Should SGLT2 inhibitors and GLP-1 receptor agonists be initiated in the hospital?

Presenters: Sandeep Das, MD, and Jennifer B. Green, MD

The inpatient cardiovascular care setting is an opportunity to initiate SGLT2 inhibitors and GLP-1 receptor agonists, both of which have demonstrated efficacy in reducing the rate of major adverse cardiac events (MACE) in patients with type 2 diabetes. But should they be started in acutely ill inpatients to improve cardiovascular outcomes, which would be an extrapolation of existing data?

In arguing for initiation of these drug classes in the inpatient setting, Sandeep Das, MD, noted that the greatest risk for recurrent MACE comes in the days after an event. Unfortunately, these agents are underused in at-risk populations, so any risk in initiating treatment in the inpatient setting is outweighed by the risk of never starting these medications.

“I would argue, start whenever you think you safely can,” said Dr. Das, associate professor of medicine, University of Texas Southwestern Medical Center, Dallas.

A number of clinical trials have demonstrated a significantly favorable effect of GLP-1 receptor agonists and SGLT2 inhibitors versus placebo on MACE in patients with atherosclerotic cardiovascular disease (ASCVD) with or without diabetes. In addition, rates of all-cause death and heart failure hospitalizations are reduced with SGLT2 inhibitor treatment in patients with heart failure with reduced ejection fraction.1 A reduction in the rate of adverse renal outcomes has also been realized with SGLT2 inhibitors.2 The sustained weight loss from SGLT2 inhibitor and GLP-1 receptor agonist use can be a potent motivator for medication adherence.

“The effect of these drugs on those outcomes is dramatic,” said Dr. Das. The relative reduction in the rate of MACE in patients with type 2 diabetes and ASCVD, for example, is about 15%, with survival curves separating early. SGLT2 inhibitors have demonstrated about a 30% relative reduction in heart failure hospitalization and cardiovascular death and a relative 35% reduction in chronic kidney disease progression. “This is a massive burden of mortality that can be avoided,” he said.

Although these trials initiated a GLP-1 receptor agonist or SGLT2 inhibitor in the outpatient setting, the SOLOIST WHF trial randomized patients in the hospital or within 3 days of discharge to sotagliflozin or placebo, and found a significant reduction in the rate of a composite outcome of total cardiovascular death, hospitalization for heart failure, and urgent heart failure visits with active treatment versus placebo.3

The safety of these agents has also been established, supporting inpatient initiation, he said. In clinical trials, the impact on diuretic dose4 and blood pressure5 has been minimal. Rates of hypoglycemia have been similar with SGLT2 inhibitors compared with placebo.6

GLP-1 receptor agonists are more difficult to get to target because of gastrointestinal (GI) side effects, and therefore require patient counseling and education. Weight loss effects require titration to effective doses, which takes time. In the hospital setting, time is ample for teaching patients how to inject the medication.

Initiating both classes of agents in the hospital requires caution if oral intake is decreased, especially if they are to be taken in concert with insulin. Similar to insulin, they can be held on the day of procedures.

Jennifer B. Green, MD, professor of medicine, Duke University Medical Center, Durham, N.C.,

urged caution before proceeding to initiation in the inpatient cardiovasscular setting, as most patients enrolled in cardiovascular outcomes clinical trials to date were outpatients. The benefit of in-hospital use of these medications therefore remains largely unproven. Also, the short-term benefit-to-risk ratio may be altered in the hospitalized patient.

Safety issues with SGLT2 inhibitors include “euglycemic” diabetic ketoacidosis (DKA), although rare. Retrospective data show an incidence of DKA developing in the community and during hospital admission of 1.02 per 1,000 in SGLT2 inhibitor users versus 0.69 per 1,000 in nonusers.7 She noted that 38% of DKA cases in users of SGLT2 inhibitors developed during the course of an inpatient admission.7 The Standards of Medical Care in Diabetes—2021 recommends that SGLT2 inhibitors be avoided in cases of severe illness, in patients with ketonemia or ketonuria, and during prolonged fasting and surgical procedures. “Until safety and effectiveness are established, SGLT2 inhibitors are not recommended for routine hospital use,” the report states.8

In the case of GLP-1 receptor agonists, GI side effects may be particularly undesirable in some cardiac patients, such as those undergoing coronary artery bypass graft surgery. These GI side effects are more likely to occur when the drug is started and the dosage uptitrated. Further, poor appetite and malnutrition as a result of GI side effects may contribute to impaired wound healing and rehabilitation. “These side effects could be difficult to differentiate from other acute issues common to inpatients, such as development of an ileus or infectious diarrhea,” she said.

An alternative to universal inpatient is enhanced implementation in the outpatient setting. “One way to do this is prescription of these medications at the time of discharge,” said Dr. Green.

References

  1. 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;396:819-829.
  2. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-1446.
  3. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117-128.
  4. Serenelli M, Böhm M, Inzucchi SE, et al. Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Eur Heart J 2020;41:3402-3418.
  5. Jackson AM, Dewan P, Anand IS, et al. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation 2020;142:1040-1054.
  6. 6.McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
  7. Hamblin PS, Wong R, Ekinci EI, et al. SGLT2 inhibitors increase the risk of diabetic ketoacidosis developing in the community and during hospital admission. J Clin Endocrinol Metab 2019;104:3077-3087.
  8. American Diabetes Association. 15. Diabetes care in the hospital: Standards of medical care in diabetes—2021. Diabetes Care 2021;44(Suppl 1):S211-S220.

Disclosures

Dr. Das has nothing to disclose.

Dr. Green discloses the following relationships. Consultant: AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Hawthorne Effect/Omada, Lexicon Pharmaceuticals, Inc., Novo Nordisk, Pfizer Inc., Sanofi. Research support: Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Roche Diabetes Care, Sanofi.

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