Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease

Wanner, Christoph; Lachin, John M.; Inzucchi, Silvio E.; Fitchett, David; Mattheus, Michaela; George, Jyothis T.; Woerle, Hans-Juergen; Broedl, Uli C.; Eynatten, Maximilian von; Zinman, Bernard

doi:10.1161/circulationaha.117.028268

Cited by 396 publications

(309 citation statements)

References 33 publications

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“…The EMPA-REG OUTCOME study also demonstrated impressive beneficial renal outcomes (7). Compared with placebo, empagliflozin treatment was associated with a 46% risk reduction in the composite of doubling of serum creatinine, initiation of renal replacement therapy (dialysis or renal transplant), or death caused by renal disease (P = 0.0002) ( Table 2).…”

mentioning

confidence: 94%

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis

2016

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Type 2 diabetes mellitus causes excessive morbidity and premature cardiovascular (CV) mortality. Although tight glycemic control improves microvascular complications, its effects on macrovascular complications are unclear. The recent publication of the EMPA-REG OUTCOME study documenting impressive benefits with empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on CV and all-cause mortality and hospitalization for heart failure without any effects on classic atherothrombotic events is puzzling. More puzzling is that the curves for heart failure hospitalization, renal outcomes, and CV mortality begin to separate widely within 3 months and are maintained for >3 years. Modest improvements in glycemic, lipid, or blood pressure control unlikely contributed significantly to the beneficial cardiorenal outcomes within 3 months. Other known effects of SGLT2 inhibitors on visceral adiposity, vascular endothelium, natriuresis, and neurohormonal mechanisms are also unlikely major contributors to the CV/renal benefits. We postulate that the cardiorenal benefits of empagliflozin are due to a shift in myocardial and renal fuel metabolism away from fat and glucose oxidation, which are energy inefficient in the setting of the type 2 diabetic heart and kidney, toward an energy-efficient super fuel like ketone bodies, which improve myocardial/renal work efficiency and function. Even small beneficial changes in energetics minute to minute translate into large differences in efficiency, and improved cardiorenal outcomes over weeks to months continue to be sustained. Well-planned physiologic and imaging studies need to be done to characterize fuel energeticsbased mechanisms for the CV/renal benefits.Type 2 diabetes mellitus (T2DM) is a chronic debilitating disease that leads to excessive morbidity and premature cardiovascular (CV) mortality worldwide. Although studies have documented the benefits of optimal glycemic control on microvascular complications, the effect of tight glycemic control on macrovascular complications is unclear (1). In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, tight glycemic control increased CV and all-cause mortality (2). Glitazones and saxagliptin (a dipeptidyl peptidase 4 inhibitor) increase the risk of hospitalization for heart failure (HF) (3,4). In this context, the recent publication of the EMPA-REG OUTCOME study documenting impressive benefits with empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on CV/all-cause mortality and hospitalization for HF is a game changer, and if replicated, it may lead to a

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confidence: 94%

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis

2016

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“…The EMPAREG trial looked at the effects of empagliflozin [17]. When we look at cardiovascular death in people with or without prevalent kidney disease, and the endpoint for hospitalization for heart failure, the effects are consistent in both subgroups, regardless of the prevalence of kidney disease or not.…”

Section: Diabetic Nephropathy: Hiddo Lambers Heerspink (The Netherlands)mentioning

confidence: 99%

Nephro Update Europe 2018

Kesel¹

2019

Kidney Dis

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“…In EMPA-REG OUTCOME trial (empagliflozin cardiovascular event outcome event trial in type 2 diabetes mellitus (T2DM) patients) [22,23], the effect of empagliflozin was studied on cardiac outcomes in patients with T2DM. However, worsening renal end points (defined as progression to macroalbuminuria [UACR to 300mg/gm], doubling of serum creatinine, dialysis, or mortality from renal causes) was one of the secondary outcomes in this study.…”

Section: Therapiesmentioning

confidence: 99%

Diabetic nephropathy: newer therapeutic perspectives

Keri

Samji

Blumenthal

2018

Journal of Community Hospital Internal Medicine Perspectives

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Diabetic nephropathy (DN is a dreaded consequence of diabetes mellitus, accounting for about 40% of end-stage renal disease (ESRD). It is responsible for significant morbidity and mortality, both directly by causing ESRD and indirectly by increasing cardiovascular risk. Extensive research in this field has thrown light on multiple pathways that can be pharmacologically targeted, to control or reverse the process of DN. Glomerulocentric approach of DN still continues to produce favourable results as evidenced by the recent data on SGLT-2 (sodium glucose co-transporter type 2) inhibitors. Beyond the glomerular mechanisms, numerous novel pathways have been discovered in the last decade. Some of these pathways target inflammatory and oxidative damage, while the others target more specific mechanisms such as AGE-RAGE (advanced glycation end products-receptors for advanced glycation end products), ASK (apoptotic signal-regulating kinase), and endothelin-associated pathways. As a result of the research, a handful of clinically relevant drugs have made it to the human trials which have been elucidated in the following review, bearing in the mind that there are many more to come over the next few years. Ongoing research is expected to inform the clinicians regarding the use of the newer drugs in DN.Abbreviations: USFDA: Unites States Food and Drug Administration; SGLT-2: Sodium glucose transporter type 2; GLP-1: Glucagon-like peptide-1; DDP-4: Dipeptidyl peptidase-4; UACR: urinary albumin creatinine ratio; eGFR: Estimated glomerular filtration rate; CKD: Chronic kidney disease; DN: Diabetic nephropathy; TGF: Tubuloglomerular feedback; RAAS: Renin angiotensin aldosterone system; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; RCT: Randomized controlled trial; AGE-RAGE: Advanced glycation end products-receptors for advanced glycation end products; ASK-1: Apoptotic signal-regulating kinase-1; Nrf-2: Nuclear 1 factor [erythroid derived-2]-related factor 2; ml/min/1.73m2: Millilitre/minute/1.73 square meters of body surface area; ~: Approximately.

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Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease

Abstract: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676.

Cited by 396 publications

References 33 publications

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis

Nephro Update Europe 2018

Diabetic nephropathy: newer therapeutic perspectives

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