Is DAPAGLIFLOZIN a magic word in cardiovascular surgery now?




Take Home Message

The proportion of patients with Type 2 diabetes mellitus undergoing coronary artery bypass grafting (CABG) and other surgeries is rapidly increasing surgeons will begin to encounter these medications with greater frequency.

After all, restricting dietary sodium consumption, changing the diuretic dose, and combining diuretic classes have all been shown to be highly efficacious in the management of therapy-resistant volume overload, and these measures may prove to have a similar effect on long-term cardiovascular and renal protection.

Abstract

The proportion of patients with Type 2 diabetes mellitus undergoing coronary artery bypass grafting (CABG) and other surgeries is rapidly increasing surgeons will begin to encounter these medications with greater frequency.

After all, restricting dietary sodium consumption, changing the diuretic dose, and combining diuretic classes have all been shown to be highly efficacious in the management of therapy-resistant volume overload, and these measures may prove to have a similar effect on long-term cardiovascular and renal protection.

My commentary

By José Daniel Espinoza-Hernández MD, FACS, FCCP

Cardiovascular surgeon, Tijuana, Mexico

espinoziux@hotmail.com

 

The advantage of new antihyperglycemic agents sodium-glucose cotransporter-2 inhibitors

(SGLTIs) and glucagonlike peptide-1 receptor agonists (GLP1RAs) relative to classic medications for patients with diabetes is the significant risk reduction for major adverse cardiovascular events (MACEs). [1,2]

In 2019, was published the DAPA HF trial, [3] in the methodology they randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.

Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.

They concluded that among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.

And to make this more interesting, in October 2020 another article was published that relates dapagliflozin with the improvement of kidney function, DAPA CKD [4]. They randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin to creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.

The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P=0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P=0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed.

They concluded that Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo.

If we focus on patients with heart failure and knowing the results of the DAPA HF trial, the use of dapagliflozin plus the angiotensin receptor neprilysin inhibitor sacubitril/valsartan

was also already studied [5] A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan. They concluded that dapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with Heart failure with reduced ejection fraction.

The timing of initiation of SGLT2is or GLP-1RAs with relation to surgery in general, and CABG specifically, has not been studied. Therefore, it is unknown whether these medications could safely be started preoperatively to achieve glycemic control. However, given that these medications can be associated with hypoglycemia, especially

when used in conjunction with other antihyperglycemia agents, use of these medications around the time of surgery should be approached with caution. surgeons will need to be aware both potential benefits of these medications as well as potential risks.

References
  1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al; EMPAREG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117-28.
  2. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA,et al.Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med.2016; 375:311-22.
  3. McMurray J.J.V., Solomon S.D., Inzucchi S.E., et al. DAPA-HF Trial Committees and Investigators. "Dapagliflozin in patients with heart failure and reduced ejection fraction". N Engl J Med 2019;381:1995-2008.
  4. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al., DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383:1436–46.
  5. Solomon SD, Jhund PJ, Claggett BL, Dewan P, Køber L, Kosiborod MN, Martinez FA. Effect of Dapagliflozin in Patients with HFrEF Treated with Sacubitril/Valsartan: The DAPA-HF Trial; JACC 2020: Heart Failure, Vol. 8 No. 10