Management of coronary disease in diabetes - Is it different?

Management of CAD in DM patients with CKD – Is it different?

Dr Vivek BaligaConsultant, Internal Medicine

Introduction

• Both diabetes and CKD are very important CV risk factors and also considered “CAD equivalents”

• To reduce CV risk in DM + CKD patients, multiple risk factors (BP, glucose, lipids, eGFR) has to be controlled simultaneously

• Here we discuss management of CAD in DM + CKD patients

Diabetic Nephropathy

• Diabetes is the commonest cause of CKD (chronic kidney disease)

• Up to 44% of the patients with ESRD who require dialysis are diabetics

• 40% patients with diagnosed or undiagnosed diabetes had some degree of CKD

• Individuals with diabetic nephropathy have an increased risk of all-cause mortality, cardiovascular mortality and kidney failure

• Presence of nephropathy increases the cost of DM management by 3 times

World J Diabetes 2013 December 15; 4(6): 245-255, Mayo Clin Proc. 2011;86(5):444-456ESRD: End Stage Renal Disease

Presence of DM and CKD both further increase CV risk

Data from 1,268,029 participants in the Alberta Kidney Disease cohort. CKD refers to eGFR 15-59.9 ml/min

Kidney International Supplements (2013) 3, 271–279

5

What are Diabetics with Nephropathy Dying From?

Stroke MyocardialInfarction

HeartFailure

SuddenDeath

Natural History in Type 2 DM• GFR decline once proteinuria present 10-12

ml/min/year (if untreated)• Patients often die of other causes (CVS disease)

before ESRD– Other causes of nephropathy may exist such as HTN– Slower progression compared to type 1 DM

• CVS risk rises 2-3 times with microalbuminuria, 9-10 times with clinical proteinuria

• Higher rates of ESRD in T1DM than T2DM

Stage of hyper- filtration

Microalbumi- nuria

Macroalbumi- nuria

Azotemia (Renal failure)

End stage Renal disease

Normoalbumi-nuria

NATURAL HISTORY OF NEPHROPATHY IN T1DM

15 - 20 yrs 1 yrs 4 - 5 yrs

• Hyperglycaemia Early histological lesions reversible

with normoglycaemia• Hypertension

Predicts microalbuminuria proteinuria paralleled by gradual rise in BP Correlation between BP and rate of of GFR

• Proteinuria Induces tubulointerstitial damage/ contributes to progression Highly selective in early disease

Pathogenesis of DN

Five Stages of diabetic nephropathy

Stage Clinical features /Pathology Lab Findings

Stage 1 Early hyperfunction and hypertrophy (↑GFR)

ACR < 30 mg/g creatinine

Stage 2 Morphologic lesionswithout signs of clinical disease

Stage 3 Microalbuminuria ACR > 30 and < 300 mg/g creatinine

Stage 4 Overt nephropathy (hypertension is common)

ACR > 300 mg/g creatinine and/or persistent proteinuria with serum creatinine > 2.0 mg/dL

Stage 5 End-stage renal diseasewith uremia

On dialysis

GFR: Glomerular Filtration Rate, ACR: Albumin Creatinine RatioWorld J Diabetes 2013 December 15; 4(6): 245-255

CKD stages as per eGFR

Proteinuria Predicts Stroke & CHD Events in T2DM

P<0.00140

30

20

10

0Stroke CHD

Events80604020

0

0.5

0.6

0.7

0.8

0.9

1

Surv

ival

Cur

ves

For

CV

Mor

talit

y

Overall: P<0.001C

BA

Inci

denc

e(%

)Months

Miettinen H et al. Stroke. 1996;27:2033-2039.

B: U-Prot 150–300 mg/LA: U-Prot <150 mg/L C: U-Prot >300 mg/L

0

U-Prot = Urinary protein concentration. CHD: Coronary heart Disease

100

Management of CAD in DM Nephropathy

• BP Control• Glycemic control• Lipid Control• Revascularisation

BP control in DM + CKD patients

• RAAS blockers (ACEI and ARBs) are most recommended antihypertensive drugs for DM + CKD patients

• These drugs not only control progression of CKD, but reduce cardiovascular risk also.

• These CV and renal benefits are partially independent of BP control

• Target BP levels are generally lower in patients with heavy proteinuria

N Engl J Med 2012; 367:2204-2213

No benefit of Aliskiren in those DM patients already on ACEI/ARBs

N Engl J Med 2012; 367:2204-2213

ALTITUDE: Adverse Events

Aliskiren increased risk of hyperkalemia and hypotension in DM patients already on ACEI/ARBs

N Engl J Med 2012; 367:2204-2213

2013 KDIGO guidelines for BP control in DM + CKD patients

ARBs in DM + CKD patients : RENAAL Study

• Population: 1,513 T2DM + CKD patients (31-70 years) • Albumin/creatinine ratio 300 mg/g• Serum creatinine between 1.3–3.0 mg/dL (1.5–3.0 mg/dL

for men >60 kg)• Randomized to Losartan or placebo, Mean follow up: 3.4 yearsPrimary Endpoint: Composite of a doubling of serum creatinine,

end stage renal disease, or deathSecondary Endpoints: MI, Stroke, First hospitalization for

CHF/unstable angina, Death from CV causes, Coronary /peripheral revascularization

Exclusion: Type 1 DM, Non diabetic RF, RAS, MI, CABG within 30 days, CVA, PCI within 6 months, CCF

Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.

*The differences between the treatment groups were not statistically significant

RENAAL Baseline Characteristics*

Losartan‡

Group n=751

Placebo‡ Groupn=762

Mean Age (yrs) 60 60Male (%) 62 65Mean Systolic BP (mmHg)Mean Diastolic BP (mmHg)

15282

15382

Mean BMI (kg/m2) 30 29 Median urinary albumin:creatinine ratio (mg/g) 1237 1261Mean serum creatinine (mg/dL) 1.9 1.9Mean glycosylated hemoglobin (%)

8.5 8.4


RENAAL:Primary Endpoint*Losartan‡

Group n=751

Placebo‡

Group n=762

P

value

% RiskReduction(95% CI)

n % n %

Primary composite endpoint* 327 43.5 359 47.1 0.02 16 (2 to 28)• Doubling of serum creatinine• ESRD• Death

162147158

21.619.621.0

198194155

26.025.520.3

0.0060.0020.88

25 (8 to 39)28 (11 to 42)-2 (-27 to 19)

• ESRD or Death 255 34.0 300 39.4 0.01 20 (5 to 32)• Doubling of serum creatinine and ESRD 226 30.1 263 34.5 0.01 21 (5 to 34)


Losartan treatment reduced both renal and CV end points in DM + CKD patients

RENAAL Impact of Losartan on Secondary Endpoints

32% RRR in first CHF hospitalization (P=0.005)35% RRR in proteinuria (P<0.001)18% RRR in the decline of renal function (P=0.01)15.2% RRR in the estimated GFR decline (P=0.01)

RRR: Relative risk reduction


NKF 2012 Glycemic control guidelines in DM + CKD

• A target HbA1c of 7.0% to prevent or delay progression of the microvascular complications of diabetes, including DKD. (1A)

• Do not treat to an HbA1c target of <7.0% in patients at risk of hypoglycemia. (1B)

• Target HbA1c be extended > 7.0% in individuals with co-morbidities or limited life expectancy and risk of hypoglycemia. (2C)

Intensive glycemic control can prevent CKD progression

Intensive glycemic control in DM CKD patients: ACCORD 2015 data

• Out of > 10,000 patients, 3636 patients in ACCORD had CKD at baseline

• Incidence of primary outcome, all-cause and CV mortality, risk of hypoglycemia were evaluated in CKD patients in intensive vs standard glycemic control.

Kidney International (2015) 87, 649–659

Intensive glycemic control in DM CKD patients: ACCORD



Tight glycemic control increased CV and all cause mortality in CKD patients with T2DM



Tight glycemic control increased risk of hypoglycemia in CKD patients with T2DM


Lipid control in DM + CKD patients

• Statin therapy can reduce CAD risk in all CKD (non-ESRD) patients (with or without DM)

• Exact role of statin in patients on dialysis is still not clear

• Drugs like fenofibrate can further reduce eGFR, should be used carefully in DM + CKD

2013 KDIGO guidelines for lipid management in CKD

All DM patients with CKD > 18 yrs require statin therapy (except those on dialysis)

Kidney International Supplements (2013) 3: 259-305

2013 KDIGO guidelines for lipid management in CKD

Effect of different statin on renal function in DM Nephropathy: PLANET I

• 353 DM patients on ACEI/ARB were randomized to 10 mg or 40 mg rosuvastatin or 80 mg atorvastatin

• Primary End Point: Change in urine protein/creatinine ratio

• Secondary End Point: change in eGFR• Follow up: 1 yr

de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27, 2010; Munich, Germany.

Effect of different statin on renal function in DM Nephropathy: PLANET I:

Adverse event

Rosuvastatin10 mg/day(n = 116)

Rosuvastatin 40 mg/day(n = 123)

Atorvastatin 80 mg/day(n = 110) p

Any renaladverse event

7.8 9.8 4.5 NS

Acute renal failure 0.0 4.1 0.9 <0.05

Serum creatininedoubling

0.0 4.9 0.0 <0.01

Serum creatininedoubling or acute

renal failure

0.0 7.3 0.9 <0.01Atorvastatin is safer than rosuvastatin in DM patients with proteinuria

Statin/Ezetimibe in DM Nephropathy patients: SHARP study

• This randomised double-blind trial included 9270 patients with CKD (3023 on dialysis and 6247 not on dialysis) without CVD

• Out of these 23% (n=2093) were diabetics• Patients were randomly assigned to statin 20 mg plus

ezetimibe 10 mg daily versus matching placebo. • Follow up: 4.9 yrs• The key pre-specified outcome: first major

atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure).

SHARP: Study of Heart and Renal ProtectionLancet. 2011 Jun 25;377(9784):2181-92

SHARP study: Primary outcome

Statin + Ezetimibe

Statin/Ezetimibe reduced CV events by 17%

Lancet. 2011 Jun 25;377(9784):2181-92

SHARP study: Primary outcome

statin + Ezetimibe Placebo0

5

10

15

20

25

18.3

22.5

DM group sub-analysis

% p

atie

nts

deve

lopi

ng e

vent

s

HR: 0.78P< 0.05

Statin/Ezetimibe reduced CV events by 22% in patients with DM

Lancet. 2011 Jun 25;377(9784):2181-92

Prevention and management of DM nephropathy: Summary

Parameter Goals TherapyGlycemic Control

< 7% (if no comorbidity, to prevent nephropathy) > 7% if comorbidities or nephropathies already present)

Metformin (if GFR > 30 ml/min)

BP < 130/80 mm Hg (if proteinuria is present)< 140/90 mm Hg if proteinuria is absent

ARBs or ACEIsCCBs/diuretics as 2nd choice

LDL-C < 70 mg/dl Statin alone or statin+ Ezetimbe

Challenges in CKD patients for revascularization (with or without DM)

• Greater underlying comorbidities, • Coronary lesion calcification and complexity • Increased thrombotic and bleeding risk• Tendency for restenosis with bare-metal stents• Relatively less data for such patient groups for both DES

and CABG • SYNTAX and FREEDOM trial assessed PCI (DES) vs,

CABG.

Circ Cardiovasc Interv. 2015;8:e001973

PCI vs CABG in DM + CKD patients: 2015 study

• Retrospective population based analysis• A 1786 propensity-matched patients from 4006 patients

with CKD undergoing index revascularization for multi-vessel disease with either DES or isolated CABG (n=893 each) were analyzed in a Canadian study

• Follow up: 3 yrs • Early 30-day and late clinical outcomes after

revascularization were measured• 43% patients had diabetes, a sub-analysis was done for

DM patients


Independent Predictors of Late Mortality and Late MACCE

In DM + CKD patients, mortality and MACCE associated with revascularization is

significantly increased


PCI vs CABG in DM + CKD patients


In DM + CKD patients, MACCE are lower in CABG compared to PCI

Management of CAD in DM + CKD: Summary

Parameter Goals TherapyGlycemic Control

< 7% (if no comorbidity,) > 7% if comorbidities or nephropathies already present)

Metformin (if GFR > 30 ml/min)

BP < 130/80 mm Hg (if proteinuria is present)< 140/90 mm Hg if proteinuria is absent

ARBs or ACEIsCCBs/diuretics as 2nd choice

LDL-C All patients not on dialysis with eGFR < 60 ml/min should be treated

Statin alone or statin+ Ezetimbe

Revascularization

CABG is preferred

Take Home Message• Patients with DM + CKD are at very high risk of CAD• Control of multiple risk factor (BP and lipid) can reduce

risk of CAD in such patients• Tight glycemic control does not provide any CV benefit,

though it may prevent progression of CKD• Statins, ACEI/ARB are preferred drugs for reducing

CAD risk in DM + CKD patients• Specific clinical trials are required to further evaluate

exact role of revascularisation in DM + CKD

Management of coronary disease in diabetes - Is it different?

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