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Current Updates & Challenges InManaging Diabetes in CVD

Nor Azmi KamaruddinDiabetes Clinic

Department of MedicineNational University of Malaysia (UKM)

Kuala Lumpur

Preventive Cardiovascular Conference 2016Instituit Jantung Negara

12th November 2016

Disclosure of Financial Relationships with Pharmaceutical Companies(Conflict of Interest Declaration)

Nor Azmi Kamaruddin MBBS, MMed, DIS, AM, FACE

Research Contracts & Grants (Principal Investigator):Abbott, Astra-Zeneca, Bohringer-Ingelheim , GSK, Johnson & Johnson, Merck, MSD, Novo Nordisk, Pfizer , Quintiles, Sanofi-Aventis

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)

Deliver Lectures For The Following:Abbott, Astra Zeneca, GSK, Novartis, Novo Nordisk, Pharmalink, Roche, Sanofi-Aventis

National University of Malaysia

Controversies in DM & CVD1. 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 CVD6. Anti-Diabetic Agents have to be tested for CVD

safety7. Newer agents are more effective than old

agents? Same goes with insulin ?8. Women with DM have poorer prognosis than

men ?

Outline of Presentation1. Eleven pathologies involved in

hyperglycaemia of T2DM2. 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)

0

10

20

30

40

50

No DM, No MI No DM, MI DM, No MI DM, MI

No Diabetes Diabetes

3.5%

18.8%20.2%

45.0%P<0.001 P<0.001

7-Ye

ar In

cide

nce

Rat

e of

MI

CHD=coronary heart disease; MI=myocardial infarction; DM=diabetes mellitusHaffner SM et al. N Engl J Med. 1998;339:229-234.

J Gen Intern Med 31(4):387–93

2002-2011

Kaiser Permanente Northern CaliforniaHealthcare Delivery System

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

J Am Coll Cardiol. 2016;67(13_S):2278-2278

(Peripheral Arterial Disease) (Carotid Art Dis)

British Regional Heart Study

DM & AMI Status and Hazard Ratios for CVD Events

> 60 yrs old < 60 yrs old

Hadaegh et al. Cardiovascular Diabetology 2010, 9:84

Newly Diagnosed And Known Type 2 Diabetes As Coronary Heart Disease Equivalent

5198 subjects7.6 year follow-upFrom 2001-2008

Hadaegh et al. Cardiovascular Diabetology 2010, 9:84

Newly Diagnosed And Known Type 2 Diabetes As Coronary Heart Disease Equivalent

5198 subjects7.6 year follow-upFrom 2001-2008

Hadaegh et al. Cardiovascular Diabetology 2010, 9:84

5198 subjects7.6 year follow-upFrom 2001-2008

Newly Diagnosed And Known Type 2 Diabetes As Coronary Heart Disease Equivalent

0.9 0.7 1.1 1.5

Di Angelantonio E et al, The Emerging Risk Factors Collaboration, JAMA 311: 1225-1233, 2014

Glycated Hemoglobin Measurement and Prediction of Cardiovascular DiseaseHazard 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

adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c and CVD risk

5.56.0 7.0 8.9

Diabetes Care 2015 Jan; 38(1): 51-58.

Dia

bete

s P

reve

ntio

n P

rogr

am (D

PP

) & 1

0-Ye

ar F

ollo

w U

P

ELIXA

• 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)

Trial design: Patients with type 2 diabetes and prior acute coronary syndrome were randomized to daily injection of lixisenatide vs. placebo.

Results

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

Lixisenatide Placebo

%

(p for non-inferiority < 0.05)

13.4 13.2

Issues with Leader Trial1. 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 semaglutidecf 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-Reg1. No satisfactory explanation for early benefit in CV

mortality2. Individual empagliflozin arms did not reach statistical

significance in outcomes compared to placebo3. 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 haematocrit6. 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-Reg8. Many deaths (n=124) were categorized as “non-

assessable” 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 “non-assessable” deaths from the primary endpoint, empagliflozin was no longer demonstrated to be superior to placebo (HR 0.90, 95% CI 0.77, 1.06).

Recommendations based on 5 priorities;

1. Safety2. Convenience to aid compliance3. CVD Global Risk Reduction (eg obesity)4. Glycaemic Efficacy5. Cost

Answers the question: What would you give yourself if you were a patient?

DM + CVD

High Risk*Age > 65 years

AMI

CCF

GFR 45-60 units

GLIP1-RA(Liraglutide, Semaglutide)

Treatment Recommendation

* Having any of the following combination of risk factors

Low Risk*No AMI

No CCF

Normal Kidney Function

Metformin

SGLT2i (Empaglifozin)

DPPIVi / Gliclazide

Basal Insulin

Basal Bolus

Insulin

Metformin

SGLT2i (Empaglifozin)

GLIP1-RA(Liraglutide, Semaglutide)

DPPIVi / Gliclazide

Basal Insulin

Basal Bolus

Insulin

Metformin

SGLT2i (Empaglifozin)

GLIP1-RA

Gliclazide / DPPIVi

Basal Insulin

Basal Bolus

Insulin

Metformin

SGLT2i (Empaglifozin)

GLIP1-RA

DPPIVi / Gliclazide

Basal Insulin

Basal Bolus

Insulin

DPPIVi

Gliclazide

Basal Bolus

Insulin

Patient assessed as unlikely to comply to insulin

Bolus Insulin

CCFModify dose of diuretic if on SGLT2i

ObeseBMI > 27.5kg/m2

CKD Stage 4 & 5GFR < 45 ml/min/1.73m3

Remember what can happen

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