BACKGROUNDDoubling of serum creatinine [equivalent to 57% reduction in estimated glomerular filtration rate (eGFR)] is an established surrogate for end-stage kidney disease (ESKD); however, this endpoint necessitates lengthy follow-up and large sample sizes in clinical trials. We explored whether alternative eGFR decline thresholds provide more feasible surrogate kidney endpoints.METHODSThe study involved post hoc analysis of the EMPA-REG OUTCOME® trial. Adults with type 2 diabetes, high cardiovascular risk and eGFR ≥30 mL/min/1.73 m2 were assigned empagliflozin 10 mg or 25 mg (n = 4687) or placebo (n = 2333), on top of standard of care. We assessed composite endpoints incorporating different eGFR decline thresholds (≥30, ≥40, ≥50 or ≥57%) combined with initiation of renal replacement therapy (RRT) or renal death. This trial is registered with ClinicalTrials.gov (NCT01131676).RESULTSEmpagliflozin versus placebo significantly lowered the risk of decline in eGFR for each threshold listed above, combined with initiation of RRT or renal death, ranging from a hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.72-0.91] for endpoints based on 30% eGFR decline to an HR of 0.37 (0.23-0.61) for endpoints based on 57% eGFR decline. Lower thresholds (e.g. 30%) were associated with higher event rates but weaker treatment effects. The time to the 95% CI of the HR falling to <1.0 decreased with increasing eGFR threshold.CONCLUSIONSThe composite of 40% decline in eGFR, ESKD or renal death appears to provide reliable results similar to the traditional 57% decline in eGFR.

Importance Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. Objective This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. Design, Setting, and Participants Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. Interventions Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. Main Outcomes and Measures The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. Results Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]). Conclusions and Relevance Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome. Trial Registration ClinicalTrials.gov Identifier: NCT01243424.

In the original publication, disclosure statement for the author Ian J. Neeland was published incorrectly. The correct statement should read as "Ian J. Neeland received financial assistance for publishing/article processing fees from Boehringer Ingelheim".

OBJECTIVE To assess the effect of empagliflozin on bone fractures and bone mineral density in patients with type 2 diabetes in pooled placebo-controlled trial data and a head-to-head study versus glimepiride. RESEARCH DESIGN AND METHODS Pooled data were analyzed from patients who were randomized 1:1:1 to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in phase I–III clinical trials. Data were also analyzed from the EMPA-REG H2H-SU trial in which patients received empagliflozin 25 mg or glimepiride as an add-on to metformin for 104 weeks with a 104-week extension. Bone fracture adverse events (AEs) were evaluated through a search of investigator-reported (nonadjudicated) events. RESULTS In the pooled analysis, bone fracture AEs were reported in 119 of 4,221 (2.8%), 105 of 4,196 (2.5%), and 123 of 4,203 (2.9%) patients in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively (rates of 1.55, 1.36, and 1.69/100 patient-years, respectively). In the EMPA-REG H2H-SU trial, bone fracture AEs were reported in 31 of 765 (4.1%) patients receiving empagliflozin 25 mg and in 33 of 780 (4.2%) patients receiving glimepiride (rates of 1.28 and 1.40/100 patient-years, respectively). CONCLUSIONS Empagliflozin did not increase the risk of bone fracture compared with placebo in a pooled analysis of >12,000 patients or compared with glimepiride in a 4-year head-to-head study.

Background: Subjects with type 2 diabetes (T2DM) and peripheral artery disease (PAD) represent 1 of the highest-risk groups for cardiovascular (CV) complications, and risk reduction strategies are urgently needed. In the EMPA-REG OUTCOME trial, empagliflozin (EMPA) reduced the risk of CV death, all-cause mortality (ACM) and hospitalization for heart failure (HHF) vs. placebo (PBO). We report the clinical outcomes of patients with PAD.

Aim Research Design and Methods To report results at week 208, including a 104-week masked extension, of the EMPA-REG H2H-SU trial in patients with type 2 diabetes with inadequate glycaemic control on metformin, in which empagliflozin 25 mg given for 104 weeks provided a sustained reduction in glycated haemoglobin (HbA1c) with a small but statistically significant benefit vs glimepiride, sustained reductions in weight and blood pressure, and low risk of hypoglycaemia. Patients with type 2 diabetes and HbA1c 53-86 mmol/mol (7% to 10%) were randomized to empagliflozin 25 mg or glimepiride 1 to 4 mg for 104 weeks as add-on to metformin. Patients who completed the randomized treatment period could participate in a 104-week extension in which they continued the double-blind treatment allocated at randomization. Results Conclusions Of 765 and 780 patients treated with empagliflozin and glimepiride, 576 and 549 patients, respectively, entered the extension period of the study. At week 208, the adjusted mean difference in change from baseline in HbA1c with empagliflozin vs glimepiride was -1.96 mmol/mol, 95% CI -3.57, -0.35 (-0.18%, 95% CI -0.33, -0.03); P = 0.0172. Rescue therapy was given to 23% of patients on empagliflozin and 34% on glimepiride (odds ratio 0.56 [95% CI 0.45, 0.71]; P < 0.0001). Confirmed hypoglycaemic adverse events (plasma glucose <= 3.9 mmol/L and/or requiring assistance) occurred in 3% of patients on empagliflozin and 28% on glimepiride (odds ratio 0.08 [95% CI 0.05, 0.13]; P < 0.0001). In patients with type 2 diabetes, empagliflozin 25 mg as add-on to metformin for 208 weeks reduced HbA1c with a significantly lower risk of hypoglycaemia and a significantly smaller proportion of patients receiving rescue therapy compared with glimepiride.

In the original publication, disclosure statement for the author Ian J. Neeland was published incorrectly. The correct statement should read as "Ian J. Neeland received financial assistance for publishing/article processing fees from Boehringer Ingelheim".

Diabetes is associated with a significant decrease in life expectancy [(1)][1]. In the EMPA-REG OUTCOME trial ([NCT01131676][2]), empagliflozin given in addition to standard of care reduced the risk of cardiovascular death by 38% (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.49 to 0.77;

HomeCirculationVol. 138, No. 15Long-Term Benefit of Empagliflozin on Life Expectancy in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLong-Term Benefit of Empagliflozin on Life Expectancy in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular DiseaseSurvival Estimates From the EMPA-REG OUTCOME Trial Brian Claggett, PhD, John M. Lachin, ScD, Stefan Hantel, PhD, David Fitchett, MD, Silvio E. Inzucchi, MD, Hans J. Woerle, MD, Jyothis T. George, MBBS, PhD, FRCP and Bernard Zinman, MD Brian ClaggettBrian Claggett Brian Claggett, PhD, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. Email E-mail Address: [email protected] Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA (B.C.). Search for more papers by this author , John M. LachinJohn M. Lachin Biostatistics Center, George Washington University, Rockville, MD (J.M.L.). Search for more papers by this author , Stefan HantelStefan Hantel Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany (S.H.). Search for more papers by this author , David FitchettDavid Fitchett St. Michael’s Hospital, Division of Cardiology (D.F.), Canada. University of Toronto (D.F., B.Z.), Canada. Search for more papers by this author , Silvio E. InzucchiSilvio E. Inzucchi Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.). Search for more papers by this author , Hans J. WoerleHans J. Woerle Boehringer Ingelheim International GmbH, Germany (H.J.W., J.T.G.). Search for more papers by this author , Jyothis T. GeorgeJyothis T. George Boehringer Ingelheim International GmbH, Germany (H.J.W., J.T.G.). Search for more papers by this author and Bernard ZinmanBernard Zinman University of Toronto (D.F., B.Z.), Canada. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada (B.Z.). Search for more papers by this author Originally published8 Oct 2018https://doi.org/10.1161/CIRCULATIONAHA.118.033810Circulation. 2018;138:1599–1601Diminished life expectancy is a key concern in patients with diabetes mellitus, with 6 to 7 years of life estimated to be lost in a 60-year-old patient with diabetes mellitus compared with an individual of the same age without diabetes mellitus.1 In the EMPA-REG OUTCOME trial, the sodium-glucose cotransporter 2 inhibitor empagliflozin reduced the risk of cardiovascular death by 38% (hazard ratio, 0.62; 95% CI, 0.49–0.77) and all-cause mortality by 32% (hazard ratio, 0.68; 95% CI, 0.57–0.82) over a median observation period of 3.1 years when given in addition to standard of care in patients with type 2 diabetes mellitus and established cardiovascular disease.2 Clinical trials are the gold standard for estimating treatment effectiveness over a relatively short period, but estimation of long-term treatment effects generally requires additional assumptions. Furthermore, analyses of relative risk based on hazard ratios do not convey the years of life lost as a result of premature death. We performed an actuarial analysis of data from the EMPA-REG OUTCOME trial to estimate the long-term benefit of empagliflozin on the residual life span.In the EMPA-REG OUTCOME trial, patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All patients provided written informed consent. A total of 7020 patients were treated. In this analysis, complete follow-up data from all 7020 treated patients (mean±SD age, 63±9 years) were used. We estimated the effect of empagliflozin versus placebo on all-cause mortality over the duration of patients’ lifetimes using patient age, rather than the time since randomization, as the time scale. We produced actuarial estimates of the age-specific probabilities of death for the pooled empagliflozin group and the placebo group. These estimates were used to obtain nonparametric age-based Kaplan-Meier estimates of the survival curve for patients at each year of age in each treatment group.3,4 For patients in each treatment group at each year of age, the expected residual years of survival were estimated as the area under the survival curve up to a maximum age of 90 years. Because patient age and treatment are independent of each other owing to randomization, the difference in the areas under the survival curve can be interpreted as the effect of treatment on time spent event-free. This process was repeated to produce estimated treatment effects for each year of age between 45 and 80. The estimated treatment differences in mean survival and 95% CIs were smoothed with a locally weighted scatterplot smoothing procedure.Estimated mean survival was longer with empagliflozin than placebo at all ages. Differences in estimated mean years of survival with empagliflozin versus placebo ranged from 1 to nearly 5 years (Figure [A]). Estimated mean survival at age 45 years was 32.1 years with empagliflozin versus 27.6 years with placebo (difference, 4.5 years; 95% CI, 1.3–7.8; P=0.007), at age 50 was 28.5 versus 25.4 years (difference, 3.1 years; 95% CI, 0.9–5.3; P=0.005), at age 60 was 21.8 versus 19.2 years (difference, 2.5 years; 95% CI, 1.1–3.9; P=0.001), at age 70 was 14.8 versus 12.8 years (difference, 2.0 years; 95% CI, 0.7–3.2; P=0.003), and at age 80 was 7.7 versus 6.7 years, respectively (difference, 1.0 year; 95% CI, −0.3 to 2.2; P=0.13; Figure [B]). The absolute increases in mean survival with empagliflozin versus placebo decreased with age, whereas the relative increases were consistent regardless of age and ranged between 12% and 15%.Download figureDownload PowerPointFigure. Estimated mean survival times and treatment differences in mean survival by age. A, Estimated mean survival times as a function of patient age with empagliflozin and placebo using data from the EMPA-REG OUTCOME trial in patients with type 2 diabetes mellitus and established cardiovascular disease. B, Differences in mean survival by age with empagliflozin versus placebo estimated using data from the EMPA-REG OUTCOME trial in patients with type 2 diabetes mellitus and established cardiovascular disease.Using data from the EMPA-REG OUTCOME trial and actuarial methods and assuming that the beneficial effects of empagliflozin remain consistent with long-term use, we estimated that empagliflozin improved survival by 1 to 5 years in patients with type 2 diabetes mellitus and established cardiovascular disease. An alternative analysis that assumes complete adherence would likely show even greater benefits. The present analysis includes study drug discontinuation as observed in the study. Data from randomized controlled trials of glucose-lowering therapies show differences in effects on mortality.5 These analyses based on EMPA-REG OUTCOME data demonstrate the potential impact of the reduction in mortality with empagliflozin in patients with type 2 diabetes mellitus and established cardiovascular disease.AcknowledgmentsMedical writing assistance, supported financially by Boehringer Ingelheim, was provided by Elizabeth Ng and Wendy Morris of FleishmanHillard Fishburn, London, UK, during the preparation of this article. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.Sources of FundingThe EMPA-REG OUTCOME trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.DisclosuresDr Claggett has received consultancy fees from Boehringer Ingelheim, Gilead, AOBiome, and Corvia. Dr Lachin has received consultancy fees from Boehringer Ingelheim, Merck, Gilead, and Janssen. Dr Fitchett has received honoraria from Sanofi, Merck & Co, Amgen, AstraZeneca, Eli Lilly and Co, and Boehringer Ingelheim. Dr Inzucchi has consulted for Janssen, vTv Therapeutics, and Alere; served on Clinical Trial Steering/Executive committees for Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Sanofi/Lexicon Pharmaceuticals, Daiichi-Sankyo, and Eisai (TIMI [Thrombolysis in Myocardial Infarction]); and served on Data Monitoring committees for Intarcia Therapeutics, Inc. Dr Zinman has received research grants awarded to his institution from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk, as well as honoraria from Janssen, Sanofi, Eli Lilly and Co, Boehringer Ingelheim, Novo Nordisk, and Merck. Drs Hantel and George are employees of Boehringer Ingelheim. Dr Woerle was an employee of Boehringer Ingelheim at the time that this work was performed.FootnotesData sharing: The data that support the findings of this analysis are available from the corresponding author on reasonable request.https://www.ahajournals.org/journal/circBrian Claggett, PhD, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. Email [email protected]harvard.eduReferences1. Emerging Risk Factors Collaboration. Association of cardiometabolic multimorbidity with mortality.JAMA. 2015; 314:52–60. doi: 10.1001/jama.2015.7008CrossrefMedlineGoogle Scholar2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373:2117–2128. doi: 10.1056/NEJMoa1504720CrossrefMedlineGoogle Scholar3. Claggett B, Packer M, McMurray JJ, Swedberg K, Rouleau J, Zile MR, Jhund P, Lefkowitz M, Shi V, Solomon SD; PARADIGM-HF Investigators. Estimating the long-term treatment benefits of sacubitril-valsartan.N Engl J Med. 2015; 373:2289–2290. doi: 10.1056/NEJMc1509753CrossrefMedlineGoogle Scholar4. Dehbi HM, Royston P, Hackshaw A. Life expectancy difference and life expectancy ratio: two measures of treatment effects in randomised trials with non-proportional hazards.BMJ. 2017; 357:j2250. doi: 10.1136/bmj.j2250CrossrefMedlineGoogle Scholar5. Paneni F, Lüscher TF. 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Bauduceau B, Bordier L, Bringer J, Chabrier G, Charbonnel B, Cosson E, Darmon P, Detournay B, Fontaine P, Gourdy P, Grimaldi A, Guerci B, Hanaire H, Penfornis A, Riveline J and Scheen A (2019) Prise de position de la Société Francophone du Diabète (SFD) : évaluation du rapport bénéfices-risques des inhibiteurs de SGLT2, Médecine des Maladies Métaboliques, 10.1016/S1957-2557(19)30056-2, 13:2, (195-209), Online publication date: 1-Mar-2019. Kurian M, Rentzepis P, Carracher A and Close K (2018) European Association for the Study of Diabetes 2018, Journal of Diabetes, 10.1111/1753-0407.12876 October 9, 2018Vol 138, Issue 15 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.033810PMID: 30354516 Originally publishedOctober 8, 2018 Keywordsempagliflozincardiovascular diseasesdiabetes mellitusPDF download Advertisement SubjectsCardiovascular DiseaseMortality/Survival

In the EMPA-REG OUTCOME trial, empagliflozin given in addition to standard of care significantly reduced cardiovascular (CV) death vs. placebo (HR 0.62; 95% CI 0.49, 0.77) in patients with type 2 diabetes (T2DM) and established CV disease. We investigated whether baseline HbA1c or change in HbA1c influenced the effect of empagliflozin on CV death.

AimsEmpagliflozin reduced the risk of cardiovascular (CV) death and heart failure (HF) hospitalizations in patients with type 2 diabetes (T2D) and established CV disease (CVD) in the EMPA-REG OUTCOME® trial. We investigated whether the benefit of empagliflozin was observed across the spectrum of HF risk.Methods and resultsSeven thousand and twenty patients with T2D (HbA1c 7-10% and eGFR > 30 mL/min/1.73 m2) were treated with empagliflozin 10 or 25 mg, or placebo once daily and followed for median 3.1 years. In patients without HF at baseline (89.9%), we derived the 5-year risk for incident HF using the 9-variable Health ABC HF Risk score [classified as low-to-average (<10%), high (10-20%), and very high (≥ 20%)]. Overall, 67.2% of the population had low-to-average, 24.2% high, and 5.1% very high 5-year HF risk. Across these groups, the effect on CV death and HF hospitalization with empagliflozin was consistent [hazard ratio 0.71 (95% confidence interval: 0.52, 0.96), 0.52 (0.36, 0.75), and 0.55 (0.30, 1.00), respectively]. Effects on CV death in the ostensibly highest HF risk group (HF at baseline and/or incident HF during the trial) in whom 37.9% of the overall CV deaths occurred, was also beneficial [0.67 (0.47, 0.97)], yet, similar benefits were seen in the lower risk patients.ConclusionIn patients with T2D and established CVD, a sizeable proportion without HF at baseline are at high or very high risk for HF outcomes, indicating the need for active case finding in this patient population. Empagliflozin consistently improved HF outcomes both in patients at low or high HF risk.

Background: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and established cardiovascular disease in the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. We investigated the effects of empagliflozin on clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Methods: Patients with type 2 diabetes mellitus, established cardiovascular disease, and estimated glomerular filtration rate (eGFR) ≥30 mL·min −1 ·1.73 m −2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. We analyzed cardiovascular death, hospitalization for heart failure, all-cause hospitalization, and all-cause mortality in patients with prevalent kidney disease (defined as eGFR <60 mL·min −1 ·1.73 m −2 and/or urine albumin-creatinine ratio >300 mg/g) at baseline. Additional analyses were performed in subgroups by baseline eGFR (<45, 45–<60, 60–<90, ≥90 mL·min −1 ·1.73 m −2 ) and baseline urine albumin-creatinine ratio (>300, 30–≤300, <30 mg/g). Results: Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes mellitus for >10 years, 58% were receiving insulin, and 84% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52–0.98), the risk of all-cause mortality by 24% (HR, 0.76; 95% CI, 0.59–0.99), the risk of hospitalization for heart failure by 39% (HR, 0.61; 95% CI, 0.42–0.87), and the risk of all-cause hospitalization by 19% (HR, 0.81; 95% CI, 0.72–0.92). Effects of empagliflozin on these outcomes were consistent across categories of eGFR and urine albumin-creatinine ratio at baseline and across the 2 doses studied. The adverse event profile of empagliflozin in patients with eGFR <60 mL·min −1 ·1.73 m −2 was consistent with the overall trial population. Conclusions: Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.

Background and Purpose— In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), empagliflozin added to standard of care in patients with type 2 diabetes mellitus and high cardiovascular risk reduced the risk of 3-point major adverse cardiovascular events, driven by a reduction in cardiovascular mortality, with no significant difference between empagliflozin and placebo in risk of myocardial infarction or stroke. In a modified intent-to-treat analysis, the hazard ratio for stroke was 1.18 (95% confidence interval, 0.89–1.56; P =0.26). We further investigated cerebrovascular events. Methods— Patients were randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo; 7020 patients were treated. Median observation time was 3.1 years. Results— The numeric difference in stroke between empagliflozin and placebo in the modified intent-to-treat analysis was primarily because of 18 patients in the empagliflozin group with a first event >90 days after last intake of study drug (versus 3 on placebo). In a sensitivity analysis based on events during treatment or ≤90 days after last dose of drug, the hazard ratio for stroke with empagliflozin versus placebo was 1.08 (95% confidence interval, 0.81–1.45; P =0.60). There were no differences in risk of recurrent, fatal, or disabling strokes, or transient ischemic attack, with empagliflozin versus placebo. Patients with the largest increases in hematocrit or largest decreases in systolic blood pressure did not have an increased risk of stroke. Conclusions— In patients with type 2 diabetes mellitus and high cardiovascular risk, there was no significant difference in the risk of cerebrovascular events with empagliflozin versus placebo. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01131676.

with volume depletion in either the empagliflozin or placebo groups. 4n conclusion, while we agree that effects on volume may be one of the mechanisms behind the observed reductions in the risk of CV death and heart failure outcomes with empagliflozin, we find no evidence that concomitant of diuretics and empagliflozin was associated with an increased risk of stroke in patients in EMPA-REG OUTCOME trial.

Inhibition of sodium glucose cotransporter 2 with empagliflozin results in caloric loss by increasing urinary glucose excretion and has a mild diuretic effect. Diuretic effects are usually associated with reflex-mediated increases in sympathetic tone, whereas caloric loss is associated with decreased sympathetic tone. In an open label trial, muscle sympathetic nerve activity (MSNA) (burst frequency, burst incidence, and total MSNA) was assessed using microneurograPhy performed off-treatment and on day 4 of treatment with empagliflozin 25 mg once daily in 22 metformin-treated patients with type II diabetes (mean [range] age 54 [40-65] years).,Systolic and diastolic blood pressure (BP), heart rate, urine volume, and body weight were assessed before and on day 4 (BP, heart rate), day 5 (urine volume), or day 6 (body weight) of treatment with empagliflozin. After 4 days of treatment with empagliflozin, no significant changes in MSNA were apparent despite a numerical increase in urine volume, numerical reductions in BP, and significant weight loss. There were no clinically relevant changes in heart rate. Empagliflozin is not associated with clinically relevant reflex-mediated sympathetic activation in contrast to increases observed with diuretics in other studies. Our study suggests a novel mechanism through which sodium glucose cotransporter 2 inhibition affects human autonomic cardiovascular regulation. (C) 2017 American Society of Hypertension. All rights reserved.