Preventing Serious Health Consequences of Type 2 Diabetes

Preventing Serious Health Consequences of Type 2 Diabetes The Evidence Hertzel C. Gerstein MD MSc FRCPC Professor and Population Health Institute Chair in Diabetes Research McMaster University and Hamilton Health Sciences Hamilton, Ontario, Canada

Disclosures for Hertzel C. Gerstein Relationships with Commerical Interests Grants/Research Support: Speakers Honoraria: Consulting Fees: Sanofi, Lilly, Astra Zeneca, Merck Sanofi, Lilly, Merck Novo Nordisk, AstraZeneca, Boehringer Ingelheim Sanofi, Lilly, AstraZeneca, Merck, Novo Nordisk, Abbott, Boehringer Ingelheim, Jannsen

Outline What are the serious health consequences of diabetes? What is their link to glucose? What does glucose lowering do? What do the glucose-lowering drugs do in addition to lowering glucose? Preventive effect of non-glycemic therapies

Serious Health Consequences of Diabetes Blindness Cataracts Kidney Failure Nerve Damage/Pain Foot pain, ulcers Leg/Foot Amputations PVD MI & Strokes Heart Failure NASH/Cirrhosis Cancers Cognitive Decline Depression Sleep Apnea Hip Fractures Imbalance & Frailty Joint Complaints Erectile Dysfunction Sexual Dysfunction Infertility Gut Problems

Diabetes & Death by Comorbidity 128,843 deaths (N=689,300 in 91 cohorts up to 2013; median F/U=12.8y) a sex-adjusted to age 60; mortality is per 1000 py Emerging HCG 2018 Risk Factors Collaboration. JAMA 2015; 52-60

Years Life Lost by Comorbidity 128,843 deaths (N=689,300 in 91 cohorts up to 2013; median F/U=12.8y) Years Lost by a 60y Old Man Woman Diabetes 5.7 6.7 Diabetes + MI or Stroke 12 13 ~60% of years lost are due to vascular causes Emerging Risk Factors Collaboration. JAMA 2015; 52-60

7 Diabetes & Risk of Heart Failure Hosp/Death 60 HF ref: adjusted HR 1.60 95% CI 1.44 1.77; p<0.0001 Diabetes (HF ref) Cumulative incidence (%) 40 20 HF pef: adjusted HR 2.0 95% CI 1.70 2.36; p<0.0001 Diabetes (HF pef) No diabetes (HF ref) No diabetes (HF pef) 0 0 0.5 1 1.5 2 2.5 3 3.5 Follow-up (years) MacDonald et al. Eur Heart J 2008;29:1377-85

Type 2 DM: A1c & the Hazard of Death Swedish Registry from 98: NEJM 2015;373:1720 Cases (N=435,369) vs. controls (5/case = 2,117,483) without diabetes Adjusted for sex, time-updated age, birth country, education, diabetes duration Mean follow-up = 5 y < 55 55 64 65 74 > 75 < 6.9% 7%-7.8% 7.9%-8.7% 8.8%-9.6% 9.7%+ < 6.9% 7%-7.8% 7.9%-8.7% 8.8%-9.6% 9.7%+ < 6.9% 7%-7.8% 7.9%-8.7% 8.8%-9.6% 9.7%+ < 6.9% 7%-7.8% 7.9%-8.7% 8.8%-9.6% 9.7%+ HR 0.5 1 2 4

Type 2 DM: Glucose Lowering Trials Study Duration (yrs) N Glycemia Target Achieved A1c UKPDS 10 3867 FPG < 6 (110) 7.0% vs. 7.9% ACCORD 3.5 10251 A1C < 6.0% 6.4% vs. 7.5% ADVANCE 5 11140 A1C < 6.5% 6.5% vs. 7.3% VADT 6.3 1791 A1C < 6.0% 6.9% vs. 8.4% UKPDS - Lancet 1998:837-853; ACCORD - NEJM 2011:818-828 ADVANCE - NEJM 2008:2560-72; VADT - NEJM 360;129-39 16

G Lowering & Eye/Kidney/Nerve Disease T2 DM RCTs, Single Patient Meta-analysis: Lancet D&E 2017;5:431

Meta-Analysis of Glucose Lowering Trials: CVD ACCORD ADVANCE UKPDS (@ 5y) VADT Turnbull et al. Diabetologia 2009;2288

SAVOR-TIMI 53 n = 16,492 3-P MACE EXAMINE n = 5,380 3-P MACE TECOS n = 14,671 4-P MACE CARMELINA n = 8,300 3-P MACE, renal composite Cefalu et al. Diabetes Care 2018;41:14 CAROLINA n = 6,115 3-P MACE 2013 2015 2016 2017 2018 2019 2020 EMPA-REG OUTCOME n = 7,020 3-P MACE ELIXA n = 6,068 4-P MACE SUSTAIN-6 n = 3,297 3-P MACE CANVAS n = 4,330 3-P MACE CANVAS-R n = 5,813 Progression of albuminuria EXSCEL n = 14,000 3-P MACE VERTIS CV n = 3,900 3-P MACE Dapa-HF n = 4,500 CV death, HF hospitalization, HF urgent visit REWIND n = 9,622 3-P MACE CREDENCE n = 4,200 ESRD, doubling of creatinine, renal/cv death DECLARE-TIMI 58 n = 17,150 3-P MACE, CVD Dapa-CKD n = 4,000 50% sustained decline in egfr or reaching ESRD or CV death or renal death EMPEROR- Reduced n = 2,850 CV death or HF hospitalization DPP-4 inhibitors SGLT2 inhibitors LEADER n = 9,340 3-P MACE FREEDOM-CVO n = 4,000 4-P MACE HARMONY n = 9,400 3-P MACE EMPEROR- Preserved n = 4,126 CV death or HF hospitalization GLP-1 receptor agonists Insulin TZD Acarbose DEVOTE n = 7,637 3-P MACE TOSCA.IT n = 3,371 4-P MACE ACE n = 6,526 5-P MACE (3-P MACE plus hospitalization for HF or unstable angina)

Glucose Lowering Drug Categories Sulfonylureas Metformin Acarbose Meglitinides Insulin TZDs DPP4 inhibitors GLP-1 receptor agonists SGLT-2 inhibitors Other drugs Colesevalam Bromocriptine Pramlintide not approved in Brazil ADA. Diabetes Care 2018; 41(Supp 1): S1-S153

Glargine Insulin: IFG, IGT, T2DM ORIGIN: NEJM 2012;367:319-328 HR (95% CI) P Insulin Standard N = 12,537; 59% with CVD; Mean A1c=6.4%; Mean age=64 /100 py /100 py 1 st Glargine-mediated Coprimary 1.02 (0.94, normoglycemia 1.11) 0.63 vs. no insulin 2.94 2.85 2 nd Coprimary 1.04 (0.97, 1.11) 0.27 Median F/U = 6.2 yrs; Control 1 st 5.52 5.28 primary event rate = 2.9%/yr Microvascular 0.97 (0.90, 1.05) 0.43 3.87 3.99 Death 0.98 (0.90, 1.08) 0.70 2.57 2.60 MI 1.02 (0.88, 1.19) 0.75 0.93 0.90 Stroke 1.03 (0.89, 1.21) 0.69 0.91 0.88 CV Death 1.00 (0.89, 1.13) 0.98 1.57 1.55 CHF Hospital 0.90 (0.77, 1.05) 0.16 0.85 0.95 Revascularized 1.06 (0.96, 1.16) 0.24 2.69 2.52 0.5 1 2 HR Favors Insulin Favors Standard HR

Effect of Glargine on Recurrent Heart Failure ORIGIN Circulation 2018;137:89

Insulin Glargine & Serious Health Outcomes ORIGIN NEJM 2012:319-328 HR (95% CI) P Insulin Standard /100 py /100 py Angina 0.95 (0.85, 1.05) 0.29 2.07 2.17 Unstable 0.91 (0.76, 1.08) 0.28 0.66 0.72 New angina 0.72 (0.56, 0.93) 0.01 0.27 0.38 Worsening 1.02 (0.89, 1.16) 0.80 1.29 1.26 Amputation 0.89 (0.60, 1.31) 0.55 0.13 0.14 CV Hosp 1.00 (0.95, 1.07) 0.90 6.98 6.91 Non-CV Hosp 0.99 (0.94, 1.05) 0.85 7.90 7.93 Any Cancer 1.00 (0.88, 1.13) 0.97 1.32 1.32 Cancer Death 0.94 (0.77, 1.15) 0.52 0.51 0.54 0.5 1 2 Favors Insulin Favors Standard HR

Degludec U100 vs. Glargine U100 : Ambulatory T2DM DEVOTE NEJM 2017 Online N = 7,637; 84% on insulin; Mean A1c=8.4%; Mean age = 65; Previous CV or Renal Disease = 86% Masked Degludec U100 vs. Masked Glargine U100 titrated to FG 4-5 (72-90) Median F/U =2.0 yrs; Glargine event rate = 4.7%/yr

Pioglitazone: No DM post Stroke/TIA IRIS study; NEJM 2016 N = 3876, no DM with stroke/tia in prior 6 mo & HOMA IR > 3 24% euglycemic (FPG<5.6 mm & HbA1c < 5.7%) Pioglitazone 45 mg/d or placebo Median F/U = 4.8 yrs; Placebo Event Rate ~ 2.5%/yr

GLP1RA CVOTs: Meta-Analysis Bethel et al. Lancet 2018; 6:105 3 Point MACE 3 Point MACE Mortality Mortality Bethel et al. Lancet Bethel D&E et al. 2017; Lancet Online D&E 2017; Online

GLP1RA CVOTs: Meta-Analysis Bethel et al. Lancet 2018; 6:105 CV Death CV Death MI MI Stroke Stroke Bethel HCG 2018 et al. Lancet Bethel D&E et al. 2017; Lancet Online D&E 2017; Online HR 0.5 1.0 2.0

GLP1RA CVOTs: Meta-Analysis Bethel et al. Lancet 2018; 6:105 Severe Hypo Severe Hypo Pancreatitis Pancreatitis Pancreas Cancer Pancreas Cancer Bethel et al. Lancet Bethel D&E et al. 2017; Lancet Online D&E 2017; Online HR

HARMONY Outcomes Trial Time to MACE Outcome Lancet 2018; Online Cumulative Incidence (%) 16 14 12 10 People at risk Placebo 4,732 Albiglutide 4,731 8 6 4 2 0 Placebo (428 events) Albiglutide (338 events) HR: 0.78 (95% CI 0.68, 0.90) P=0.0006 0 4 8 12 16 20 24 28 4,460 4,503 Time (months) N = 9463 with prior CVD; Median 1.6 y f/u Albiglutide 30-50 mg/wk vs. placebo 3,074 3,148 Event rate per 100 person-years Placebo 5.87 Albiglutide 4.57 1,030 1,064

GLP1RA Meta-analysis Renal/Eye Effects Avgerinos et al. Diabetes Obesity Metabolism 2018: Online

Ongoing GLP1RA Trials REWIND (Dulaglutide Wkly): MACE (NCT01394952*) N ~ 9901; DM with prior CVD (31%) or risk factors Began Aug 2011, est. completion 2018 (F/U~5 y) Dulaglutide 1.5 mg/wk vs. placebo PIONEER 6 (Oral Semaglutide - Daily): MACE N ~ 3000; DM age 50+ with CVD or age 60+ with > 1 RF Began Feb 2016, ext. completion Oct 2018 (F/U~1.5 y) Daily oral Semaglutide vs. placebo *Clinicaltrials.gov

Empagliflozin: T2DM & Prior CVD EMPA-REG Outcome; NEJM 2015; 373:2217 N = 7020 men & women with prior CVD Empagliflozin 10 mg/d, 25 mg/d or placebo Median F/U = 3.1 yrs; Placebo Event Rate = 4.4%/yr

EMPA-REG: Other Outcomes Mortality & HF - NEJM 2015;373:2217 CV Death HR 0.62 (95% CI 0.49, 0.77) p<0.0001 Heart Failure Hospitalization HR 0.65 (95% CI 0.50, 0.85) p=0.0017 All Cause Mortality HR 0.68 (95% CI 0.57, 0.82) p<0.0001

Canagliflozin: Ambulatory T2DM CANVAS NEJM 2017;377:644 N = 10,142; 66% with CVD; Mean A1c=8.2%; Mean age = 63 Canagliflozin 100 mg or 300 mg/d vs. placebo Median F/U =2.4 yrs; Placebo event rate = 3.2%/yr CV Death, Nonfatal MI Nonfatal Stroke

Canagliflozin: Ambulatory T2DM CANVAS NEJM 2017;377:644 Mortality Heart Failure Hospitalization

Canagliflozin: Ambulatory T2DM - Amputations CANVAS NEJM 2017;377:644 In other analyses, amputations were independent of other risk factors Could this be due to volume depletion

RCT- Proven Non-glycemic Protective Rx Eyes Eye exams; BP control; Fibrates? Kidneys BP control; RAS blockers Foot CVD Liver Inspection; Foot care Smoking cessation; LDL lowering; BP control; Beta Blockers; RAS blockers; ASA post MI; ASA+Rivaroxaban Weight loss, Bariatric Surgery

Summary Diabetes independently increases many serious consequences Glucose lowering clearly reduces eye & kidney disease with controversial effects on other consequences Glucose lowering drugs have important non-glycemic effects: Glargine, degludec, nateglinide, sitagliptin, alogliptin, saxagliptin, lixisenatide & acarbose safe, neutral effect on CVD Empagliflozin, canagliflozin, liraglutide, semaglutide & albiglutide reduce CVD & renal disease; exenatide may reduce death Pioglitazone reduces CVD in non-dm at risk for stroke Several nonglycemic therapies that work in people without diabetes also have protective effects in diabetes

Many Proven Ways to Reduce Outcomes in T2 DM We knew exactly how to reduce outcomes when we had no good data but now, after ~ 15 years of good clinical outcomes trials, we know how to reduce serious health outcomes in people with diabetes