cardio vascular risk reduction in diabetes mellitus

Cardio vascular risk reduction in Diabetes mellitus

Dr S.VenkatesanCardiologist Madras medical collegeChennai TAN-CSI Thiruvanandhapuram10-9- 2017

www.drsvenkatesan.com

•DM pathology in CVD•Risk quantification•Risk reduction •Conventional DM management •CVOT focussed strategies•What we have achieved ?•Introspection & Future


CAD pathology In Diabetes


Higher HbA1c predicts higher CV risk

Meta-analysis: Increase of 1% of HbA1C is concomitant with-

17% increase in CVD 15% increase in CHD

29% increase in PAD 11% increase in Stroke

Zhang Y et al. 2012. PLoS ONE 7(8): e42551

Stroke


Macro

Micro RetinalNephroNeuro

CardiacCerebralPeripheral


Brownlee’s Unifying hypothesis


Type 1

DM

Type 2

DM

Blurring margins between two types


Diffuse macro vascular disease


Diabetes and heart failure

Is it macro or macro vascular complication ?

Microalbuminuria is strongly correlated with diabetic risk of cardiac failure


How risky is DM in CVD ?


2013 ACC/AHA down graded it as Just another risk factor in 2013

Some controversies risk assessment

DM is CHD equivalent IN 2001 by ATP 3 (Alarmist reaction meant 100% )


Risk reduction how good it is ?


Impact of Intensive vs Conventional Glycemic-Lowering Strategies on Risk of CV Outcomes Is Unclear

StudyDiabetes Duration (mean)

Antihyperglycemic Medicationa

Follow-up(median)

HbA1c: Baseline, Between-arm

Difference

Microvascular

CVDMortalit

y

UKPDS1

Newly diagnosed

SU/insulin or metformina vs dietary

restriction

10 years7.1% (all

patients)b, –0.9%c

↓ ↔ ↔UKPDSLong-term

follow-up2

10 years post

intervention

No difference in HbA1c between

treatment armsd↓ ↓ ↓

ADVANCE3 8 years

Intensive glucose control including gliclazide vs standard treatment

5 years7.5% (both

arms)b, –0.8%d

↓ ↔ ↔ACCORD4,

5 10 yearsMultiple drugs in both

arms3.4 years

8.1% (both arms)e, –1.1%c

↓ ↔ ↑

VADT6 11.5 yearsMultiple drugs in both

arms5.6 years

9.4% (both arms)b, –1.5%d

↔ ↔ ↔

aObese patients; bMean baseline HbA1c; cMedian between-arm difference; dMean between-arm difference; eMedian baseline HbA1c.

CV = cardiovascular; UKPDS = United Kingdom Prospective Diabetes Study (UKPDS); ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ACCORD = Action to Control Cardiovascular Risk in Diabetes; VADT = Veterans Affairs Diabetes Trial.

1. UKPDS Group. Lancet. 1998;352:837–853. 2. Holman RR et al. N Engl J Med. 2008;359:1577–1589. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4. Gerstein HC et al. N Engl J Med. 2008;358:2545–2559. 5. Ismail-Beigi F et al. Lancet. 2010;376:419–430. 6. Duckworth W et al. N Engl J Med. 2009;360:129–139.

Lowering HbA1c may prevent macrovascular disease if started early, but the effects may not be apparent for a very long time


Conventional drugs : Big let down ? :

Except Metformin, ? GlimiperideGlitazone was good but risky ?


• Difficult • Incomplete • Not uniform • Prone with risk

Challenges in Diabetic CVD risk reduction


Search for new strategies . . .


Back to basics


We realised its essentially Islet cell mismatch between Alpha and beta and a literal fight between Insulin and the counter hormone Glucagon


DPP-4 inhibitorsSitagliptin, Saxagliptin,Alogliptin, linagliptin

EXAMINE [Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care] trial),2 saxagliptin (in the SAVOR-TIMI 53 [SaxagliptinAssessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53] trial),3 and sitagliptin (in TECOS [Trial Evaluating Cardiovascular Outcomes


http://www.nejm.org/doi/full/10.1056/NEJMe1607413

http://www.nejm.org/doi/full/10.1056/NEJMe1607413

Vildagliptin does not have an ongoing CV outcomes trial

Linagliptin CARMELINA (N=8,300)4

Pre-existing CVD + albuminuria or impaired renal function

Risk Factors Stable CAD-CVD-PAD Post ACS patients

Sitagliptin TECOS (N=~14,000)3

Pre-existing CVD

Alogliptin EXAMINE (N=5,380)1

ACS within 15–90 days

Saxagliptin SAVOR-TIMI (N=16,492)2

Pre-existing CVD or multiple risk factors for CVD

CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; CAD = coronary artery disease; CVD = cardiovascular disease; PAD = peripheral artery disease; ACS = acute coronary syndrome; ACS = acute coronary syndrome; EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk.

1. White W et al. N Engl J Med. 2013;369:1327–1335. 2. Scirica BM et al. N Engl J Med. 2013;369:1317–1326. 3. Green JB et al. Am Heart J 2013;166:983–989.e7. 4. CARMELINA: Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov web site. http://clinicaltrials.gov/ct2/show/ NCT01703298. Accessed September 12, 2014.

Baseline Risk of Patient Populations Enrolled in CV Outcome Trials of DPP-4 Inhibitors


DPPI summary

Powerful Insulin sensitising action

Good anti hyperglycemic effect

Still, not good enough to for meaningfullCVD protection


LEADERS study www.drsvenkatesan.com

GLP

Lir


Moving away from pancreas . . .


SGLT2 are not new molecules !


EMPA-REG Outcome CANVASDECLARE

CVOT trials on SGL2 Inhibitors


EmpagliflozinType 2 diabetes

57 % DM > 10 years

99 % Had CAD

Reduced the composite outcome of MI, stroke, and cardiovascular death by 14% cardiovascular death by 38%

FDA recently added a new indication for empagliflozin, to reduce the risk of cardiovascular death in adults with type 2 diabetes and cardiovascular disease.


Ketogenic drug www.drsvenkatesan.com

Troublesome in few www.drsvenkatesan.com

DM practice changing break through ?


Insulin & CVOT

Has no direct mortality benefit

Still ,will remain the key

For rapid control

In difficult profiled patients


Future of Empaglifloxin

Usefulness in Heart failure will tested –EMPEROR Study


DM management in specific situations

Hypertension Obesity DyslipidemiaPregnancy ACS


LDL

BP

HBA1C

Statin

Aspirin

ACEI/ARB

Multiple targets


How to treat hypertension in DM ?

ACCORD, ADVANCE, SPRINT, AND HOT

Less than 140 mm hg is suffice

Beta blockers : Still safe in documented CAD !


Caution with aggressive management

ICU setting

ACS

Hyperglycemia is stress induced Physiological response


NICE-SUGARNormoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation

6104 patients ; 1/3 (surgical) and 2/3( medical) Only 20% had known diabetes

Intensive-Rx Group

Conventional Group

Subjects received IV insulin

97% 69%

Mean BG achieved 115 mg/dL. 144 mg/dL.

Mortality rate at 90 days

27.5% 14% higher mortality rate OR

1.14 (85% CI, 0.4 to 4.8)

24.9%

Severe hypoglycemia 6.8% 0.5%

(P<0.001) (BG ≤40 mg/dL) www.drsvenkatesan.com

Concluding analysis Introspection !


Diabetes is not simple elevated blood sugar ,Rather hyperglycemiais one of the markers of diabetes


Diabetes is not simply excess sugar in the body


Are we fighting a wrong target ?

Why we struggle to arrest progressive vascular disease ?

Why risk reduction is not absolute ?


Regulatory bodies & knowledge(Data ?) creators


Watch for safety warnings


Current CVOT landscape

Aleglitazar, a dual agonist of peroxisome proliferator–activated receptors was the first OAD which failed to qualify

Approximately 150,000 are being or have been followed in CVOTs

Mannucci E. et al. Diabetes Care. 2016 Aug;39 Suppl 2:S196-204


Luckily ,common sense rediscovered as breaking news science !

INTERHEART study reveals Activity and diet can reduce risk of CVD and DM tremendously

Drugs vs Diet & Excercise


Benefits for 10 % weight loss


Diabetes is a metabolic disease . . .


A diabetic diet simply means eating the healthiest foods in moderate amounts and sticking to regular mealtimes.

Non weight gaining or preferably weight loosing diet .

Fat vs cardbohydrate controversy not likely to end !(PURE study 2017)


Key messages

DM increases CVD risk many fold

Controlling DM do bring CVD risk down, but never to the basal levels.

Old generation OHA Metforminremains corner stone

New generation drugs are promising.But, caution is required www.drsvenkatesan.com

Patient

Cardiologist

Physician

Diabetologist

Industry

Who shall take care ?


Thank you www.drsvenkatesan.com

cardio vascular risk reduction in diabetes mellitus

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