SGLT2 Inhibitors: The Future is Flozin!

SGLT2 inhibitors

Meet the “Flozins”:

  • canagliflozin (Invokana)
  • dapagliflozin (Farxiga)
  • empagliflozin (Jardiance)
  • ertugliflozin (Steglatro)

MOA: 

The figure below shows how glucose is reabsorbed via sodium-glucose cotransporter 1 and 2 (SGLT1 and SGLT2, respectively) in the normal kidney and diabetic kidney. Found in the proximal convoluted tubule, SGLT2 reabsorbs about 90% of urinary glucose and SGLT1 about 10%. 

SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with T2DM. Of note, although the currently developed SGLT2 inhibitors almost completely block proximal tubular glucose reabsorption, the measured inhibition is less than 50% based on urine glucose excretion.

Source: Alicic et al. Sodium-Glucose Cotransporter 2 Inhibition and Diabetic Kidney Disease. Diabetes. 2019 Feb;68(2):248-257. PMID: 30665953.

Pros: 

  • Beneficial effect in ASCVD, heart failure (see below), and diabetic kidney disease
    • Specifically, SGLT2 inhibitors appear to reduce frequency of CHF exacerbations, decrease CKD progression, and reduce frequency of MACE
  • Weight loss (via caloric loss in glycosuria)
  • Lower risk of hypoglycemia compared to other oral agents for DM

Per the ADA Standards of Medical Care Recommendations:

“Among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease or indicators of high risk, established kidney disease, or heart failure, a sodium-glucose cotransporter 2 inhibitor or glucagon-like peptide 1 receptor agonist with demonstrated cardiovascular disease benefit is recommended as part of the glucose-lowering regimen independent of A1C and in consideration of patient-specific factors”

Cons: 

  • Expensive! 
  • Relatively weak glucose-lowering agents (mean reductions in A1C compared with placebo range between 0.4-1.1% depending on baseline level of hyperglycemia)
  • ADE: increased risk of fracture, DKA, GU infections, hypovolemia, hypotension, and (maybe) LE amputation (canagliflozin only)

We previously discussed oral medications for DM in another post. The remainder of this post will focus on a few major articles from the past year regarding SGLT2 inhibitors in HFrEF. 


DAPA-HF trial

  • Study: Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
  • Design: industry-funded, randomized, placebo controlled trial
  • Study population: 4744 patients w/ class II (66% of patients enrolled) or higher HF and an ejection fraction of ≤40%
    • Mean age 66yo; 23% women
    • 45% of patients had T2DM
    • ~50% had been hospitalized before for CHF exacerbations
    • All patients were initiated on and adherent with GDMT including devices if implicated
  • Endpoints: Worsening HF (requiring hospitalization or urgent visit for intravenous therapy) or cardiovascular death.
    • Secondary outcomes were number of hospitalizations, worsening of CHF symptoms, and change in renal function
  • Results: Combined primary outcomes were significantly fewer — 16.3% versus 21.2% (hazard ratio, 0.74). Subgroup analysis demonstrate a similar benefit in patients that did not have diabetes.
    • Dapagliflozin was statistically better in preventing worsening HF (9.7% vs. 13.4%) and cardiovascular death (9.6% vs. 11.5%). Deaths from any cause reduced with dapagliflozin (11.6% vs. 13.9%) as did symptoms. No important safety issues were raised with dapagliflozin. Renal decline was also significantly reduced in treatment group.
  • Limitations: <5% of the patients were black and relatively few were very elderly with multiple coexisting illnesses.
  • Adverse events: Few patients stopped dapagliflozin or placebo because of any adverse effect (<5% of the patients in either treatment group). Major hypoglycemia was rare, as was DKA, and both of these adverse events occurred only in patients with diabetes.

EMPEROR-Reduced Trial

  • Study: Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure
  • Design: manufacturer-sponsored, double-blind, randomized, placebo-controlled
  • Study population: 3730 participants; 73% had EF <30%; 50% had T2DM; 48% had eGFR <60
    • Overall “sicker” population of patients compared to DAPA-HF
    • Most had prior hospitalizations for CHF
  • Endpoints: Primary endpoint of cardiovascular death or hospitalization for worsening HF.
    • Secondary outcomes: change in eGFR and number of hospitalizations
  • Results: At a mean follow-up of 16 months, patients receiving empagliflozin had a 25% lower risk for the primary endpoint of cardiovascular death or hospitalization for worsening HF than placebo recipients (19.4% vs. 24.7%) with hazard ratio of 0.75 (95% CI was 0.65 to 0.86; P<0.001)
    • Empagliflozin-treated patients had a lower risk of serious renal outcomes including AKI and sustained reduction in eGFR
  • Adverse events: Higher rates of uncomplicated genital tract infections (1.3% vs. 0.4%)
    • The frequency of hypoglycemia, lower limb amputation, and bone fracture did not differ between the two groups.
  • Limitations: Patient population predominantly white and Asian. No cost analysis.

Subsequent meta-analysis of the above studies


Practical approaches to coverage and prescribing

  • Only dapagliflozin is FDA-approved to treat HF in patients without DM (for now!)
  • Cost is a huge barrier to widespread use of SGLT2 inhibitors
  • Documentation is key to insurance approval of these drugs
    • Discuss all indicated reasons for use in documentation [e.g. high ASCVD risk, HFrEF, CKD (albuminuria or eGFR <60) for patients with DM]
  • Discuss any relative contraindications to other therapies:
    • TZDs not preferred in patients with morbid obesity or heart disease
    • SU not preferred in elderly or patients with documented hypoglycemia
  • Counsel patients extensively on indications and side effects!

Blog post based on Med-Peds Forum talk by Roger Auth, PGY4