Dapagliflozin Versus Placebo on Left Ventricular Remodeling in Patients With Diabetes and Heart Failure: The REFORM Trial

Singh, Jagdeep; Mordi, Ify; Vickneson, Keeran; Fathi, Amir; Donnan, Peter T.; Mohan, Mohapradeep; Choy, Anna Maria; Gandy, Stephen J.; George, Jacob; Khan, Faisel; Pearson, Ewan R.; Houston, John G.; Struthers, Allan D.; Lang, Chim C.

doi:10.2337/dc19-2187

Cited by 112 publications

(119 citation statements)

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“…Patients required a reduction in loop diuretic dose, which was also reported in the REFORM trial (Research Into the Effect of SGLT2 Inhibition on Left Ventricular Remodelling in Patients With Heart Failure and Diabetes Mellitus). 23 After cessation of empagliflozin, some patients also noted increasing congestion requiring an increase in loop diuretic or had a HF hospitalization, although our trial was clearly not powered for clinical outcomes. In a post hoc analysis of DAPA-HF, the benefit of dapagliflozin was consistent irrespective of baseline diuretic use; however, in patients on a diuretic, adverse events related to volume depletion occurred more frequently with dapagliflozin compared with placebo.…”

Section: Discussionmentioning

confidence: 93%

Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure

et al. 2020

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Background: Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors improve heart failure (HF) associated-outcomes in patients with type 2 diabetes (T2D). In patients with HF, SGLT2 inhibitors will likely be co-prescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics. Methods: The RECEDE-CHF trial (NCT03226457) was a randomized, double-blind, placebo-controlled, cross-over trial of patients with T2D and HF with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline at week 6. Results: Twenty-three participants (mean age 69.8 years, 73.9% male, mean furosemide dose of 49.6±31.3mg/day, mean HbA1c 7.9±3.8%) were recruited. Compared to placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference 535 ml, 95% CI 133 to 936, p =0.005) and week 6, (mean difference 545 ml, 95% CI 136 to 954 p = 0.005) after adjustment for treatment order, baseline 24-hour urine volume and percentage change in loop diuretic dose. At 6 weeks empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference -7.85 mmol/L, 95% CI -2.43 to 6.73, p = 0.57). Empagliflozin caused a non-significant increase in fractional excretion of sodium at day 3 which was absent at week 6 (mean difference day 3: 0.30%, 95% CI -0.03 to 0.63, p=0.09; week 6 0.11%, 95% CI -0.22 to 0.44, p > 0.99) and a significant increase in electrolyte-free water clearance at week 6 (mean difference 312 ml, 95% CI 26 to 598, p=0.026) compared to placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6. Conclusions: Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03226457

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Section: Discussionmentioning

confidence: 93%

Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure

et al. 2020

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“…At baseline, the median trial mean glycated haemoglobin A1c was 8.1% and BMI was 30.1. Eligibility criteria included coronary artery disease or macrovascular disease in 35 trials, 3 6 7 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 atrial fibrillation in 1 trial, 65 heart failure in 9 trials, 66 67 68 69 70 71 72 73 74 chronic kidney disease and/or albuminuria in 37 trials, 8 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 …”

Section: Resultsmentioning

confidence: 99%

Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

Palmer

Tendal

Mustafa

et al. 2021

BMJ

416

310

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Objective To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. Design Network meta-analysis. Data sources Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. Eligibility criteria for selecting studies Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. Main outcome measures Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. Results 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced mortality and admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 5 to 48 fewer deaths in 1000 patients over five years; see interactive decision support tool ( https://magicevidence.org/match-it/200820dist/#!/ ) for all outcomes. Conclusions In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with notable differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. Systematic review registration PROSPERO CRD42019153180.

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Section: Discussionmentioning

confidence: 99%

The renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with type 2 diabetes and chronic heart failure (RECEDE-CHF) trial

Mordi

Singh

et al. 2020

European Heart Journal

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Introduction The SGLT2 inhibitors have been shown to reduce heart failure (HF) hospitalisations in patients with Type 2 diabetes (T2D), and to improve outcomes in those with HF irrespective of T2D status. Given this, it is likely that they will be co-prescribed with a loop diuretic. The combined diuretic effect of SGLT2 inhibitors and loop diuretic has not been well defined. Purpose The aim of this study was to assess the diuretic and natriuretic effect of empagliflozin in patients with T2D and chronic HF in combination with loop diuretics. Methods and analysis RECEDE-CHF (Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop Diuretics in patients with T2D and Chronic HF) was a randomised, double-blind, placebo-controlled, cross-over trial. Patients were randomised to empagliflozin 25 mg once a day or placebo for 6 weeks with study assessments at day 3 and week 6. Following a 2 week washout period, patients then entered the second treatment arm. The primary outcome was change in 24-hour urinary volume, when compared to placebo at day 3 and week 6. Results 23 participants mean age 69.8 years, (male 73.9%) with T2D and chronic HF (all ejection fraction <50%) on a mean furosemide dose of 49.6 mg/day were recruited. In comparison to placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both time points (day 3, mean difference of 549.3 ml, 95% confidence interval 151.4 to 947.2, p=0.004 and week 6, mean difference of 542.8 ml, 95% CI 134.9 to 950.7, p=0.005), adjusted for treatment order and baseline 24-hour urine volume. Empagliflozin did not cause a significant increase in the 24-hour urinary sodium as measured in mmol/L at both time points (day 3, mean difference compared to placebo −2.96 mmol/L, 95% CI: −21.55 to 15.64, p=1.00, week 6 mean difference compared to placebo −8.41 mmol/L, 95% CI: −27.00 to 10.18, p=0.81). Empagliflozin caused a significant increase in electrolyte-free water clearance (cH20e) at day 3 (mean difference compared to placebo 287.36 ml/min, (95% CI 31.79 to 542.93, p=0.022) and at week 6 (mean difference when compared to placebo 255.69 ml/min (95% CI: −284.12 to 220.76, p=0.048) when corrected for furosemide dose. 21.7% (n=5) participants had to have their furosemide dose reduced by 50% whilst on the active treatment arm of empagliflozin by day 3. On discontinuation of the active treatment arm with empagliflozin, two participants experienced hospital admissions with decompensated cardiac congestion. Conclusions Empagliflozin caused a significant increase in 24-hour urine volume when used in combination with loop diuretic when compared to placebo. There was no increase in 24-hour urinary sodium excretion. The greater electrolyte-free water clearance induced by empagliflozin observed in this study may support a proposed hypothesis that this could result in a greater fluid clearance from the interstitial space than from the circulating volume. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation (BHF)

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Dapagliflozin Versus Placebo on Left Ventricular Remodeling in Patients With Diabetes and Heart Failure: The REFORM Trial

Cited by 112 publications

References 12 publications

Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure

Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure

Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

The renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with type 2 diabetes and chronic heart failure (RECEDE-CHF) trial

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