- Email: [email protected]
EMPA-REG OUTCOME: The Endocrinologist's Point of View
CLINICAL RESEARCH STUDY
EMPA-REG OUTCOME: The Endocrinologist’s Point of View Leigh Perreault, MD University of Colorado Anschutz Medical Campus, Aurora.
ABSTRACT For many years, it was widely accepted that control of plasma lipids and blood pressure could lower macrovascular risk in patients with type 2 diabetes mellitus (T2DM), whereas the benefits of lowering plasma glucose were largely limited to improvements in microvascular complications. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus PatientseRemoving Excess Glucose (EMPA-REG OUTCOME) study demonstrated for the first time that a glucose-lowering agent, the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, could reduce major adverse cardiovascular events, cardiovascular mortality, hospitalization for heart failure, and overall mortality when given in addition to standard care in patients with T2DM at high cardiovascular risk. These results were entirely unexpected and have led to much speculation regarding the potential mechanisms underlying cardiovascular benefits. In this review, the results of EMPA-REG OUTCOME are summarized and put into perspective for the endocrinologist who is treating patients with T2DM and cardiovascular disease. Ó 2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The American Journal of Medicine (2017) 130, S51-S56 KEYWORDS: Cardiovascular outcomes; Empagliflozin; EMPA-REG OUTCOME; Major adverse cardiovascular events; Type 2 diabetes mellitus
Macrovascular disease remains the leading cause of death in people with type 2 diabetes mellitus (T2DM). Thus, it is somewhat surprising that major landmark trials using glucose-lowering interventions in people with T2DM have
Funding: This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. Writing support was provided by Linda Merkel, PhD, of Envision Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. The authors received no direct compensation related to the development of the manuscript. Conflict of Interest: LP receives personal fees from Novo Nordisk, Merck, Pfizer, Sanofi, AstraZeneca, Janssen, Orexigen, and Boehringer Ingelheim outside of the submitted work. Authorship: The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The author was fully responsible for all content and editorial decisions, was involved at all stages of manuscript development, and approved the final version that reflects the author’s interpretations and conclusions. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Requests for reprints should be addressed to Leigh Perreault, MD, University of Colorado Anschutz Medical Campus, PO Box 6511, MS F8106, Aurora, CO 80045. E-mail address: [email protected]
failed to demonstrate any macrovascular benefits at the end of the intervention period, even when stringent glycemic control was achieved.1-4 In addition, the contention that some glucose-lowering interventions (eg, rosiglitazone) might actually increase the risk of cardiovascular events and death was worrisome.5 Pursuant to the latter, in 2008, the US Food and Drug Administration (FDA) mandated cardiovascular safety studies for all new glucose-lowering therapies.6 Subsequently, results from many cardiovascular outcome trials have been published.7-11 For dipeptidyl peptidase-4 inhibitor cardiovascular outcome trials, there was an unexpected increase in the risk of hospitalization for heart failure in patients receiving saxagliptin versus those on placebo in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellituse Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.07-1.51; P ¼ .007),10 although no statistically significant differences in this end point were noted for alogliptin versus placebo in a post hoc analysis of the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study (HR, 1.07; 95%
0002-9343/Ó 2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.amjmed.2017.04.005
S52 CI, 0.79-1.46; P ¼ .657)12 or for sitagliptin in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) primary analysis (HR, 1.00; 95% CI, 0.83-1.20; P ¼ .98).7 The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus PatientseRemoving Excess Glucose (EMPA-REG OUTCOME), the cardiovascular outcome trial investigating the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, was the first clinical study of a glucose-lowering agent to demonstrate superiority for the primary end point and boasted a particularly robust reduction in the risk of cardiovascular death in patients with T2DM and established cardiovascular disease.13 Although the major action of SGLT2 inhibitors is to target the kidney to reduce the reabsorption of glucose and promote urinary glucose excretion (reviewed in the articles by Thrasher14 and Wanner15), the surprising results of EMPA-REG OUTCOME have generated numerous postulated mechanisms of action for the observed reduction in cardiovascular disease risk in patients with T2DM (reviewed in the article by Staels16 in this Supplement).
SUMMARY OF EMPA-REG OUTCOME RESULTS It is important to first point out that EMPA-REG OUTCOME was not designed to assess the glucoselowering effects of empagliflozin or how glucose-lowering affects cardiovascular outcomes. Instead, EMPA-REG OUTCOME was designed to assess the cardiovascular safety of empagliflozin. Nevertheless, the study design did prespecify that it would test the superiority of empagliflozin over placebo for cardiovascular protection if noninferiority was achieved. The results demonstrated a reduction in major adverse cardiovascular events (MACE), cardiovascular mortality, and hospitalization for heart failure in patients with T2DM and preexisting cardiovascular disease who received empagliflozin in addition to standard care13 when tested for both noninferiority and superiority. The trial continued until a primary outcome event had occurred in at least 691 patients; the median duration of treatment was 2.6 years, and the median observation time was 3.1 years. The EMPA-REG OUTCOME population had a mean age of 63 years and long-standing diabetes (>10 years in 57% of patients), and more than 99% of patients had established cardiovascular disease (76% had coronary artery disease; 47% had a history of myocardial infarction). The primary end point occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group (10 mg and 25 mg doses) and in 282 of 2333 patients (12.1%) in the placebo group, resulting in a 14% relative risk reduction for the primary composite 3-point MACE outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in patients receiving empagliflozin compared with those receiving placebo (HR, 0.86; 95.02% CI, 0.74-0.99; P <.001 for noninferiority). With no significant decrease in the relative risk of stroke or myocardial infarction, the MACE risk reduction was primarily driven by a 38% relative risk
The American Journal of Medicine, Vol 130, No 6S, June 2017 reduction in cardiovascular death (HR, 0.62; 95% CI, 0.49-0.77; P <.001). In addition, there was a 32% relative risk reduction in all-cause mortality (HR, 0.68; 95% CI, 0.57-0.82; P <.001) and a 35% relative risk reduction in the incidence of hospitalization for heart failure (HR, 0.65; 95% CI, 0.50-0.85; P ¼ .002). An analysis of secondary microvascular outcomes demonstrated that patients on empagliflozin experienced slower progression of kidney disease and a lower risk of progressing to macroalbuminuria than those on placebo17 (this is discussed in the article by Wanner15).
MULTIPLE RISK FACTOR REDUCTION WITH EMPAGLIFLOZIN Given the beneficial effects of empagliflozin on glycated hemoglobin (HbA1c), blood pressure, and body weight, it is intuitive to liken EMPA-REG OUTCOME to a traditional multiple risk factor intervention trial.18 For example, HbA1c was reduced by 0.45%, blood pressure was reduced by approximately 5/2 mm Hg, and body weight was reduced by approximately 2% in the active treatment group.19 Nevertheless, the difference in the primary outcome became evident approximately 3 months after starting empagliflozin,20 making it highly unlikely that the mechanism is related to glucose-lowering or antiatherosclerotic effects. For example, statin trials have demonstrated reduction in cardiovascular events in patients with T2DM after significant time exposure to the drugs (ie, 1-2 years), with generally more pronounced effects on cardiovascular events than on cardiovascular mortality.21,22 Specifically, statins have been shown to reduce myocardial infarction and stroke by approximately 20%, whereas the effect on cardiovascular death and all-cause mortality is more limited (e13% and e9%, respectively, per mmol/L low-density lipoprotein cholesterol reduction).22 Even when a formal multifactorial intervention is undertaken, such as in the Intensified Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria (STENO-2) trial (ie, reninangiotensin system blockers, aspirin, and lipid-lowering agents), cardiovascular protection is not observed for several years.23 Last, although the glucagon-like peptide-1 agonist, liraglutide, has been shown to lower 3-point MACE (in addition to lowering HbA1c and body weight),8 its impact on cardiovascular outcomes did not become apparent until 12 to 18 months of treatment. Collectively, the short time course for risk reduction in cardiovascular outcomes seen in EMPA-REG OUTCOME has generated as much discussion as the major results themselves. The early separation of the Kaplan-Meier survival curves for cardiovascular death in EMPA-REG OUTCOME resembles results observed in heart failure studies, which showed separation of survival curves within 3 to 6 months of starting treatment with a b-blocker.24,25 In addition, eplerenone (a diuretic selectively targeting aldosterone receptors) significantly reduced the risk of the composite end point of cardiovascular mortality and cardiovascular hospitalization by 17% in a subgroup of patients with T2DM and
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POTENTIAL MECHANISMS INVOLVED IN CARDIORENAL BENEFITS OF EMPAGLIFLOZIN
congestive heart failure; this effect was reported within months of beginning study treatment.26 Given that only 10% of participants (706/7020) in EMPA-REG OUTCOME had known heart failure on enrollment, the 35% reduction in hospitalization for heart failure may represent prevention of new-onset heart failure or prevention of an exacerbation of existing, potentially undiagnosed heart failure in this population.27,28 Indeed, the effect of empagliflozin on cardiac hemodynamics is an area of intense scientific investigation.29 Finally, the results of EMPA-REG OUTCOME become even more impressive when we consider that they occurred in addition to a background of near-optimal treatment of blood pressure, plasma lipids, and coagulation status. For example, 95% of patients received antihypertensive therapy (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, 81%; b-blockers, 65%; and diuretics, 43%), 77% of patients received statins, and 83% of patients received aspirin. This speaks to the ability of empagliflozin to tackle some of the residual cardiovascular risk not achieved by traditional means.
Multiple potential mechanisms of action have been proposed to explain the cardiovascular benefits of empagliflozin since the completion of EMPA-REG OUTCOME30 and are discussed in detail in the articles by Wanner,15 Staels,16 and Pham and Chilton29 in this Supplement. These include metabolic factors, such as reductions in HbA1c, body weight, uric acid, and visceral adiposity; hemodynamic effects, such as reductions of blood pressure and intravascular volume, osmotic diuresis, and sympatholysis; hormonal effects, such as increased glucagon, and effects on the reninangiotensin-aldosterone system; and fuel energetics, such as a shift from glucose or fatty acids to ketone use (Figure). The fuel shift hypothesis is particularly interesting for the endocrinologist because people with T2DM display altered fatty acid oxidation and impaired glucose uptake/oxidation in the heart, predisposing them to myocardial dysfunction and heart failure.31,32 Unlike those individuals without T2DM, in individuals with T2DM, the heart is less adaptable in using usual energy sources, such as glucose and free
Liver
Pancreas – α cells Improved Glycemic Control
Glucagon Ketones
FFA FFA
Preload
Aortic stiffness Wall stress
Adipose tissue
Weight loss
ECFV
AT2
Blood pressure
Ang 1-7 Uric acid excretion
Systemic vascular resistance
NaCI/H2O excretion
Figure Schematic representation of the potential metabolic and hemodynamic pathways responsible for the reduction in mortality and hospitalization for heart failure observed with empagliflozin in EMPA-REG OUTCOME.19 American Diabetes Association “SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study.” American Diabetes Association, 2016 Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association. Ang 1-7 ¼ angiotensin 1-7; AT2 ¼ angiotensin 2 receptor; ECFV ¼ extracellular fluid volume; FFA ¼ free fatty acids.
S54 fatty acids, and will preferentially mobilize ketones for fuel when they are available.32 The glucosuria caused by SGLT2 inhibitor therapy creates a plasma milieu that favors hepatic ketone production (ie, lowering glucose and insulin and increasing glucagon and free fatty acids).33 This mild and persistent hyperketonemia is thought to induce a shift in fuel metabolism in the heart, making it more energy efficient. One small study was able to demonstrate a 2- to 3-fold increase in plasma ketone concentration in people with T2DM treated with empagliflozin for as little as 4 weeks.34 Experimental evidence in animals and humans demonstrates that ketones are preferentially oxidized over fatty acids by myocardial cells.32,34 This shift to ketone use is associated with increased energy release in the form of adenosine triphosphate and translates into increased cardiac efficiency and function, a scenario that can occur quickly and may partially explain the cardiovascular benefits observed in EMPA-REG OUTCOME.35,36 The shift in metabolic fuel also occurs in other organs, including the kidney, possibly explaining some of the renal benefits observed in EMPA-REG OUTCOME. As a relevant aside, it is important to note that ketosis cannot occur unless a patient is insulin deficient. In the EMPA-REG OUTCOME postrandomization, more patients on placebo received add-on treatment with insulin (11.5% vs 5.8% with empagliflozin, respectively) and sulfonylurea (7.0% vs 3.8% with empagliflozin, respectively). Although no difference in the number of hypoglycemic events was found between the 2 groups, it is possible that placebotreated patients experienced more episodes of low blood glucose and arrhythmic events compared with those treated with empagliflozin. This companion hypothesis for the observed benefit is not mutually exclusive of the shift in myocardial substrate use, but rather underscores that the cardiovascular benefit observed in EMPA-REG OUTCOME was likely multifactorial.
IMPLICATIONS FOR CLINICAL PRACTICE Cardiovascular survival has dramatically improved with the advent of cardiovascular outcomes trials in T2DM using antihypertensives, statins, and aspirin,18,37 and the adoption of these results into evidence-based medical practice. Nonetheless, although trials are conducted in populations, healthcare providers have to decide how these results can be applied to individual patients. Several take-away messages from EMPA-REG OUTCOME are relevant to practitioners caring for individuals with T2DM and preexisting cardiovascular disease. First, identification of patients with T2DM at high risk for cardiovascular disease is an essential first step in improving their outcomes. Observations from the Diabetes Collaborative Registry, a US outpatient registry of patients with T2DM, found that approximately 1 in 6 patients (16%) meets the main EMPA-REG OUTCOME eligibility criteria. However, only 4% of these patients are currently treated with SGLT2 inhibitors.38 It will be interesting to see
The American Journal of Medicine, Vol 130, No 6S, June 2017 whether this number will increase now that empagliflozin also is indicated for the reduction of the risk of cardiovascular death in adult patients with T2DM and established cardiovascular disease,39 and the American Diabetes Association recommends empagliflozin (or liraglutide) in patients with long-standing suboptimally controlled T2DM and established cardiovascular disease.37 Whether empagliflozin can improve cardiovascular outcomes in patients with T2DM without pre-existing cardiovascular disease or in patients with preexisting cardiovascular disease without T2DM is not known. Second, it is not currently known whether the benefits observed in EMPA-REG OUTCOME are specific to empagliflozin or are a class effect of SGLT2 inhibitors. Long-term cardiovascular outcomes trials with other SGLT2 inhibitors are currently ongoing, namely, the CANagliflozin CardioVascular Assessment Study (CANVAS; NCT01032629),40 the Dapagliflozin Effect on CardiovascuLAR Event 58 study (DECLARE-TIMI 58; NCT01730534), and the Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease Study (VERTIS CV; NCT01986881). This drug class has a shared mechanism of action, and most adverse events observed in clinical trials and in postmarketing reports have been similar within a class, such as the postmarketing reports of acute kidney injury with SGLT2 inhibitors, which have prompted the FDA to revise and strengthen the existing warning about this condition in the drug labels and to add recommendations on how to minimize the risk.6,39 Other adverse events remain unique to individual drugs.41 For example, for canagliflozin, an increased risk of leg and foot amputations (mostly affecting the toes) was observed in the ongoing CANVAS trial, resulting in a safety alert from the FDA.41 In addition, clinical data demonstrated that canagliflozin was associated with an increased risk of bone fractures as early as 12 weeks after starting the drug and caused a greater loss of bone density in the hip in older individuals compared with placebo,42 resulting in a label update for canagliflozin.43 In addition, dapagliflozin use is not recommended in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2,44 whereas canagliflozin and empagliflozin should not be initiated or should be discontinued if the eGFR persistently decreases to < 45 mL/ min/1.73 m2.39,43 Therefore, although one can speculate about the potential benefits of the SGLT2 class, issues related to small differences in the drugs and the clinical trial designs used to assess their safety remain. Last, the benefit of empagliflozin was observed in addition to (not in place of) standard care. As the mechanism behind the benefit undergoes investigation, attention to current standard care— with or without empagliflozin—remains imperative.
CONCLUSIONS As recently as 18 months ago, we had almost abandoned the notion that a glucose-lowering agent could prevent cardiovascular disease in people with T2DM. The results from
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EMPA-REG OUTCOME, showing a reduction in adverse cardiovascular outcomes with the study drug versus placebo, were wholly unexpected and have rekindled enthusiasm for tackling residual cardiovascular risk in patients with T2DM. Furthermore, scientific investigations have begun to unmask the mechanisms behind the observed benefits. However, other questions remain to be answered, including the following: (1) Can empagliflozin reduce cardiovascular events in people with T2DM without preexisting cardiovascular disease? (2) Can empagliflozin reduce cardiovascular events in people without T2DM with preexisting cardiovascular disease? (3) Can empagliflozin reduce cardiovascular events or deterioration of renal function in people without T2DM and an eGFR <45 mL/ min/1.73 m2? (4) Can empagliflozin reduce cardiovascular events in people without T2DM who have hypertension, obstructive sleep apnea, or heart failure? Results from the EMPA-REG OUTCOME trial remind us there is much to be learned about diabetes and SGLT2 inhibition.
References 1. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853. 2. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139. 3. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358: 2545-2559. 4. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572. 5. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471. 6. Food and Drug Administration Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available at: http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm071627.pdf. Accessed November 28, 2016. 7. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373: 232-242. 8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375: 311-322. 9. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373: 2247-2257. 10. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326. 11. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335. 12. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-2076.
S55 13. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373: 2117-2128. 14. Thrasher J. Management of type 2 diabetes mellitus: available therapies. Am J Med. 2017;130:S4-S17. 15. Wanner C. EMPA-REG OUTCOME: the nephrologist’s point of view. Am J Med. 2017;130:S63-S72. 16. Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms of action. Am J Med. 2017;130: S30-S39. 17. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375: 323-334. 18. Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia. 2016;59:2298-2307. 19. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPAREG OUTCOME study. Diabetes Care. 2016;39:717-725. 20. Trujillo JM, Wettergreen SA, Nuffer WA, Ellis SL, McDermott MT. Cardiovascular outcomes of new medications for type 2 diabetes. Diabetes Technol Ther. 2016;18:749-758. 21. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364: 685-696. 22. Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterollowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117-125. 23. Gaede P, Valentine WJ, Palmer AJ, et al. Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the Steno-2 study. Diabetes Care. 2008;31:1510-1515. 24. Goldstein S, Fagerberg B, Hjalmarson A, et al. Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study. J Am Coll Cardiol. 2001;38: 932-938. 25. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194-2199. 26. Zannad F, Gattis Stough W, Rossignol P, et al. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice. Eur Heart J. 2012;33: 2782-2795. 27. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOMEÒ trial. Eur Heart J. 2016;37:1526-1534. 28. Raz I, Cahn A. Heart failure: SGLT2 inhibitors and heart failure e clinical implications. Nat Rev Cardiol. 2016;13:185-186. 29. Pham SV, Chilton R. EMPA-REG OUTCOME: the cardiologist’s point of view. Am J Med. 2017;130:S57-S62. 30. DeFronzo RA. The EMPA-REG study: what has it told us? A diabetologist’s perspective. J Diabetes Complications. 2016;30:1-2. 31. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39:1108-1114. 32. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39: 1115-1122. 33. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499-508.
S56 34. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65:1190-1195. 35. Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2013;304: H1060-H1076. 36. Dedkova EN, Blatter LA. Role of beta-hydroxybutyrate, its polymer poly-beta-hydroxybutyrate and inorganic polyphosphate in mammalian health and disease. Front Physiol. 2014;5:260. 37. American Diabetes Association. Standards of Medical Care in Diabetes-2017. Diabetes Care. 2017;40:S4-S5. 38. Arnold SV, Inzucchi SE, Maddox TM, et al. Defining the potential “realworld” impact of the EMPA-REG OUTCOME trial on improving cardiovascular outcomes: observations from the Diabetes Collaborative Registry (DCR). Diabetologia. 2016;59(Suppl 1), Abstract #729. 39. Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information (12/2016) JARDIANCEÒ (empagliflozin) tablets, for oral use. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/ 204629s008lbl.pdf. Accessed December 19, 2016.
The American Journal of Medicine, Vol 130, No 6S, June 2017 40. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)ea randomized placebo-controlled trial. Am Heart J. 2013;166:217-223e11. 41. Food and Drug Administration. FDA drug safety communication: interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. Available at: http://www. fda.gov/Drugs/DrugSafety/ucm500965.htm. Accessed June 1, 2016. 42. Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab. 2016;101:44-51. 43. Janssen Pharmaceuticals. Prescribing Information (02/2017) INVOKANAÒ (canagliflozin) tablets, for oral use. Available at: https:// www.invokanahcp.com/sites/www.invokanahcp.com/files/prescribinginformation-invokana.pdf. Accessed April 11, 2017. 44. AstraZeneca Pharmaceuticals LP. Prescribing information (03/2017) FARXIGAÒ (dapagliflozin) tablets, for oral use. Available at: https:// www.accessdata.fda.gov/drugsatfda_docs/label/2017/202293s011lbl. pdf. Accessed April 11, 2017.
EMPA-REG OUTCOME: The Endocrinologist’s Point of View Leigh Perreault, MD University of Colorado Anschutz Medical Campus, Aurora.
ABSTRACT For many years, it was widely accepted that control of plasma lipids and blood pressure could lower macrovascular risk in patients with type 2 diabetes mellitus (T2DM), whereas the benefits of lowering plasma glucose were largely limited to improvements in microvascular complications. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus PatientseRemoving Excess Glucose (EMPA-REG OUTCOME) study demonstrated for the first time that a glucose-lowering agent, the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, could reduce major adverse cardiovascular events, cardiovascular mortality, hospitalization for heart failure, and overall mortality when given in addition to standard care in patients with T2DM at high cardiovascular risk. These results were entirely unexpected and have led to much speculation regarding the potential mechanisms underlying cardiovascular benefits. In this review, the results of EMPA-REG OUTCOME are summarized and put into perspective for the endocrinologist who is treating patients with T2DM and cardiovascular disease. Ó 2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The American Journal of Medicine (2017) 130, S51-S56 KEYWORDS: Cardiovascular outcomes; Empagliflozin; EMPA-REG OUTCOME; Major adverse cardiovascular events; Type 2 diabetes mellitus
Macrovascular disease remains the leading cause of death in people with type 2 diabetes mellitus (T2DM). Thus, it is somewhat surprising that major landmark trials using glucose-lowering interventions in people with T2DM have
Funding: This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. Writing support was provided by Linda Merkel, PhD, of Envision Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. The authors received no direct compensation related to the development of the manuscript. Conflict of Interest: LP receives personal fees from Novo Nordisk, Merck, Pfizer, Sanofi, AstraZeneca, Janssen, Orexigen, and Boehringer Ingelheim outside of the submitted work. Authorship: The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The author was fully responsible for all content and editorial decisions, was involved at all stages of manuscript development, and approved the final version that reflects the author’s interpretations and conclusions. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Requests for reprints should be addressed to Leigh Perreault, MD, University of Colorado Anschutz Medical Campus, PO Box 6511, MS F8106, Aurora, CO 80045. E-mail address: [email protected]
failed to demonstrate any macrovascular benefits at the end of the intervention period, even when stringent glycemic control was achieved.1-4 In addition, the contention that some glucose-lowering interventions (eg, rosiglitazone) might actually increase the risk of cardiovascular events and death was worrisome.5 Pursuant to the latter, in 2008, the US Food and Drug Administration (FDA) mandated cardiovascular safety studies for all new glucose-lowering therapies.6 Subsequently, results from many cardiovascular outcome trials have been published.7-11 For dipeptidyl peptidase-4 inhibitor cardiovascular outcome trials, there was an unexpected increase in the risk of hospitalization for heart failure in patients receiving saxagliptin versus those on placebo in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellituse Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.07-1.51; P ¼ .007),10 although no statistically significant differences in this end point were noted for alogliptin versus placebo in a post hoc analysis of the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study (HR, 1.07; 95%
0002-9343/Ó 2017 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.amjmed.2017.04.005
S52 CI, 0.79-1.46; P ¼ .657)12 or for sitagliptin in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) primary analysis (HR, 1.00; 95% CI, 0.83-1.20; P ¼ .98).7 The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus PatientseRemoving Excess Glucose (EMPA-REG OUTCOME), the cardiovascular outcome trial investigating the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, was the first clinical study of a glucose-lowering agent to demonstrate superiority for the primary end point and boasted a particularly robust reduction in the risk of cardiovascular death in patients with T2DM and established cardiovascular disease.13 Although the major action of SGLT2 inhibitors is to target the kidney to reduce the reabsorption of glucose and promote urinary glucose excretion (reviewed in the articles by Thrasher14 and Wanner15), the surprising results of EMPA-REG OUTCOME have generated numerous postulated mechanisms of action for the observed reduction in cardiovascular disease risk in patients with T2DM (reviewed in the article by Staels16 in this Supplement).
SUMMARY OF EMPA-REG OUTCOME RESULTS It is important to first point out that EMPA-REG OUTCOME was not designed to assess the glucoselowering effects of empagliflozin or how glucose-lowering affects cardiovascular outcomes. Instead, EMPA-REG OUTCOME was designed to assess the cardiovascular safety of empagliflozin. Nevertheless, the study design did prespecify that it would test the superiority of empagliflozin over placebo for cardiovascular protection if noninferiority was achieved. The results demonstrated a reduction in major adverse cardiovascular events (MACE), cardiovascular mortality, and hospitalization for heart failure in patients with T2DM and preexisting cardiovascular disease who received empagliflozin in addition to standard care13 when tested for both noninferiority and superiority. The trial continued until a primary outcome event had occurred in at least 691 patients; the median duration of treatment was 2.6 years, and the median observation time was 3.1 years. The EMPA-REG OUTCOME population had a mean age of 63 years and long-standing diabetes (>10 years in 57% of patients), and more than 99% of patients had established cardiovascular disease (76% had coronary artery disease; 47% had a history of myocardial infarction). The primary end point occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group (10 mg and 25 mg doses) and in 282 of 2333 patients (12.1%) in the placebo group, resulting in a 14% relative risk reduction for the primary composite 3-point MACE outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in patients receiving empagliflozin compared with those receiving placebo (HR, 0.86; 95.02% CI, 0.74-0.99; P <.001 for noninferiority). With no significant decrease in the relative risk of stroke or myocardial infarction, the MACE risk reduction was primarily driven by a 38% relative risk
The American Journal of Medicine, Vol 130, No 6S, June 2017 reduction in cardiovascular death (HR, 0.62; 95% CI, 0.49-0.77; P <.001). In addition, there was a 32% relative risk reduction in all-cause mortality (HR, 0.68; 95% CI, 0.57-0.82; P <.001) and a 35% relative risk reduction in the incidence of hospitalization for heart failure (HR, 0.65; 95% CI, 0.50-0.85; P ¼ .002). An analysis of secondary microvascular outcomes demonstrated that patients on empagliflozin experienced slower progression of kidney disease and a lower risk of progressing to macroalbuminuria than those on placebo17 (this is discussed in the article by Wanner15).
MULTIPLE RISK FACTOR REDUCTION WITH EMPAGLIFLOZIN Given the beneficial effects of empagliflozin on glycated hemoglobin (HbA1c), blood pressure, and body weight, it is intuitive to liken EMPA-REG OUTCOME to a traditional multiple risk factor intervention trial.18 For example, HbA1c was reduced by 0.45%, blood pressure was reduced by approximately 5/2 mm Hg, and body weight was reduced by approximately 2% in the active treatment group.19 Nevertheless, the difference in the primary outcome became evident approximately 3 months after starting empagliflozin,20 making it highly unlikely that the mechanism is related to glucose-lowering or antiatherosclerotic effects. For example, statin trials have demonstrated reduction in cardiovascular events in patients with T2DM after significant time exposure to the drugs (ie, 1-2 years), with generally more pronounced effects on cardiovascular events than on cardiovascular mortality.21,22 Specifically, statins have been shown to reduce myocardial infarction and stroke by approximately 20%, whereas the effect on cardiovascular death and all-cause mortality is more limited (e13% and e9%, respectively, per mmol/L low-density lipoprotein cholesterol reduction).22 Even when a formal multifactorial intervention is undertaken, such as in the Intensified Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria (STENO-2) trial (ie, reninangiotensin system blockers, aspirin, and lipid-lowering agents), cardiovascular protection is not observed for several years.23 Last, although the glucagon-like peptide-1 agonist, liraglutide, has been shown to lower 3-point MACE (in addition to lowering HbA1c and body weight),8 its impact on cardiovascular outcomes did not become apparent until 12 to 18 months of treatment. Collectively, the short time course for risk reduction in cardiovascular outcomes seen in EMPA-REG OUTCOME has generated as much discussion as the major results themselves. The early separation of the Kaplan-Meier survival curves for cardiovascular death in EMPA-REG OUTCOME resembles results observed in heart failure studies, which showed separation of survival curves within 3 to 6 months of starting treatment with a b-blocker.24,25 In addition, eplerenone (a diuretic selectively targeting aldosterone receptors) significantly reduced the risk of the composite end point of cardiovascular mortality and cardiovascular hospitalization by 17% in a subgroup of patients with T2DM and
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congestive heart failure; this effect was reported within months of beginning study treatment.26 Given that only 10% of participants (706/7020) in EMPA-REG OUTCOME had known heart failure on enrollment, the 35% reduction in hospitalization for heart failure may represent prevention of new-onset heart failure or prevention of an exacerbation of existing, potentially undiagnosed heart failure in this population.27,28 Indeed, the effect of empagliflozin on cardiac hemodynamics is an area of intense scientific investigation.29 Finally, the results of EMPA-REG OUTCOME become even more impressive when we consider that they occurred in addition to a background of near-optimal treatment of blood pressure, plasma lipids, and coagulation status. For example, 95% of patients received antihypertensive therapy (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, 81%; b-blockers, 65%; and diuretics, 43%), 77% of patients received statins, and 83% of patients received aspirin. This speaks to the ability of empagliflozin to tackle some of the residual cardiovascular risk not achieved by traditional means.
Multiple potential mechanisms of action have been proposed to explain the cardiovascular benefits of empagliflozin since the completion of EMPA-REG OUTCOME30 and are discussed in detail in the articles by Wanner,15 Staels,16 and Pham and Chilton29 in this Supplement. These include metabolic factors, such as reductions in HbA1c, body weight, uric acid, and visceral adiposity; hemodynamic effects, such as reductions of blood pressure and intravascular volume, osmotic diuresis, and sympatholysis; hormonal effects, such as increased glucagon, and effects on the reninangiotensin-aldosterone system; and fuel energetics, such as a shift from glucose or fatty acids to ketone use (Figure). The fuel shift hypothesis is particularly interesting for the endocrinologist because people with T2DM display altered fatty acid oxidation and impaired glucose uptake/oxidation in the heart, predisposing them to myocardial dysfunction and heart failure.31,32 Unlike those individuals without T2DM, in individuals with T2DM, the heart is less adaptable in using usual energy sources, such as glucose and free
Liver
Pancreas – α cells Improved Glycemic Control
Glucagon Ketones
FFA FFA
Preload
Aortic stiffness Wall stress
Adipose tissue
Weight loss
ECFV
AT2
Blood pressure
Ang 1-7 Uric acid excretion
Systemic vascular resistance
NaCI/H2O excretion
Figure Schematic representation of the potential metabolic and hemodynamic pathways responsible for the reduction in mortality and hospitalization for heart failure observed with empagliflozin in EMPA-REG OUTCOME.19 American Diabetes Association “SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study.” American Diabetes Association, 2016 Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association. Ang 1-7 ¼ angiotensin 1-7; AT2 ¼ angiotensin 2 receptor; ECFV ¼ extracellular fluid volume; FFA ¼ free fatty acids.
S54 fatty acids, and will preferentially mobilize ketones for fuel when they are available.32 The glucosuria caused by SGLT2 inhibitor therapy creates a plasma milieu that favors hepatic ketone production (ie, lowering glucose and insulin and increasing glucagon and free fatty acids).33 This mild and persistent hyperketonemia is thought to induce a shift in fuel metabolism in the heart, making it more energy efficient. One small study was able to demonstrate a 2- to 3-fold increase in plasma ketone concentration in people with T2DM treated with empagliflozin for as little as 4 weeks.34 Experimental evidence in animals and humans demonstrates that ketones are preferentially oxidized over fatty acids by myocardial cells.32,34 This shift to ketone use is associated with increased energy release in the form of adenosine triphosphate and translates into increased cardiac efficiency and function, a scenario that can occur quickly and may partially explain the cardiovascular benefits observed in EMPA-REG OUTCOME.35,36 The shift in metabolic fuel also occurs in other organs, including the kidney, possibly explaining some of the renal benefits observed in EMPA-REG OUTCOME. As a relevant aside, it is important to note that ketosis cannot occur unless a patient is insulin deficient. In the EMPA-REG OUTCOME postrandomization, more patients on placebo received add-on treatment with insulin (11.5% vs 5.8% with empagliflozin, respectively) and sulfonylurea (7.0% vs 3.8% with empagliflozin, respectively). Although no difference in the number of hypoglycemic events was found between the 2 groups, it is possible that placebotreated patients experienced more episodes of low blood glucose and arrhythmic events compared with those treated with empagliflozin. This companion hypothesis for the observed benefit is not mutually exclusive of the shift in myocardial substrate use, but rather underscores that the cardiovascular benefit observed in EMPA-REG OUTCOME was likely multifactorial.
IMPLICATIONS FOR CLINICAL PRACTICE Cardiovascular survival has dramatically improved with the advent of cardiovascular outcomes trials in T2DM using antihypertensives, statins, and aspirin,18,37 and the adoption of these results into evidence-based medical practice. Nonetheless, although trials are conducted in populations, healthcare providers have to decide how these results can be applied to individual patients. Several take-away messages from EMPA-REG OUTCOME are relevant to practitioners caring for individuals with T2DM and preexisting cardiovascular disease. First, identification of patients with T2DM at high risk for cardiovascular disease is an essential first step in improving their outcomes. Observations from the Diabetes Collaborative Registry, a US outpatient registry of patients with T2DM, found that approximately 1 in 6 patients (16%) meets the main EMPA-REG OUTCOME eligibility criteria. However, only 4% of these patients are currently treated with SGLT2 inhibitors.38 It will be interesting to see
The American Journal of Medicine, Vol 130, No 6S, June 2017 whether this number will increase now that empagliflozin also is indicated for the reduction of the risk of cardiovascular death in adult patients with T2DM and established cardiovascular disease,39 and the American Diabetes Association recommends empagliflozin (or liraglutide) in patients with long-standing suboptimally controlled T2DM and established cardiovascular disease.37 Whether empagliflozin can improve cardiovascular outcomes in patients with T2DM without pre-existing cardiovascular disease or in patients with preexisting cardiovascular disease without T2DM is not known. Second, it is not currently known whether the benefits observed in EMPA-REG OUTCOME are specific to empagliflozin or are a class effect of SGLT2 inhibitors. Long-term cardiovascular outcomes trials with other SGLT2 inhibitors are currently ongoing, namely, the CANagliflozin CardioVascular Assessment Study (CANVAS; NCT01032629),40 the Dapagliflozin Effect on CardiovascuLAR Event 58 study (DECLARE-TIMI 58; NCT01730534), and the Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease Study (VERTIS CV; NCT01986881). This drug class has a shared mechanism of action, and most adverse events observed in clinical trials and in postmarketing reports have been similar within a class, such as the postmarketing reports of acute kidney injury with SGLT2 inhibitors, which have prompted the FDA to revise and strengthen the existing warning about this condition in the drug labels and to add recommendations on how to minimize the risk.6,39 Other adverse events remain unique to individual drugs.41 For example, for canagliflozin, an increased risk of leg and foot amputations (mostly affecting the toes) was observed in the ongoing CANVAS trial, resulting in a safety alert from the FDA.41 In addition, clinical data demonstrated that canagliflozin was associated with an increased risk of bone fractures as early as 12 weeks after starting the drug and caused a greater loss of bone density in the hip in older individuals compared with placebo,42 resulting in a label update for canagliflozin.43 In addition, dapagliflozin use is not recommended in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2,44 whereas canagliflozin and empagliflozin should not be initiated or should be discontinued if the eGFR persistently decreases to < 45 mL/ min/1.73 m2.39,43 Therefore, although one can speculate about the potential benefits of the SGLT2 class, issues related to small differences in the drugs and the clinical trial designs used to assess their safety remain. Last, the benefit of empagliflozin was observed in addition to (not in place of) standard care. As the mechanism behind the benefit undergoes investigation, attention to current standard care— with or without empagliflozin—remains imperative.
CONCLUSIONS As recently as 18 months ago, we had almost abandoned the notion that a glucose-lowering agent could prevent cardiovascular disease in people with T2DM. The results from
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EMPA-REG OUTCOME, showing a reduction in adverse cardiovascular outcomes with the study drug versus placebo, were wholly unexpected and have rekindled enthusiasm for tackling residual cardiovascular risk in patients with T2DM. Furthermore, scientific investigations have begun to unmask the mechanisms behind the observed benefits. However, other questions remain to be answered, including the following: (1) Can empagliflozin reduce cardiovascular events in people with T2DM without preexisting cardiovascular disease? (2) Can empagliflozin reduce cardiovascular events in people without T2DM with preexisting cardiovascular disease? (3) Can empagliflozin reduce cardiovascular events or deterioration of renal function in people without T2DM and an eGFR <45 mL/ min/1.73 m2? (4) Can empagliflozin reduce cardiovascular events in people without T2DM who have hypertension, obstructive sleep apnea, or heart failure? Results from the EMPA-REG OUTCOME trial remind us there is much to be learned about diabetes and SGLT2 inhibition.
References 1. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853. 2. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139. 3. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358: 2545-2559. 4. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572. 5. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471. 6. Food and Drug Administration Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available at: http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm071627.pdf. Accessed November 28, 2016. 7. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373: 232-242. 8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375: 311-322. 9. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373: 2247-2257. 10. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326. 11. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335. 12. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-2076.
S55 13. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373: 2117-2128. 14. Thrasher J. Management of type 2 diabetes mellitus: available therapies. Am J Med. 2017;130:S4-S17. 15. Wanner C. EMPA-REG OUTCOME: the nephrologist’s point of view. Am J Med. 2017;130:S63-S72. 16. Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms of action. Am J Med. 2017;130: S30-S39. 17. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375: 323-334. 18. Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia. 2016;59:2298-2307. 19. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPAREG OUTCOME study. Diabetes Care. 2016;39:717-725. 20. Trujillo JM, Wettergreen SA, Nuffer WA, Ellis SL, McDermott MT. Cardiovascular outcomes of new medications for type 2 diabetes. Diabetes Technol Ther. 2016;18:749-758. 21. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364: 685-696. 22. Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterollowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117-125. 23. Gaede P, Valentine WJ, Palmer AJ, et al. Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the Steno-2 study. Diabetes Care. 2008;31:1510-1515. 24. Goldstein S, Fagerberg B, Hjalmarson A, et al. Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study. J Am Coll Cardiol. 2001;38: 932-938. 25. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194-2199. 26. Zannad F, Gattis Stough W, Rossignol P, et al. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice. Eur Heart J. 2012;33: 2782-2795. 27. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOMEÒ trial. Eur Heart J. 2016;37:1526-1534. 28. Raz I, Cahn A. Heart failure: SGLT2 inhibitors and heart failure e clinical implications. Nat Rev Cardiol. 2016;13:185-186. 29. Pham SV, Chilton R. EMPA-REG OUTCOME: the cardiologist’s point of view. Am J Med. 2017;130:S57-S62. 30. DeFronzo RA. The EMPA-REG study: what has it told us? A diabetologist’s perspective. J Diabetes Complications. 2016;30:1-2. 31. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39:1108-1114. 32. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39: 1115-1122. 33. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499-508.
S56 34. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65:1190-1195. 35. Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2013;304: H1060-H1076. 36. Dedkova EN, Blatter LA. Role of beta-hydroxybutyrate, its polymer poly-beta-hydroxybutyrate and inorganic polyphosphate in mammalian health and disease. Front Physiol. 2014;5:260. 37. American Diabetes Association. Standards of Medical Care in Diabetes-2017. Diabetes Care. 2017;40:S4-S5. 38. Arnold SV, Inzucchi SE, Maddox TM, et al. Defining the potential “realworld” impact of the EMPA-REG OUTCOME trial on improving cardiovascular outcomes: observations from the Diabetes Collaborative Registry (DCR). Diabetologia. 2016;59(Suppl 1), Abstract #729. 39. Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing information (12/2016) JARDIANCEÒ (empagliflozin) tablets, for oral use. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/ 204629s008lbl.pdf. Accessed December 19, 2016.
The American Journal of Medicine, Vol 130, No 6S, June 2017 40. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)ea randomized placebo-controlled trial. Am Heart J. 2013;166:217-223e11. 41. Food and Drug Administration. FDA drug safety communication: interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. Available at: http://www. fda.gov/Drugs/DrugSafety/ucm500965.htm. Accessed June 1, 2016. 42. Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab. 2016;101:44-51. 43. Janssen Pharmaceuticals. Prescribing Information (02/2017) INVOKANAÒ (canagliflozin) tablets, for oral use. Available at: https:// www.invokanahcp.com/sites/www.invokanahcp.com/files/prescribinginformation-invokana.pdf. Accessed April 11, 2017. 44. AstraZeneca Pharmaceuticals LP. Prescribing information (03/2017) FARXIGAÒ (dapagliflozin) tablets, for oral use. Available at: https:// www.accessdata.fda.gov/drugsatfda_docs/label/2017/202293s011lbl. pdf. Accessed April 11, 2017.