heart failure, provide renal protection (in pts with and without CKD). Overall reductions of 23% in hospitalisation for HF or cardiovascular death, similar benefit in those with or without HF or CVD. Risk of MACE reduced by 11%, only in those with established CVD.
• In pts with T1DM: weight reduction, improved HbA1c & total daily insulin use- approved for this use overseas but restricted to overweight given these pts are @ lower risk of DKA.
• Reduce hospitalisation for heart failure or cardiovascular death - in pts with AND WITHOUT diabetes & in those with diabetes & good glycemic control
• EMPEROR preserved has found that in adults with class II-IV HFpEF (>40%), empagliflozin reduced risk of hospitalisation for HF or CV death in pts with and without diabetes- NNT 31. Important as most HF therapies ore ineffective or only weakly effective in pts with higher EF. DELIVER trial is investigating use of dapagliflozin for EF >40%.
• SGLT2 inhibitors are reno-protective in pts with & without DM & with & without CKD- including reducing the risk of eGFR decline, ESKD, renal or CF death, NNT=19

SO, even in T2DM pts with good glycemic control, data justifies addition of SGLT2 inhibitors to prevent HF & progression of renal disease.

Question 3

What are some perioperative risks of SGLT2 inhibitors? do they cause hypocalcaemia?

Answer 3

UTIs- these are the most common complication from SGLT2 -s, due to glycosuria. genital hygiene advice vital for high-risk procedures. Consider screening for UTI with Hx & urine dipstick for pts @ high risk of complications eg, joint replacement or cardiac surgery, catheter carefully considered.
urosepsis & pyelonephritis
vulvovaginal candidiasis
fournier’s gangrene

hypotension (due to osmotic diuresis & intravascular volume contraction)- particularly in older pts or those taking ACE inhibitors or ARBs

use with caution in pts predisposed to acute renal injury (eg. meds which may predispose such as NSAIDs, ACEI, ARBs, diuretics)- SGLT2is have been ass’d with incr rates of AKI (which improve when the drug discontinued)

increased rate of lower limb amputation (avoid SGLT2is in pts @ risk of foot amputation)

bone fractures ?may be due to orthostatic hypoT–> dizziness & falls but may also be an osteoporotic mechanism as pts on SGLT2 is may have lower bone mass (canagliflozin)

ketoacidosis: euglycaemic ketoacidosis higher risk in pts fasting acute illness, underlying poor glycemic control. All pts on sglT2 inhibitors should be educated re: “sick day” medication management (withhold while unwell, fast). Pts on SGLT2 - may also get hyperglycaemic DKA. should NOT be used for T1DM.

they DON’T cause hypocalcaemia- more likely hypERCa

Question 4

What is the potential mechanism for SGLT2 inhibitors enhancing CV outcomes?

Answer 4

given the magnitude & short latency (within months) of effect of SGLT2 inhibitors on CV outcomes, mechanism is likely unrelated to glycemic control- potentially direct cardioprotective effects
They don’t provide benefit for atherosclerotic complications so likely benefits are a mechanism separate from anti-hyperglycaemic effects
Given benefits are also seen for pts with HF already optimised on conventional guideline-directed medical therapy, the mechanism is likely independent of traditional neurohormonal pathways of HF treatment.

Part of benefits for prevention of cardiovascular death in heart failure are due to haemoconcentration & diuresis.

1. SGLT2 inhibitors have diuretic attributes, acting on renal PCT to prevent glucose reabsorption & inducing a natriuresis & osmotic diuresis without impacting plasma osmolality.
2. Reno-protective benefits may be that increased osmolality at the macula dense stimulates afferent tubule VC, reducing glomerular HTN.
3. May reduce IF clearance to relieve organ congestion without reducing IV volume (which means it doesn’t promote RAAS activation & counter-productive VC & Na+ retention as do other diuretics)
4. Afterload reduction reducing myocardial O2 demand (modest reductions in SBP 4-10mmHg & MAP 2mmHg) due to diuresis & other mechanisms
5. increase in circulating ketones provides an energy source for the failing heart, synergistic with O2
6. inhibit myocardial Na/H exchange proteins which increase myocardial Ca++ availability. This is associated with beneficial cardiac remodelling, reducing cardiac hypertrophy, fibrosis & systolic dysfunction.
7. BENEFICIAL MYOCARDIAL REMODELLING: reductions in LV ESV & EDV in pts with HFrEF, reductions in LV mass, reduced cardiac fibrosis.

Question 5

What complication is responsible for up to 20% of pt deaths in T1DM?

Answer 5

DKA

Question 6

What are the leading causes of CKD?

Answer 6

DM
HTN
older age
obesity

Question 7

What’s the risk of euglycaemic DKA in non-diabetic patients using SGLT2 inhibitors?

Answer 7

Low & similar to placebo but it’s unclear if these data apply perioperatively where pts may be @ higher risk of relative insulin deficiency if fasting or under physiological stress.

Question 8

For how many days should SGLT2 inhibitors be ceased prior to non-day surgery or bowel prep for colonoscopy? how about day procedures? when to restart?

Answer 8

3 days (day of surgery & 2 days before)

For day procedures (incl gastroscopy), SGLT2i can be stopped just for the day of the procedure, but fasting before & after should be minimised.

restart once normal PO intake resumed & acute illness has resolved, provide written advice on discharge re; seeking medical advice if unwell

Question 9

Which situations may increase the risk of DKA in a pt on SGLT2 inhibitors? So what should pts be educated on?

Answer 9

fasting
dehydrated
bowel prep
surgical stress
intercurrent illness (eg. active infection)

When SGLT2 inhibitors commence, pts should be informed about the risk of DKA with illness & procedures & receive written advice with “sick day” management plans

Question 10

Is urine ketone monitoring reliable?

Answer 10

no

Question 11

What are the signs/symptoms/Ix that may herald DKA?

Answer 11

abdo pain, nausea, vomit, fatigue
fingerprick capillary ketone >1.0mmol/L with or without hyperglycaemia
metabolic acidosis
low (negative) base excess (BE) < -5mmol/L on arterial or venous gas

Question 12

What should be the process on admission for a pt taking SGLT2 inhibitors?

Answer 12

if pt unwell, consider postpoining
if well & capillary ketones <1mmol/L, proceed- consider hourly BGL & ketone testing during procedure & 2 hourly following procedure until eating & drinking normally
If the SGLT2 inhibitor hasn’t been withheld as per guidelines, action depends on urgency of the procedure & pt comorbidity, surgical factors, HbA1c, ketones & base-excess;
-If HbA1c is >9%, this indicates insulin insufficiency & is higher risk of DKA
-If ketones are <1 & BE is >-5, no ketosis & no metabolic acidosis; consider proceeding with DAY SURGERY with the ketone monitoring aa, provide written post-discharge advice. For moree extensive surgery, consider goals of care & collaborate with endocrine & critical care. Perioperative insulin & dextrose infusions may reduce risk.
-if ketones >1 but BE >-5, ketosis without metabolic acidosis. endocrinology advice needed- it may reflect starvation esp if the pt had HbA1c <9%. proceeding may be considered depending on goals of care, perioperative insulin/dextrose infusion must be undertaken to reduce the risk of ketosis & acidosis.
-If ketones >1 & BE

Question 13

What are the findings confirming euglycaemic ketoacidosis? management?

Answer 13

BE 1 mmol/L, BGL <14 mmol/L
seek endocrinology advice; rehydrate, IV insulin (add dextrose if BGL <15mmol/L), hourly BGL, ketone & blood gas monitoring