Management of CAD in Diabetes the cardiovascular equivalent is challenging.The slides take you from the epidemiology,ADD,and CV benefit and how to manage CAD

2.  Leading cause of death in both type1 and type2 diabetes mellitus.
 CV disease equivalent ( mortality in diabetics same as those with
previous MI).
 The risk increases with duration of diabetes.
 Overall worse prognosis.
 2ᵒ prevention of CV events is not synonymous with cardio protection
in diabetes.
 Efficacy of cardio protection of anti-diabetic drugs is essential. (CVOT
trials needed for FDA approval).
Benjamin EJ, Blaha MJ, Chiuve SE, et al. Circulation 2017;135:e146-603.
Saydah SH, Eberhardt MS, Loria CM, Brancati FL. Am J Epidemiol 2002;156:714-9.
Schramm TK,Gislason GH,Kober L,et al. Circulation 2008;117:195-54.
Berry C,Tardif JC,Bourassa MG. JACC 2007;49:643-56.
GoAS,Mozaffarian D, Roger VL, et al. Circulation 2014;129:e28-292.
Donahoe SM, Stewart GC,Mc Cabe CH,et al. JAMA 2007;298:765-75
Cardiovascular Disease (CVD) in Diabetes

4. Management of CAD in diabetes
Issues
 1.Lifestyle and diet – how different are they ?
 2.How intensive the glucose levels to be controlled?
 3.Statins and risk of diabetes – are they safe ?
 4.How cardioprotective are the antidiabetics?
 5.Risk of stent thrombosis?
 6.Which to prefer CABG or PCI in multivessel disease ?

5. Glycemic control –How aggressive ?
Trial Evidence
Trial Name No. of
patients
Standard
Arm HBA1C
Intensive
Arm HBA1C
Events
ACCORD >10,000 Target of
7-8%
Median 7.5%
Target of
<6%
Median 6.4%
22% increase in mortality in intensive
strategy.
ADVANCE 11,140 7.0% 6.3% Reduction in composite outcome of both
micro and macro complications by 10%
(major was reduction in nephropathy)
No observed reduction when considered for
macrovascular complications separately.
VADT 1791 7.5% < 6.0% No significant difference over a 5.6 year
followup period on outcome of MI,
stroke,CV death,revascularization.
1).ACCORD - Action to Control Cardiovascular Risk in Diabetes,NEJM 2008;358:2560-72.
2).ADVANCE- Action in Diabetes and Vascular Disease :A Preterax and Diamicron Modified Release Controlled Evaluation.
NEJM 2008;358:2560-72. 3).VADT Veterans Affairs Diabetes Trial. NEJM 2009;360:129-39.

6. Hypoglycemia effect
 Independent risk of mortality.
 5-17% in ICCU.
 Decreases myocardial blood
flow reserve and increases
infarct size.
 No additional benefit from
lowering blood glucose levels
below range of 140-180 mg/dl
 Insulin infusion therapy to aim
blood glucose levels in the
same range.
Unrecognized hypogyclemic
episodes
Cardiac ischemia,fatal arrhythmia
Increased thrombogenesis
vasoconstriction
Sympatho adrenal activation
Abnormal cardiac repolarization

7. • Reasonable to attempt to reduce
microvascular complications
• Patients with Low risk of
hypoglycemia,short duration of
diabetes,long life expectancy,and
no significant CVD.
Lower
HBA1c
• Risks outweigh the benefits.
• Long duration of diabetes, history
of severe hypoglycemia, advanced
atherosclerosis, and advanced
age/fraility.
HBA1c
7.5-8%

8. Newer Antidiabetic drugs

9. Antidiabetic Drug Safety
 Most oral diabetic medications reduce HbA1c levels by a similar
amount,by approx. 1 absolute percentage point.
 Are all Cardioprotective ? NO
 It is disappointing, that neither intensive glycemic control nor the
use of specific diabetes medications is associated with any
suggestion of cardiovascular benefit.
 HbA1c – not a valid surrogate for assessing either the CV risks or
benefits of diabetes therapy..
 2008 – pre and post approval for all new antidiabetic drugs to rule
out excess CV risk. (CVOT trials)
Bennett WL,Maruthur NM et al.Ann Intern Med 2011;154:602-13
Hiatt WR,Kaul S et al.NEJM 2013;369:1285-7.

10. Therapuetic Classes Effect on CVD risk factors Other Direct and Indirect Effects
on Heart
Biguanides (Metformin) ↓ in macrovascular end points
Improved Lipid profile
-
Sulfonylureas Weight gain Hypoglycemia
Impaired Ischemic preconditioning
Prandial glucose regulators
(Meglinitides)
Weight gain Hypoglycemia
Thiazolidinediones/
Glitazones
Increased LDL levels
Reduced restenosis after
coronary stenting
Heart failure
Excess ischemic CV risk with
rosiglitazone
Alpha glucosidase inhibitors Reduce inflammatory markers
Possible ↓ in risk of CV event
-
DPP4 inhibitors(Gliptins) - Heart failure
Amylin analogues Weight loss
Incretin mimetics Weight loss
Insulin Weight gain Hypoglycemia

12. The other effects of Anti Diabetic Drugs

13. Completed and ongoing CVOTs
William T. Cefalu et al. Dia Care 2018;41:14-31

14. SGLT2 inhibitors
Superficial genital infections
UTI
Amputation and bone
fractures
FDA warning
Osmotic Diuresis
Decreases weight
Left ventricular afterload
Modulates cardiorenal axis
Reduces progression of
renal disease
CV
benefits
Adverse
effects

15. Lancet Diabetes Endocrinol 2017;15:709-717
Parameter Hazard Ratio P value
CV mortality due to heart
failure
0.53 <0.0001
Major adverse CV events 0.78 <0.0001
Hospitalization due to HF 0.70 <0.0001
Severe hypoglycemia 0.75 0.001
Reduction of CV endpoints and risk of hypoglycemia
among patients receiving SGLT2 inhibitors vs other glucose
lowering drugs

16. EMPA –REG OUTCOME trial
Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes
Mellitus Patients
 CV effects of 10 or 25 mg of empagliflozin added to standard
therapy
 Diabetic patients with known CVD
 Beneficial CV effects – hemodynamic rather than anti
atherosclerotic mechanism of action (much earlier than other
drugs).
N Engl J Med 2015; 373:2117-2128

17. N Engl J Med 2015; 373:2117-2128
Outcome Placebo
N = 2333
Empagliflozin
N= 4687
HR
95% CI
P value
% Rate/1000
patient years
% Rate /1000
patient years
Death from CV
cause,non fatal
MI,non fatal
stroke
12.1 43.9 10.5 37.4 0.86 0.04
superiority
Death from any
cause
8.3 28.6 5.7 19.4 0.68
(0.57-0.82)
<0.001
Death from CV
cause
5.9 20.2 3.8 12.4 0.62 <0.001
Hospitalization 4.1 14.5 2.7 9.4 0.65
(0.50 -0.85)
0.002
Non fatal stroke 2.6 9.1 3.2 11.2 1.24
(0.92 -1.67)
0.16

18. CANVAS trial
CANAGliflozin cardioVascular Assessment Study
 Reduction in HF hospitalizations
 Superior to placebo in reducing the primary combined outcome
of CV death, MI and stroke but did not improve individually.
N Engl J Med 2017; 377:644-657

19. FDA APPROVAL FOR
CV RISK REDUCTION
OCTOBER 2018

20. Canagliflozin
Canagliflozin

21.  No hypolgycemia or weight gain
 EXAMINE - Algogliptin
 SAVOR TIMI 53 – Saxagliptin
 TECOS - Sitagliptin
All three drugs were not found to increase adverse CV events, CV
mortality, or all cause mortality
Neither was there a signal of CV benefit.
DPP4 INHIBITORS
EXAMINE ;N Engl J Med 2013; 369:1327-1335.SAVOR TIMI 53 ; N Engl J Med 2013; 369:1317-1326.TECOS ; N Engl J Med 2015; 373:232-242

22. GLP1 agonists
 Injectable drugs
 Activate the GLP1 receptor
 Inhibit glucagon secretion
 Delay gastric emptying
 CV benefit – not a class effect
CV event
reduction
LEADER
Liraglutide
SUSTAIN 6
Semaglutide
Borderline
EXSCEL
Exenatide
No benefit
ELIXA
Lixisenatide

23. Statins and Diabetics
 Mechanism is not known.
 CARDS trial (Atorvastatin) – highest CV events
 The risk of DM is approximately 1 excess case per 1000 individuals
treated with a moderate intensity statin for one year and
approximately 3 excess cases per 1000 individuals treated with a
high intensity statin for 1 year.
 Those who develop diabetes should continue statin therapy to
reduce the risk of CVD events.
Coulhon et al.Primary prevention of CVD with Atorvastatin in type 2 diabetes.Lancet 2004;365:685-96.
Stone NJ, Robinson J, Lichtenstein AH, et al. Circulation 2013.
http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.short

25. Stent thrombosis (ST)
 Multifactorial
 Delayed healing and impaired endothelialization – a common
feature of pathology in ST gets aggravated in diabetes, particularly
insulin dependent diabetes.
 ACUITY trial – IDDM is a significant independent predictor of
definite or probable ST occuring within 30 days.
 TRITON TIMI – 2:1 risk of stent thrombosis.
 HORIZONS AMI trial – risk of acute,subacute,late very late ST.
ACUITY trial. Aoki et al. Circulation 2009;119:687-98.
TRITON TIMI trial.Wiviott D et al. Circulation 2008;118:1626-36.
HORIZONS AMI trial.Dangas GD et al.Circulation 2011;123:1745-56.

26. CABG vs PCI
 CABG > PCI – Incomplete revasculariation,progression of
diffuse disease formation of new lesions in PCI patients.
 In BARI trial – CABG group 3 grafts vs PCI group 2 stents.
 Bilateral Internal thoracic grafts – increased sternal wound
complications.
 Radial artery grafts are very prone to spasm in diabetics.
 Radial grafts have less patency than SVG grafts in diabetics.
Choudhary BP, Antoniades C, Brading AF, et al. Diabetes mellitus as a predictor for radial artery vasoreactivity in patients undergoing coronary
artery bypass grafting. J Am Coll Cardiol 2007;50: 1047–53

27. Take home message
 Diabetes is Cardiovascular Disease Equivalent.
 Aggressive sugar control is not advised in patients with CAD,due to
the deleterious effects.
 Statins to be recommended in the usual doses, though the risk of
diabetes is of remote possibility.
 SGLT2 inhibitors have cardiovascular risk reduction benefit among
the newer antidiabetic drugs.
 Complete revascularization to be opted in a patient with diabetes
and Multivessel disease.

28. Thank you