LEADER and EMPA-REG. John Buse, MD, PhD. University of North Carolina School of Medicine Chapel Hill, NC, USA. Duality of Interest Declaration

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1 1 LEADER and EMPA-REG John Buse, MD, PhD University of Nth Carolina School of Medicine Chapel Hill, NC, USA Duality of Interest Declaration I rept the following potential duality/dualities of interest in the field covered by my lecture: Board Member/Advisy Panel: None Consultant: PhaseBio Employee: University of Nth Carolina School of Medicine, Chapel Hill, NC USA Research Suppt: AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, GI Dynamics, Intarcia, J&J, Lexicon, Medtronic, Novo Ndisk, Orexigen, Sanofi, Scion NeuroStim, Takeda, Theracos Speaker s Bureau: None Stock/Shareholder: PhaseBio Other (advis under contract between employer and the company): Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, Elycylex, F. Hoffman LaRoche, GI Dynamics, Lexicon, Merck, Metavention, Novo Ndisk, Orexigen, Quest, Takeda, vtv Therapeutics Travel Suppt: in conjunction with above-mentioned activities John Buse, MD, PhD; Chapel Hill, NC USA

2 2 GLP-1 Modifies CV Risk through Direct and Indirect Actions in Multiple Organs Drucker, The Cardiovascular Biology of Glucagonlike Peptide-1, Cell Metabolism (2016), j.cmet In press Direct and Indirect Actions of GLP-1 in the Heart and Blood Vessels Drucker, The Cardiovascular Biology of Glucagonlike Peptide-1, Cell Metabolism (2016), j.cmet In press

3 3 LEADER: Study design CV: cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibit; GLP-1RA: glucagon-like peptide-1 recept agonist; HbA 1c : glycated hemoglobin; MEN-2: multiple endocrine neoplasia type 2; MTC: medullary thyroid cancer; OAD: al antidiabetic drug; OD: once daily; T2DM: type 2 diabetes mellitus. Study patient disposition FAS: full analysis set.

4 4 Trial follow-up and drug exposure *Excluding pre-scheduled 30 day off-treatment follow-up period. Including off-treatment periods. IQR: interquartile range. HbA 1c Data are estimated mean values from randomization to month 48. CI: confidence interval; ETD: estimated treatment difference; HbA 1c : glycated hemoglobin.

5 5 Antihyperglycemic medications introduced during trial DPP-4: dipeptidyl peptidase-4; GLP-1RA: glucagon-like peptide-1 recept agonist; SGLT-2: sodium-glucose co-transpter-2; TZD: thiazolidinedione. Body weight Data are estimated mean values from randomization to last scheduled visit f body weight measurement (month 48). CI: confidence interval; ETD: estimated treatment difference.

6 6 Cardiovascular medication introduced during trial Blood pressure Data are estimated mean values from randomization to last scheduled visit f blood pressure measurement (month 48). CI: confidence interval; DBP: diastolic blood pressure; ETD: estimated treatment difference; SBP: systolic blood pressure.

7 7 Primary outcome CV death, non-fatal myocardial infarction, non-fatal stroke The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proptional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Primary outcome: Subgroup analyses Prespecified Cox proptional-hazard regression analyses were perfmed f subgroups of patients with respect to the primary outcome (first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke). P values signify tests of homogeneity f between-group differences with no adjustment f multiple testing. The percentages of patients with a first primary outcome between the randomization date and the date of last follow-up are shown. Race ethnic group was self-repted. CI: confidence interval.

8 8 Primary outcome: Subgroup analyses Prespecified Cox proptional-hazard regression analyses were perfmed f subgroups of patients with respect to the primary outcome (first occurrence of death from CV causes, nonfatal MI, nonfatal stroke). P values signify tests of homogeneity f between-group differences with no adjustment f multiple testing. The percentages of patients with a first primary outcome between the randomization date and the date of last follow-up are shown. There were missing data f BMI in 5 patients in the liraglutide group and 4 in the placebo group and f the duration of diabetes in 11 patients in the liraglutide group and 8 in the placebo group. Table S3. Sensitivity analysis of the primary composite outcome by baseline renal status

9 9 Primary outcome: Sensitivity analysis Analyzed using Cox proptional hazard regression with treatment as a fixed fact. FAS: full analysis set; PP: per protocol. CV death The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proptional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio.

10 10 All-cause death The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proptionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio. Primary and secondary cardiovascular outcomes* *Hazard ratios and p-values were estimated with the use of a Cox proptional-hazards model with treatment as a covariate. The primary composite outcome in the time-to-event analysis consisted of the first occurrence of death from cardiovascular causes (181 patients in the liraglutide group vs. 227 in the placebo group), non-fatal (including silent) myocardial infarction (275 vs. 304), non-fatal stroke (152 vs. 163). The p-value is f superiity. The expanded composite outcome included death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, conary revascularization, hospitalization f unstable angina pectis heart failure. This analysis was not prespecified. CI: confidence interval; CV: cardiovascular; UAP: unstable angina pectis.

11 11 Time to first microvascular event The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proptionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio. Time to first renal event Macroalbuminuria, doubling of serum creatinine, ESRD, renal death The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proptionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio.

12 12 Time to first eye event Photocoagulation treatment with intravitreal agents, vitreous hemrhage blindness The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proptionalhazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio. Time to first microvascular endpoints Full analysis set. EAC-confirmed microvascular events including events with onset between date of randomization and date of follow-up. Cox proptional hazard model adjusted f treatment. Development of diabetes-related blindness was not analyzed as an individual component as only one event was observed. *New onset of persistent macroalbuminuria: urine albumin 300 mg/g creatinine. Persistent doubling of serum creatinine level and egfr 45 ml/min/1.73 m 2 per MDRD. %: proption of patients; CI: confidence interval; EAC: event adjudication committee; N: number of patients.

13 13 Adverse events Full analysis set. A serious adverse event was defined as an experience that at any dose resulted in any of the following: death, a life-threatening experience, in-patient hospitalization prolongation of hospitalization, persistent significant disability/incapacity, congenital anomaly/birth defect, imptant medical events that may jeopardize the patient based upon appropriate medical judgement. A severe adverse event was defined as an adverse event that resulted in considerable interference with the patient s daily activities. N: number of patients. Selected adverse events of special interest Serious adverse events and nonserious medical events of special interest were identified by search in the Medical Dictionary f Regulaty Activities, version 18.0, by action to trial product: trial product permanently discontinued due to adverse event. P-values were calculated by means of Pearson s chi-square test.

14 14 AEs leading to permanent treatment discontinuation *Explaty analysis with no adjustment of p-values f multiplicity. Permanent discontinuation of the treatment regimen was indicated by the investigat in the adverse event fm. P-values were calculated by means of Pearson s chi-square test. Hypoglycemia Confirmed hypoglycemia was defined as plasma glucose level of less than 56 mg per deciliter (3.1 mmol per liter) a severe event. Severe hypoglycemia was defined as hypoglycemia f which the patient required assistance from a third party. Analyzed using a negative binomial regression model. CI: confidence interval; PG: plasma glucose.

15 15 Neoplasms Confirmed by adjudication *EAC-confirmed neoplasms with EAC onset date from randomization date to follow-up; includes malignant, pre-malignant, benign and unspecified neoplasms. Neoplasms were adjudicated by the event adjudication committee. This committee interpreted neoplastic growth as clonal disders that grow in an autonomous manner. The abnmality of clonal disder may not always have been identified n could autonomous growth always be determined, but both were considered to be fundamental aspects of neoplastic growth. Cox proptional hazard regression model adjusted f treatment. %: proption of patients; CI: confidence interval; EAC: Event Adjudication Committee; N: number of patients. Malignant neoplasms by tissue type Confirmed by adjudication Explaty analysis. CI: confidence interval.

16 16 Pancreatic cancer Pancreatitis (confirmed by adjudication) Full analysis set. The occurrence of pancreatitis was adjudicated by the event adjudication committee. P-values were calculated by means of Pearson s chi-square test. %: proption of patients; N: number of patients.

17 17 LEADER: Summary Population studied High risk of cardiovascular events receiving standard of care 81% with pri CVD CKD Potentially greater benefit in established CVD and egfr <60 ml/min/1.73 m 2 subgroups Follow-up and retention 96.8% of patients completed the study Vital status known f 99.7% of patients Robust event adjudication by external committee CKD: chronic kidney disease; CVD: cardiovascular disease; egfr: estimated glomerular filtration rate. LEADER: Summary (2) Liraglutide reduced the risk f 3-point MACE by 13% All 3 components of MACE contributed to the risk reduction Liraglutide reduced composite microvascular endpoints Driven by reduced new and persistent macroalbuminuria Liraglutide resulted in reductions in HbA 1c, body weight, and hypoglycemia Liraglutide was generally well tolerated. In line with previous trials, liraglutide was associated with gastrointestinal side effects, increases in pancreatic enzymes and heart rate HbA 1c : glycated hemoglobin; MACE: maj adverse cardiovascular event.

18 18 LEADER: Summary (3) No increase in pancreatitis but an increase in acute gallstone disease No increase in hospitalization f heart failure Liraglutide reduced the risk of all-cause death by 15% Liraglutide reduced the risk of CV death by 22% CV: cardiovascular. 36 Glucagon-like peptide-1 recept agonists ELIXA Time to first occurrence of CV death, non-fatal MI, non-fatal stroke hospitalization f unstable angina Patients with an event (%) Time from randomization (months) Patients at risk Lixisenatide Placebo Lixisenatide Placebo HR: % CI ( ) LEADER Time to first occurrence of CV death, non-fatal MI non-fatal stroke Patients with an event (%) Patients at risk Liraglutide Placebo Placebo Liraglutide HR: % CI ( ) CV: cardiovascular; HR: hazard ratio; MI: myocardial infarction. Pfeffer MA et al. N Engl J Med 2015;373:

19 19 Empagliflozin and Liraglutide EMPA-REG OUTCOME CV death, non-fatal MI, non-fatal stroke LEADER CV death, non-fatal MI, non-fatal stroke CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MI: myocardial infarction. Zinman B et al. N Engl J Med 2015;373: Individual components of the primary endpoint EMPA-REG OUTCOME LEADER *95.02% CI. CV: cardiovascular; Empa: empaglifloin; Lira: liraglutide; MACE: maj adverse cardiovascular event; MI: myocardial infarction; Pbo: placebo. Zinman B et al. Presented at European Association f the Study of Diabetes 2015, Stockholm, Sweden.

20 20 Cardiovascular death EMPA-REG OUTCOME 1 LEADER 2 9 Patients with an event (%) Empagliflozin Placebo HR= % CI (0.49 ; 0.77) P< Patients with an event (%) Liraglutide Liraglutide Placebo Placebo HR= % CI (0.66 ; 0.93) p= Month Time from randomisation (months) Patients at risk Empagliflozin Placebo Patients at risk Liraglutide Placebo CI, confidence interval; HR, hazard ratio. 1. Zinman B et al. N Engl J Med 2015;373: ; 2. Marso SP et al. N Engl J Med DOI: /NEJMoa Categies of CV death Patients with event (%) Empagliflozin Placebo HR (95% CI) (N=4687) (N=2333) CV death 172 (3.7%) 137 (5.9%) 0.62 (0.49, 0.77) Hazard ratio (95% CI) Sudden death 53 (1.1%) 38 (1.6%) 0.69 (0.45, 1.04) Wsening of heart failure cardiogenic shock 14 (0.3%) 22 (0.9%) 0.32 (0.16, 0.62) Acute MI 15 (0.3%) 11 (0.5%) 0.68 (0.31, 1.48) Stroke 16 (0.3%) 11 (0.5%) 0.72 (0.33, 1.55) Other* 74 (1.6%) 55 (2.4%) 0.66 (0.47, 0.94) Favs empagliflozin Favs placebo Cox regression analysis. *1.5% on empagliflozin and 2.3% on placebo were presumed CV death (insufficient data f the adjudication committee to categize cause of death). Fitchett D et al. J Am Coll Cardiol 2016;67:

21 21 41 The EMPAREG-OUTCOME Study Enigma Are Fuel Energetics the Answer CV protection in the EMPA-REG OUTCOME trial: a thrifty substrate hypothesis Ele Ferrannini 1 Michael Mark 2 Eric Mayoux 2 Affiliations: 1 CNR Institute of Clinical Physiology, Pisa, Italy 2 Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany Diabetes Care; Vol. 39, Supplement July, 2016

22 22 Cardiovascular Outcome Trials Known GLP-1 class differences Lixisenatide (ELIXA) - neutral Exenatide Intarcia (Freedom-CVO) - neutral Semaglutide (Sustain 6) - benefits Soon to be known Exenatide OW (EXSCEL [2018]) Dulaglutide (REWIND [2018]) Albiglutide (HARMONY-OUTCOMES [2019]) Canagliflozin (CANVAS, CANVAS-R [2017]) Dapagliflozin (DECLARE) Unknown IDegLira Oral semaglutide Obesity Contrave (LIGHT) - neutral Lcaserin (CAMELLIA-TIMI [2018]) Qsymia (AQCLAIM) Saxenda Canagliflozin phentermine 7.5% weight loss (4.1% cana, 1.9% phentermine, and 0.6% placebo) What we know: In est risk CVD population there are clear cut benefits: EMPA: CVD death, CHF death, CHF, nephropathy LIRA: Broad based benefits on CVD endpoints, nephropathy Little evidence of harms Empa is restricted to those with egfr >45 (?>30?) What we do not know: What are the effects of lira (and empa) in intermediate risk CVD populations? What is the effect of lira as initial/early therapy in risk ( intermediate risk) populations? Is the combination of lira and empa safe? Do lira and empa provide combined benefits on CVD endpoints? Lira: Retinopathy? Lira: CHF? Lira: NASH? Lira: Other complications (e.g., foot ulcer)? Precision medicine

23 23 45 F those with clinical CVD Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk gain hypoglycemia low Metfmin Sulfonylurea TZD Metfmin Thiazolidinedione low risk gain edema, HF, fxs low Metfmin Thiazolidinedione SU Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin DPP-4 Inhibit SU Metfmin EMPAGLIFLOZIN SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 LIRAGLUTIDE recept agonist low risk loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) est risk gain hypoglycemia variable Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38: ; Diabetologia 2015;58:

24 24 F those with clinical CVD (?and CKD?) Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk gain hypoglycemia low Metfmin Sulfonylurea TZD Metfmin Thiazolidinedione low risk gain edema, HF, fxs low Metfmin Thiazolidinedione SU Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin DPP-4 Inhibit SU Metfmin EMPAGLIFLOZIN SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 LIRAGLUTIDE recept agonist low risk loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) est risk gain hypoglycemia variable Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38: ; Diabetologia 2015;58: