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Current Updates & Challenges In Managing Diabetes in CVD Nor Azmi Kamaruddin Diabetes Clinic Department of Medicine National University of Malaysia (UKM) Kuala Lumpur Preventive Cardiovascular Conference 2016 Instituit Jantung Negara 1 2 th November 2016
Transcript of Current Updates & Challenges In Managing Diabetes …ijncollege.edu.my/PDF/DM CVD Update IJN...
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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