Current Updates & Challenges In Managing Diabetes in CVD

Current Updates & Challenges In Managing Diabetes in CVD Preventive Cardiovascular Conference 2016 Instituit Jantung Negara 12 th November 2016 Nor Azmi Kamaruddin Diabetes Clinic Department of Medicine National University of Malaysia (UKM) Kuala Lumpur

National University of Malaysia Disclosure of Financial Relationships with Pharmaceutical Companies (Conflict of Interest Declaration) Nor Azmi Kamaruddin MBBS, MMed, DIS, AM, FACE Advisory Board Member: Astra-Zeneca (Hyperlipidemia) Astra-Zeneca (Diabetes) Bohringer-Ingelheim (Asian SGLT2 ) Bohringer-Ingelheim (M sian DPPIV & SGLT2 ) Eli Lily (Insulin) GSK (Insulin Resistance) Novartis (Renin Inhibition) Novo Nordisk (Insulin Therapy) Sanofi Aventis (Cardio-Metabolic Risks) Sanofi Aventis (Intercontinental Diseases Registry) Research Contracts & Grants (Principal Investigator): Abbott, Astra-Zeneca, Bohringer-Ingelheim, GSK, Johnson & Johnson, Merck, MSD, Novo Nordisk, Pfizer, Quintiles, Sanofi-Aventis Deliver Lectures For The Following: Abbott, Astra Zeneca, GSK, Novartis, Novo Nordisk, Pharmalink, Roche, Sanofi-Aventis

Controversies in DM & CVD 1. DM is a CVD Equivalent Disease? 2. Diagnosis of DM based on glycaemic levels that lead to microvascular complication (retinopathy) instead of CVD? 3. SU leads to significant risk of CVD? 4. Hyperinsulin state & risk of CVD? 5. Glycaemic control doesn t improve risk of CVD 6. Anti-Diabetic Agents have to be tested for CVD safety 7. Newer agents are more effective than old agents? Same goes with insulin? 8. Women with DM have poorer prognosis than men?

Outline of Presentation 1. Eleven pathologies involved in hyperglycaemia of T2DM 2. DM a CVD Equivalent Or CVD Defining Disease? 3. Latest CVD Outcome Trials A. GLIP1-RA (Elixa, Leader, Sustain-6) B. SGLT2i (Empa-Reg) 4. Treatment Recommendation for DM with CVD

Egregious Eleven

Type 2 Diabetes and CHD 7-Year Incidence of Fatal/Nonfatal MI (East West Study) 7-Year Incidence Rate of MI 50 40 30 20 10 0 P<0.001 P<0.001 45.0% 20.2% 18.8% 3.5% No DM, No MI No DM, MI DM, No MI DM, MI No Diabetes Diabetes CHD=coronary heart disease; MI=myocardial infarction; DM=diabetes mellitus Haffner SM et al. N Engl J Med. 1998;339:229-234.

Kaiser Permanente Northern California Healthcare Delivery System 2002-2011 J Gen Intern Med 31(4):387 93

CHD Free Survival Among Those With No Previous History, History of CHD, History of DM or Both from 2002-2011 J Gen Intern Med 31(4):387 93

CHD Event Rates Among Those With No Previous History, History of CHD, History of DM or Both from 2002-2011 J Gen Intern Med 31(4):387 93

Risk of CHD by duration of diabetes versus prior CHD J Gen Intern Med 31(4):387 93

Diabetes Mellitus Is A Cardiovascular Disease (CVD) Risk Equivalent For Peripheral Arterial Disease And Carotid Artery Stenosis (Peripheral Arterial Disease) J Am Coll Cardiol. 2016;67(13_S):2278-2278 (Carotid Art Dis)

DM & AMI Status and Hazard Ratios for CVD Events British Regional Heart Study > 60 yrs old < 60 yrs old

Newly Diagnosed And Known Type 2 Diabetes As Coronary Heart Disease Equivalent 5198 subjects 7.6 year follow-up From 2001-2008 Hadaegh et al. Cardiovascular Diabetology 2010, 9:84

0.9 0.7 1.1 1.5

Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease Hazard ratios for incident CVD by baseline levels of glycemia measures 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline 5.5 8.9 7.0 6.0 adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c and CVD risk Di Angelantonio E et al, The Emerging Risk Factors Collaboration, JAMA 311: 1225-1233, 2014

Diabetes Prevention Program (DPP) & 10-Year Follow UP Diabetes Care 2015 Jan; 38(1): 51-58.

ELIXA Trial design: Patients with type 2 diabetes and prior acute coronary syndrome were randomized to daily injection of lixisenatide vs. placebo. % (p for noninferiority < 0.05) 13.4 13.2 Results CV death, MI, stroke, or hospitalization for unstable angina: 13.4% of the lixisenatide group vs. 13.2% of the placebo group (p for non-inferiority < 0.05; p for superiority = NS) Lixisenatide Placebo Conclusions Among patients with type 2 diabetes and prior acute coronary syndrome, lixisenatide was noninferior to placebo While this agent failed to demonstrate superiority compared with placebo, cardiovascular safety for this agent was established

Issues with Leader Trial 1. The incidence of pancreatic cancers in liraglutide (13 in lira vs 5(+4) in placebo, p=0.06) 2. 16.5% (28 of 170) in the placebo arm who did not received any ADA at all ended up with CVD events 3. 16.1% (361 of 2244) in the placebo with A1c > 8.3% had CVD event. 4. With the overall CVD event rate in the placebo being 14.9% (694/4672) the above 2 issues could very well had driven the CVD event rate in the placebo arm.

Issues with Sustain-6 Trial 1. A1c difference of 0.7% for 0.5 mg & 1.0% for 1.0 mg semaglutide cf to placebo. 2. Drop out rate of semaglutide bet 11.5-14.5% 3. Diabetic retinopathy complications occurred in 50 patients (3.0%) in the semaglutide group and 29 (1.8%) in the placebo group (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02) The treatment difference between groups was first seen very early in the trial. The numbers of patients who required retinal photocoagulation were 38 (2.3%) in the semaglutide group versus 20 (1.2%) in the placebo group, the numbers of those who had a vitreous hemorrhage were 16 (1.0%) versus 7 (0.4%), and the numbers of those who had an onset of diabetes-related blindness were 5 (0.3%) versus 1 (0.1%).

Issues with Empa-Reg 1. No satisfactory explanation for early benefit in CV mortality 2. Individual empagliflozin arms did not reach statistical significance in outcomes compared to placebo 3. Planned as a non-inferiority study 4. Exclusion of silent AMI from the composite endpoints. Trend of increased silent AMI with Empa. 5. Trend in increasing strokes with increased haematocrit 6. Heterogeneity in sub-groups analysis. Statistically significant reductions in the primary outcome were found only in certain subgroups, e.g., Age 65, A1C <8.5%, Asian race, BMI <30. 7. Less than 30% and 10% of subjects remained in the study after 3 years and 4 years respectively.

Issues with Empa-Reg 8. Many deaths (n=124) were categorized as nonassessable and adjudicated as presumed CV deaths (71 versus 53 for empagliflozin versus placebo). Deaths that were non-assessable but presumed to be CV-deaths comprised 40% of CV deaths, and 27% of overall deaths in the trial. In a sensitivity analysis that removes all nonassessable deaths from the primary endpoint, empagliflozin was no longer demonstrated to be superior to placebo (HR 0.90, 95% CI 0.77, 1.06).

Answers the question: What would you give yourself if you were a patient? Recommendations based on 5 priorities; 1. Safety 2. Convenience to aid compliance 3. CVD Global Risk Reduction (eg obesity) 4. Glycaemic Efficacy 5. Cost

Treatment Recommendation DM + CVD No AMI No CCF Low Risk* High Risk* Age > 65 years AMI CCF Modify dose of diuretic if on SGLT2i Obese CKD Stage 4 & 5 BMI > 27.5kg/m 2 GFR < 45 ml/min/1.73m 3 Normal Kidney Function CCF GFR 45-60 units Metformin SGLT2i (Empaglifozin) SGLT2i (Empaglifozin) SGLT2i (Empaglifozin) DPPIVi SGLT2i (Empaglifozin) GLIP1-RA (Liraglutide, Semaglutide) GLIP1-RA GLIP1-RA Gliclazide GLIP1-RA (Liraglutide, Semaglutide) Metformin Metformin Metformin Bolus Insulin DPPIVi / Gliclazide DPPIVi / Gliclazide Gliclazide / DPPIVi DPPIVi / Gliclazide Basal Bolus Insulin Basal Insulin Basal Insulin Basal Insulin Basal Insulin Basal Bolus Basal Bolus Basal Bolus Basal Bolus Insulin Insulin Insulin Insulin * Having any of the following combination of risk factors Patient assessed as unlikely to comply to insulin

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