6/26/2017. The CANVAS Program (CANagliflozin cardiovascular Assessment Study) Presenter Disclosures: Bruce Neal, MB ChB, PhD. Design.

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1 6/26/2017 The CANVAS Program (CANagliflozin cardiovascular Assessment Study) Presenter Disclosures: Bruce Neal, MB ChB, PhD Research support Australian National Health and Medical Research Council Principal Research Fellowship Janssen, Roche, Servier, Merck Schering Plough Advisory boards and/or continuing medical education Abbott, Janssen, Novartis, Pfizer, Roche, Servier Consultancy, honoraria, or travel support paid to his institution The CANVAS Program was supported by Janssen Research & Development, LLC Design CANVAS trial starts CV safety proved and marketing authorization achieved UL 95% CI <1.8 Evaluate CV safety UL 95% CI <1.3 CANVAS Program N = 10,142 CANVAS-R n = 5812 CANVAS n =

2 6/26/2017 Hypothesis Testing Plan Major cardiovascular events (non-inferiority) Superiority* CANVAS Program (CANVAS and CANVAS-R) All-cause mortality Cardiovascular death Albuminuria progression CANVAS-R alone Cardiovascular death or hospitalization for heart failure Cardiovascular death *Superiority testing was included in the Statistical Analysis Plan. Randomization CANVAS 300 mg 2-week placebo run-in R 100 mg CANVAS-R 100 mg with optional up-titration to 300 mg 2-week placebo run-in R Analytic Approach 2-week placebo run-in R 300 mg mg 2

3 6/26/2017 Inclusion Criteria Patients with type 2 diabetes HbA1c 7.0% to 10.5% egfr 30 ml/min/1.73 m 2 Age 30 years and history of prior CV event OR Age 50 years with 2 CV risk factors* *Diabetes duration 10 years, SBP >140 mmhg on 1 medication, current smoker, micro- or macroalbuminuria, or HDL cholesterol <1 mmol/l. Enrollment and Follow-up CANVAS 4330 randomized CANVAS-R 5813 randomized Integrated CANVAS Program dataset 10,142 randomized* (ITT population) 4347 placebo 5795 canagliflozin 4327 (99.5%) vital status known 4163 (95.7%) completed study 5773 (99.6%) vital status known 5571 (96.1%) completed study *One participant was randomized at 2 different sites and only the first randomization is included in the ITT analysis set. Follow-up CANVAS-R 108 weeks CANVAS 296 weeks CANVAS Program mean follow-up 188 weeks Patients remaining on randomized treatment: 71% 70% 3

4 6/26/2017 Demographics and Disease History (n = 5795) (n = 4347) Mean age, y Female, % Mean duration of diabetes, y Hypertension, % Heart failure (NYHA I-III), % Cardiovascular disease, % Baseline Therapies (n = 5795) (n = 4347) % % Antihyperglycemic agents Metformin Insulin Sulfonylurea DPP-4 inhibitor GLP-1 receptor agonist 4 4 Cardioprotective agents RAAS inhibitor Statin Antithrombotic Beta blocker Diuretic Baseline Risk Factors (n = 5795) (n = 4347) HbA1c, % Body mass index, kg/m Systolic BP, mmhg Diastolic BP, mmhg Total cholesterol, mmol/l HDL-C, mmol/l LDL-C, mmol/l Triglycerides, mmol/l

5 Mean body weight (kg) Mean systolic BP (mmhg) Mean HbA1c (%) 6/26/2017 Effects on HbA1c Mean difference % (95% CI, 0.61 to 0.56) Years since randomization No. of patients Mixed model for repeated measures (MMRM) analysis Effects on Systolic BP Mean difference 3.93 mmhg (95% CI, 4.30 to 3.56) No. of patients Years since randomization Mixed model for repeated measures (MMRM) analysis Effects on Body Weight Mean difference 1.60 kg (95% CI, 1.70 to 1.51) No. of patients Years since randomization Mixed model for repeated measures (MMRM) analysis 5

6 Patients with an event (%) 6/26/2017 Primary MACE Outcome CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke No. of patients Hazard ratio 0.86 (95% CI, ) p < for noninferiority p = for superiority Years since randomization Intent-to-treat analysis Primary Cardiovascular Outcome by Study Hazard ratio (95% CI) CANVAS 0.88 ( ) CANVAS-R 0.82 ( ) CANVAS Program 0.86 ( ) Favors Favors Intent-to-treat analysis Hypothesis Testing Outcome Major cardiovascular events (non-inferiority) Superiority* p <0.001 p = All-cause mortality Cardiovascular death p = 0.24 Exploratory Nominal effect estimates Albuminuria progression Cardiovascular death or hospitalization for heart failure Cardiovascular death *Superiority testing was included in the Statistical Analysis Plan. 6

7 Patients with an event (%) Patients with an event (%) 6/26/2017 Exploratory cardiovascular outcomes Hazard ratio (95% CI) Primary cardiovascular outcome CV death Nonfatal myocardial infarction Nonfatal stroke 0.86 ( ) 0.87 ( ) 0.85 ( ) 0.90 ( ) Hospitalization for heart failure CV death or hospitalization for heart failure All-cause mortality 0.67 ( ) 0.78 ( ) 0.87 ( ) Favors Favors Intent-to-treat analysis Progression of Albuminuria 100 Hazard ratio 0.73 (95% CI, ) Years since randomization No. of patients Intent-to-treat analysis Composite of 40% Reduction in egfr, End-stage Renal Disease, or Renal Death Hazard ratio 0.60 (95% CI, ) Events (n) 40% egfr reduction 239 End-stage renal disease/renal death No. of patients Years since randomization Intent-to-treat analysis 7

8 6/26/2017 Lower Extremity Amputation All amputations (n = 187) Event rate per 1000 patient-years ( ) Minor amputation (71%) ( ) Toe Transmetatarsal Major amputation (29%) ( ) Ankle Below-knee Above-knee Hazard ratio (95% CI) Favors Favors Fracture Adjudicated low-trauma fractures CANVAS Program (Heterogeneity p = 0.003) Event rate per 1000 patient-years Hazard ratio (95% CI) ( ) CANVAS (n = 271) ( ) CANVAS-R (n = 108) ( ) All adjudicated fractures CANVAS Program (Heterogeneity p = 0.005) ( ) CANVAS (n = 350) ( ) CANVAS-R (n = 146) ( ) Favors Favors Malignancy Event rate per 1000 patient-years Hazard ratio (95% CI) Neoplasms (n = 741) Renal cancer (n = 17) Bladder cancer (n = 38) Breast cancer (n = 37) ( ) ( ) ( ) ( ) Favors Favors 8

9 Incidence rate rate (per (per patients over over 5 years) 5 years) 6/26/2017 Kidney Event rate per 1000 patient-years Hazard ratio (95% CI) Serious renal-related (n = 83) Serious acute kidney injury (n = 58) Serious hyperkalemia (n = 15) ( ) ( ) ( ) Favors Favors Benefits and Risks fewer patients MACE 16 fewer patients 17 fewer patients Hospitalization Renal for heart failure composite 15 more patients 5 above ankle 10 toes and metatarsals Amputation Summary The CANVAS Program met its primary objective of demonstrating the cardiovascular safety and efficacy of canagliflozin use was associated with an increased risk of amputation The data suggest a favorable benefit/risk profile for many patients with type 2 diabetes at elevated cardiovascular risk 9

10 GLP-1 Agonists in Heart Failure: Evidence for Stage-Dependent Effects Kenneth B. Margulies, M.D. Professor of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, PA, USA 41 GLP-1 is a Metabolic Modulator Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin peptide that enhances cellular glucose uptake by stimulating insulin secretion and by enhancing insulin sensitivity in target tissues. Administration of exogenous GLP-1 as a continuous infusion in patients with type 2 DM increases insulin sensitivity in skeletal muscle and fat while improving insulin-mediated glucose uptake Importantly, the GLP-1 triggered increases in insulin secretion cease at glucose levels below 4 mm (72 mg/dl) which mitigates the risk of hypoglycemia Putative Cardiovascular Effects of Incretin-Based Therapies Reduced TC, LDL and TG Petrie JR. Cardiovascular Diabetology 2013: 12:130

11 Classification of HF: ACC/AHA HF Stage vs. NYHA Functional Class ACC/AHAHF Stage A High risk of developing HF B Structural heart disease but without HF symptoms C Structural heart disease with HF symptoms, either prior or current D Refractory HF requiring specialized interventions NYHA Functional Class I Asymptomatic HF No symptoms II III Mild and Moderate HF Symptoms upon mild to moderate exertion IV Severe HF Symptoms at rest GLP-1 Agonist Trials in Heart Failure (HF) LEADER: Stage A, B & early C HF SUSTAIN-6: Stage A, B & early C HF ELIXA: Stage C Heart failure (early post-acute coronary syndrome) FIGHT: Advanced Stage C LEADER (Liraglutide Effect and Action in Diabetes: Effect of Cardiovascular Outcome Results) A Phase 3B international, randomized, double-blind, placebo-controlled trial to assess CV safety in T2DM patient at increased risk for cadiovascular (CV) outcomes Includes 7,592 patients with prior CV disease and 1,748 patients with high risk but no prior CV disease Liraglutide + Standard Care vs. + Standard Care Follow-up of at least 3.5 years and up to 5 years Primary Endpoint: CV death, non-fatal MI or stroke

12 LEADER: Baseline Characteristics Clinical Features Previous CVD (n = 7,592) No previous CVD (n = 1,748) Body mass index, kg/m ± ± 6.3 Hypertension 6,888 (90.7) 1,520 (87.0) Hyperlipidemia 6,135 (80.8) 1,056 (60.4) Coronary artery disease 5,288 (69.7) 17 (1.0) Congestive heart failure 1,562 (20.6) 37 (2.1) Peripheral artery disease 1,394 (18.4) 250 (14.3) Diabetes duration, y 12.8 ± ± 7.5 HbA1c, % 8.7 ± ± 1.6 Marso SP et al. Am Heart J 2013;166: LEADER: Primary Outcome & CV Death Primary Endpoint (CV Death, MI or Stroke) Death from Cardiovascular Causes Marso SP et al. N Engl J Med 2016;375: LEADER: Heart Failure Hospitalization Marso SP et al. N Engl J Med 2016;375:

13 LEADER: Effect of Heart Failure at Baseline Marso SP et al. N Engl J Med 2016;375: SUSTAIN-6 Once Weekly GLP-1 agonist vs. Patients with type 2 diabetes at high cardiovascular risk received either once-weekly semaglutide, a glucagon-like peptide 1 analogue, or placebo. A Phase 3B international, randomized, double-blind, placebo-controlled trial to assess CV safety in T2DM patient at increased risk for cardiovascular (CV) outcomes Randomized 2,735 patients with prior CV or renal disease and 562 patients with high risk but no prior CV disease Semaglutide + Standard Care vs. + Standard Care Median observation time was 2.1 years Primary Endpoint: CV death, non-fatal MI or stroke SUSTAIN-6: Cardiovascular Outcomes Primary Endpoint Nonfatal Myocardial Infarction Nonfatal Stroke Death from CV Causes Marso SP et al. N Engl J Med 2016;375:

14 SUSTAIN-6: Secondary Outcomes Marso SP et al. N Engl J Med 2016;375: Functional Impact of GLP-1 in Heart Failure Treatment (FIGHT) A phase 2 randomized trial of liraglutide for high-risk HF patients with reduced ejection fraction Hypothesis: Sustained therapy with the GLP-1 agonist liraglutide initiated after HF hospitalization will be associated with greater clinical stability through 180 days based on a composite clinical endpoint (death, HF-Hospitalization, ΔNT-proBNP) Margulies KB et al. JAMA. 2016;316(5):500-8.

15 FIGHT: Study Population 300 adults with a prior clinical diagnosis of HF who were hospitalized for an acute heart failure syndrome (AHFS) LVEF 40% during preceding 3 months On evidence-based medication for HF Use of at least 40 mg of furosemide total daily (or equivalent) prior to admission for AHFS Both diabetics and non-diabetics were included (stratified to assure balanced Rx allocation) FIGHT: Baseline Features (n=300) Characteristic (N=146) Liraglutide (N=154) Age 60±2 60±13 Years since HF Diagnosis 7.8± ±6.8 HF Hospitalization in past year 86% 89% BMI 33±9 32±8 NYHA II/III 26%/68% 32%/61% NTproBNP 3,807±5,059 3,875±5,464 LVEF (%) 26±9 26±9 Hx of Diabetes 60% 59% There were no significant baseline differences between groups FIGHT: Baseline Features (n=300) Characteristic (N=146) Liraglutide (N=154) BMI 33±9 32±8 NYHA II/III 26%/68% 32%/61% NTproBNP 3,807±5,059 3,875±5,464 LVEF (%) 26±9 26±9 Beta-blocker Rx 95% 93% ACE-inhibitor or ARB Rx 72% 73% Hydralazine Rx 32% 33% Aldosterone Antagonist Rx 61% 58% There were no significant baseline differences between groups

16 Death or HF Re-Hospitalization Rate FIGHT: Death or HF Hospitalization Liraglutide vs. : Hazard Ratio 95% CI P-Value ( ) Days Post Randomization Liraglutide Margulies KB et al. JAMA. 2016;316(5): FIGHT: Other Endpoints All results based on changes from Baseline 180 days Margulies KB et al. JAMA. 2016;316(5): Death or HF Hospitalization Margulies KB et al. JAMA. 2016;316(5):500-8.

17 FIGHT: Summary and Conclusions The GLP-1 agonist liraglutide does not improve posthospitalization clinical stability in patients with relatively advanced HF and reduced LVEF Among diabetics with advanced HF, liraglutide was associated with a mild reduction in weight and improved blood glucose control Although not powered to assess safety, this study suggests possible harm when initiating GLP-1 agonists in advanced heart failure patients with diabetes, underscoring the need for studies of diabetes treatments in this population. Our findings do not apply to patients already treated with GLP-1 agonists because such patients were excluded from this trial. Conclusions: GLP-1 Agonists in HF Patients In evaluating both the efficacy and safety of treatments for T2DM in HF, the stage of HF is important In Stage A and B HF (no symptoms), the LEADER and SUSTAIN Studies suggests significant clinical benefit In Early Stage C patients (history of HF or mild symptoms), the LEADER, SUSTAIN and ELIXA studies suggest no CV benefit and no favorable impact on HF hospitalization In Later Stage C patients (with active symptoms and prior hospitalization for HF), introduction of the GLP-1 agonist liraglutide appears to increase the risk of HF hospitalization Acknowledgements Preclinical - UPenn Richard Shannon Michael Morley Jeff Brandimarto Thomas Cappola Clinical Trial - NHLBI HF Network Adrian Hernandez (Duke) G. Michael Felker (Duke) Kevin Anstrom, (Duke) Steve McNulty (Duke) Margaret Redfield (Mayo) Michael Givertz (Brigham) Eugene Braunwald (Brigham) Guilherme Oliveira (Case) Robert Cole (Emory) Douglas Mann (Wash U.) David J. Whellan (Jefferson) Michael S. Kiernan (Tufts) Monica R. Shah (NHLBI)

18 Stage A High risk with no symptoms Stage B Structural heart disease, no symptoms Stage C disease, prior or current symptoms Stage D Refractory symptoms CHF stages and steps of treatment VAD, TX, hospice Inotropes, nesiritide Mitral, CABG, surgery Short-term inotrope, nesiritide Adosterone antagonist CRT, ICD if applicable Sodium restriction, diuretics. Digoxin in systolic ACE inhibitors and beta-blockers in all patients ACE inhibitors,? ARB s, beta-blockers when appropriate Treat HTN, DM, CAD, dyslipidemia. ACEI when appropriate Risk factor reduction, patient and family education Jessup M, Brozena S. NEJM 2003;348:2007 Heart Failure Clinical Research Network Mayo Clinic Washington University School of Medicine in St. Louis University of Vermont Medical Center Cleveland Clinic Tufts Medical Center DCRI Coordinating Center Emory University Hospital Massachusetts General Hospital Brigham and Women s Hospital Thomas Jefferson University Hospital University of Pennsylvania Health System Duke University Medical Center Regional Clinical Centers Coordinating Center

19 Δ Weight (lbs) Δ Weight (lbs) Rationale for GLP-1 Therapy in Advanced Heart Failure: In advanced HF, the myocardium becomes insulinresistant, which limits glucose uptake and limits ATP production Glucagon-like peptide-1 (GLP-1) augments glucose uptake by increasing insulin secretion and insulin sensitivity In a pilot study of 12 patients with advanced HF and reduced EF, five weeks of therapy with continuous GLP-1 improved LVEF, exercise and quality of life compared with controls FIGHT: Weight Changes Liraglutide 6 4 Diabetics p=.0006 p=.002 p= Non-Diabetics NS NS NS Day 30 Day 90 Day Day 30 Day 90 Day 180 Data are changes from Baseline (mean±sem)

20 6/26/2017 The VuMedi Webinar Cardiovascular Disease, Diabetes and Renal Disease Influence of Sacubitril/Valsartan on Glycemic Control in Patients With Type 2 Diabetes and Heart Failure With Reduced Ejection Fraction Jelena P. Seferovic, MD, PhD Introduction Heart failure (HF) and diabetes mellitus (DM) frequently co-exist, and DM is an independent risk factor for HF progression In PARADIGM-HF 1 sacubitril/valsartan (angiotensin receptor-neprilysin inhibitor) improved morbidity and mortality in patients with HF with reduced ejection fraction (HFrEF) compared to enalapril (angiotensin converting enzyme (ACE) inhibitor) Another dual neprilysin ACE inhibitor, omapatrilat, improved insulin sensitivity in preclinical studies 2, and sacubitril/valsartan improved insulin sensitivity in obese hypertensive patients 3. 1 McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11): Wang CH, Leung N, Lapointe N, et al. Vasopeptidase inhibitor omapatrilat induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats: Studies comparing a vasopeptidase inhibitor, angiotensin-converting enzyme inhibitor, and angiotensinii type I receptor blocker. Circulation 2003; 107(14): Jordan J, Stinkens R, Jax T, et al. Improved Insulin Sensitivity with Angiotensin Receptor Neprilysin Inhibition in Individuals with Obesity and Hypertension. Clin Pharmacol Ther 2017 Feb;101(2): Hypothesis We hypothesized that sacubitril/valsartan has beneficial effect on glycemic control in DM patients with HFrEF 1

21 6/26/2017 Methods PARADIGM-HF randomized 8399 patients with HFrEF to enalapril 10mg bid or sacubitril/valsartan 200mg bid. We identified a subset of 3778 of the 8399 randomized patients who had a history of DM and/or screening HbA1c 6.5% Glycemic control was assessed using HbA1c and followed during the study (screening, 1-, 2-, 3-year) We assessed insulin therapy initiation during followup Triglycerides, HDL-cholesterol and body mass index changes were analyzed during the study Baseline characteristics of DM and non-dm patients at screening Characteristic All DM patients n=3778 Non DM patients n=4621 Age, years 64.1 ± ± Female sex, n (%) 808 (21.4) 1024 (22.2) 0.39 Race, n (%) <0.001 White 2533 (67.0) 3011 (65.2) Black 176 (4.7) 252 (5.5) Asian 740 (19.6) 769 (16.6) Other 329 (8.7) 589 (12.7) Previous DM history, n (%) 2896 (76.7) - Duration of DM, years 3.5 [0, 10.3] - Body mass index, kg/m ± ± 5.3 <0.001 Systolic BP, mmhg 129 ± ± Diastolic BP, mmhg 78 ± ± Glycated hemoglobin, % 7.4 ± ± 0.4 <0.001 Total cholesterol, mg/dl ± ± 42.5 <0.001 LDL cholesterol, mg/dl 92.8 ± ± 34.8 <0.001 HDL cholesterol, mg/dl 46.4 ± ± 15.5 <0.001 Triglycerides, mg/dl [94.8, 193.1] [85.9, 166.5] <0.001 Creatinine, mg/dl 1.13 ± ± 0.27 <0.001 egfr, ml/min/1.73m 2 67 ± ± 19 <0.001 Data are presented as means ± SD, median [25 75th percentile], or percentages; DM- diabetes mellitus, BP-blood pressure, HDL-high density lipoprotein, LDL-low density lipoprotein, egfr-estimated glomerular filtration rate P Significantly greater HbA1c decline in Sacubitril/Valsartan arm among DM patients Visit Enalapril n=1874 Sacubitril/Valsartan n=1904 Adjusted for screening values Difference (95% CI) p-value Screening 7.48 ± ± year 7.30 ± ± (-0.22,-0.05) year 7.31 ± ± (-0.28,-0.05) year 7.16 ± ± (-0.32, +0.01) 0.07 Overall* (-0.23,-0.06) Data are presented as means ± SD; *longitudinal model Number of patients with measurements of HbA1c at screening=3765, 1-year=3160, 2-year=2219, and 3-year=1040 2

22 6/26/2017 Reduced insulin initiation in DM patients randomized to Sacubitril/Valsartan Changes in triglycerides and HDL-cholesterol levels, and body mass index by treatment groups, over the course of four visits Visit Enalapril n=1874 Sacubitril/Valsartan n=1904 Adjusted for screening values Difference (95% CI) p-value Triglycerides, mg/dl Screening ± year ± ± (-1.2, 15.1) year ± ± (-24.1, -3.6) year ± ± (-19.1, 8.7) 0.46 Overall* -0.8 (-8.1, 6.5) 0.83 HDL-cholesterol, mg/dl Screening 44.7 ± ± year 44.4 ± ± (-0.5, 0.9) year 44.4 ± ± (0.3, 1.9) year 44.4 ± ± (0.9, 3.5) Overall* 0.7 (0.0, 1.3) Body mass index, kg/m 2 Screening ± ± year ± ± (0.13, 0.40) < year ± ± (0.12, 0.49) year ± ± (-0.02, 0.57) 0.06 Overall* 0.28 (0.14, 0.41) <0.001 Data are presented as means ± SD; *longitudinal model, CI-confidence interval Potential Mechanisms 3

23 6/26/2017 Limitations Sacubitril/valsartan did not reduce new onset DM No direct/indirect measures of insulin resistance Antihyperglycemic agents dosage not recorded Antihyperglycemic agents changed at will Active controlled study and post-hoc analysis Conclusions Sacubitril/valsartan treatment resulted in significantly greater HbA1c decline compared to enalapril in patients with DM and HFrEF. This beneficial metabolic effect is most likely due to neprilysin inhibition and modulation of its circulating substrates. These hypothesis-generating results suggest that patients with HF treated with sacubitril/valsartan may need adjustment of anti-hyperglycemic medication doses. These data may encourage additional research into the beneficial metabolic properties of this class of drugs. 4