CardioNerds Drs. Jason Feinman, Gurleen Kaur, and Rick Ferraro discuss the implementation of SGLT inhibitors in clinical practice with Dr. Alison Bailey. Notes were drafted by Dr. Jason Feinman.

In this episode, we discuss the implementation of SGLTi in clinical practice scenarios, including for individuals with heart failure regardless of ejection fraction, those with chronic kidney disease, and those with diabetes mellitus. The group also discusses important side effects to monitor for, as well as how to counsel patients when prescribing these medications.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Lexicon Pharmaceuticals.

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Pearls – Clinical Implementation of SGLT Inhibitors

1. 
   
2. For patients with heart failure with reduced ejection fraction, SGLT inhibitors reduce the composite outcome of cardiovascular death or heart failure hospitalization by 25%.
   
3. SGLT inhibitors can be safely started in patients with an eGFR as low as 20. There are ongoing trials investigating the safety of these medications in individuals with eGFR lower than 20 or those who are receiving dialysis.
   
4. An eGFR decrease of 3-5 ml/min on average is expected after starting an SGLTi, but this will stabilize over time and provides protective effects of renal dysfunction in the long run.
   
5. Early data that suggested an association between SGLTi and bacterial UTI development hasn’t panned out in the long run, but there is an association between SGLTi and the development of either genital mycotic infections or yeast infections. Perineal hygiene is important to prevent the development of either.
   
6. A patient-centered, shared decision-making approach should guide the choice of agents for individuals with type 2 diabetes mellitus. In certain patients, it may be reasonable to choose an SGLTi as the first-line agent.
   

Show notes – Clinical Implementation of SGLT Inhibitors

What is the data supporting the use of SGLTi in HFpEF?

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• The EMPEROR-Preserved and DELIVER trials investigated the impact of empagliflozin and dapagliflozin, respectively, on cardiovascular outcomes in patients with mildly reduced or preserved ejection fraction.
  
• The SOLOIST-WHF trial investigated a combined SGLT1/2 inhibitor, sotagliflozin, in patients with recently worsening heart failure, irrespective of ejection.SGLTi have been demonstrated to reduce the risk of cardiovascular death or worsening heart failure, including heart failure hospitalization, in these individuals.
  
• A meta-analysis of the EMPEROR-Preserved and DELIVER trials demonstrated a hazard ratio of 0.80 for cardiovascular death or first hospitalization for heart failure for empagliflozin or dapagliflozin over placebo in the setting of HFpEF.
  

What is the data supporting the use of SGLTi in HFrEF?

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• In addition to the SOLOIST-WHF trial that was previously discussed, the EMPEROR-HF and DAPA-HF investigated the impact of SGLTi medications in patients with HFrEF.
  
• In patients with HFrEF, SGLTi medications have been demonstrated to reduce the risk of either cardiovascular death or heart failure hospitalization.
  
• Dapagliflozin and empagliflozin had a pooled risk reduction of all-cause death of 13%, a pooled risk reduction of cardiovascular death of 14%, and a 26% reduction in the combination of CV death or first hospitalization for heart failure.
  

What is the expected impact of SGLTi on renal function?

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• Dapagliflozin, empagliflozin, sotagliflozin, ertugliflozin, and canagliflozin have all been studied for their impact on renal dysfunction in individuals both with and without diabetes.
  
• In the CANVAS trial, canagliflozin was associated with an initial decrease in eGFR of 3.2ml/min compared to placebo but overall decreased change from baseline in eGFR compared to placebo at trial end.In a large meta-analysis, SGLTi medications reduced the progression of kidney disease by 37%.
  
• The risk of acute kidney injury was reduced by 23%.
  

What are the recommendations for SGLTi in patients with type 2 diabetes mellitus?

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• ADA guidelines emphasize a patient-centered shared decision-making approach when choosing which pharmacologic agent to prescribe for an individual with diabetes mellitus.
  
• Factors in choosing which agent include the risk of cardiovascular disease, the risk of renal disease, and whether there is an emphasis on weight reduction.
  

What side effects should be monitored for when starting an individual on an SGLTi medication?

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• Side effects with SGLTi medications are overall rare but include DKA, genital mycotic infections, necrotizing fasciitis, and volume status derangements.
  
• In the CANVAS trial, SGLTi was associated with an increased risk of amputation, but this has not been shown to be consistent in other trials. Nevertheless, in a meta-analysis including CANVAS, SGLTi medications were associated with a 15% relative risk of amputation over placebo medications.The relative risk of DKA in the same meta-analysis was 2.12.
  
• Careful assessment of an individual’s volume status and whether they are on any other diuretic medications when initiating an SGLTi medication may allow for upfront adjustment of these medications to reduce the risk of dehydration.
  

References – Clinical Implementation of SGLT Inhibitors

1. 
   
2. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-1098.
   
3. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461.
   
4. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021;384(2):117-128.
   
5. Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022;400(10354):757-767.
   
6. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424.
   
7. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008.
   
8. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819-829.
   
9. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657.
   
10. Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400(10365):1788-1801.
    
11. American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S158-S178.