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The Importance of Blood Pressure Control in Diabetes

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Favors Lisinopril. 1.11 (0.88-1.38) Favors Chlorthalidone. Amlodipine. Lisinopril. ALLHAT: Secondary Endpoints: ESRD. ALLHAT Collaborative Research Group. JAMA. ... – PowerPoint PPT presentation

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Title: The Importance of Blood Pressure Control in Diabetes


1
The Importance of Blood Pressure Control in
Diabetes
  • Errol D. Crook, MD
  • Associate Professor and Acting Chair, Department
    of Internal Medicine
  • Wayne State University School of Medicine
  • Staff Physician, John D. Dingell VAMC

2
Prevalence of Diagnosed Diabetes in the United
States
3
Diabetes Prevalence Among US Adults According to
Race/Ethnicity2001
4
Diabetes Prevalence, 1990-2001
5
Natural History of Type 2 Diabetes
6
Development of Type 2 Diabetes
7
Hyperglycemia in Type 2 Diabetes Results From
Three Major Metabolic Defects
8
Insulin Resistance Associated Conditions
9
Association of Insulin Resistance,Type 2
Diabetes, and Cardiovascular Disease
10
The Continuum of CV Risk in Type 2 Diabetes
11
Hypertension Awareness, Treatment, and Control
US 1976 to 2000
Burt et al. Hypertention. 199525305-313 Hyman
et al. N Engl J Med. 2001345479-486 National
Center for Health Statistics. NHANES 1999-2000
(CD-ROM) NIH. The Sixth Report of the Joint
National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure
1997. NIH publication 98-4080.
12
Factors Affecting Prevalence Rates of Hypertension
  • Age
  • Mean SBP and DBP increases with age
  • 90 lifetime risk of hypertension in adults 55
    years or older
  • Race/ Ethnicity
  • African Americans have rates that among the
    highest in world
  • Gender
  • BP higher in men until age 70
  • Obesity
  • Diabetes
  • Kidney Disease
  • Prevalence of hypertension increases as renal
    function decreases.

13
Risk Factor Constellation (Metabolic Syndrome)
  • Hypertension
  • Obesity (particularly upper body)
  • Insulin resistance
  • Dyslipidemia (low HDL, high TGs)
  • diabetes
  • Salt Sensitivity
  • Microalbuminuria (vascular dysfunction)
  • Prothrombotic coagulation

14
Hypertension in Patients with Diabetes
  • Hypertension is very common in T2DM with at least
    40 having elevated blood pressure at the time
    their diabetes is diagnosed.
  • Over 80 of T2DMs with nephropathy have
    hypertension and as renal function declines this
    number may increase.
  • 92 of diabetics in our renal clinic had
    hypertension at presentation to our clinic and
    African Americans had higher blood pressure than
    non-African Americans despite being on more
    antihypertensive medications.

15
Classification and Management of Blood Pressure
for Adults JNC 7
JNC 7 JAMA (2003) 289, 2560
16
Chronic Kidney Disease (CKD) Epidemiology
  • Estimated 10.9 million in US with reduced renal
    function, not yet at level requiring renal
    replacement therapy.
  • In 2000, over 372,000 persons required renal
    replacement therapy or transplantation.
  • A large number of people have normal serum
    creatinine but have reduced renal function or
    normal renal function with kidney damage
    (proteinuria).

17
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18
Stages of Renal Disease
19
Prevalence of CKD by Stage of Disease
NHANES III (1988 1994, USRDS 1998
20
Hypertension Prevalence by GFR
21
Effect of BP on CHD Mortality MRFIT
81
CHD death rate per 10,000 person-years
48
44
37
38
35
31
26
25
25
25
25
160
24
17
140159
14
13
13
12
21
12
120139
10
9
9
9
lt120
SBP (mm Hg)
100
9099
8089
7579
7074
lt70
DBP (mm Hg)
Adapted with permission from Neaton JD et al.
Arch Intern Med. 199215256
22
Risk of Stroke Death According to Systolic BP
and Diastolic BP in MRFIT
9
Systolic
8
7
Diastolic
6
5
4
Adjusted Relative Risk
3
2
1
0
1
2
3
4
5
6
7
8
9
10
Decile
(Lowest 10)
(Highest 10)
Stamler, Stamler, Neaton. Arch Intern Med.
1993153598-615.
23
Reasons to be Aggressive in Treatment of
Hypertension in CKD
1) The adverse outcomes of CKD (kidney failure,
cardiovascular disease, premature death) can be
prevented or delayed 2) Treatment of earlier
stages of CKD is effective in retarding
progression to kidney failure and in preventing
the systemic complications that develop during
the course of progressive CKD. 3) Initiation of
therapy for cardiovascular risk factors at
earlier stages of CKD can be effective in
reducing the very high cardiovascular morbidity
and mortality of these patients.
24
Chronic Kidney Disease and Cardiovascular Disease
25
Level of Kidney Function and CVD Risk (ARIC JACC
(2003) 4147)
26
Urinary Albumin Excretion Predicts CVD and
Non-CVD Mortality in General PopulationPREVEND
Circ (2002) 1061777
Crude Incidence Rates per 1000 person-years
27
Proteinuria and CVD
  • Framingham
  • proteinuria increased the mortality rate 3-fold
  • an independent predictor of mortality in men
  • proteinuria was strongly associated with
    hypertension (3-fold higher than in
    normotensives), diabetes and cardiac enlargement.
  • MRFIT
  • dipstick positive proteinuria was an independent
    risk factor for all cause, CVD and coronary heart
    disease mortality.
  • Intervention as a Goal in Hypertension Treatment
    (INSIGHT) (long acting dihydropyridine CCB and a
    diuretic on CVD events and death).
  • Proteinuria was found to be the most powerful
    predictor of CVD among all risk factors,
    including diabetes and previous myocardial
    infarction.

28
Renal Dysfunction and Cardiovascular Outcomes
  • Valsartan in Acute Myocardial Infarction Trial
    (VALIANT) (Anavekar et. al. NEJM (2004) 3511285)
  • Inverse relationship between initial renal
    function and subsequent risk of death in patients
    post MI complicated with LV dysfunction or CHF
  • Community Based Sample from HMO (Kaiser) (Go et.
    al. NEJM (2004) 3511296)
  • Study of over 1 Million showing inverse
    relationship between renal function and CV death.

29
The Scope of Cardiovascular Complications in
Patients with Renal Disease
  • Renal disease elevations in creatinine,
    proteinuria, and microalbuminuria- is associated
    with significant increases in cardiovascular
    disease (CVD).
  • Even mild increases in serum creatinine and a
    creatinine at the high end of normal are
    associated with increased CVD.
  • Renal disease is as strong a risk factor for CVD
    as smoking and diabetes.

30
Diabetes and Cardiovascular Disease
  • Diabetics have similar risk of CVD as
    non-diabetic with existing CVD.
  • Diabetics with renal disease has CVD risk that is
    6-7 fold that of diabetic without renal disease.

31
Is Proteinuria/Microalbuminuria Associated with
CVD Risk in Diabetes?
32
CVD risk Factors that are Strongly Associated
with Diabetes and Renal Disease.
  • Hypertension
  • Obesity
  • Lipid abnormalities (esp. proteinuria)
  • Insulin Resistance
  • CHF
  • LVH
  • Elevated Uric Acid
  • Albuminuria/Proteinuria
  • Age
  • Family History

33
Studies Supporting BP Recommendations in
Diabetics
  • HOT
  • HOPE
  • LIFE
  • UKPDS
  • MDRD
  • ABCD
  • Collaborative Study Group
  • CAPPP

34
Support of BP Recommendations in Diabetic
Nephropathy
  • Hypertension Optimal Treatment Trial (HOT)
  • Intensive lowering of BP in over 18,000
    hypertensives (50 -80 yrs of age). 1501
    diabetics at study entry.
  • Treated with Felodipine with addition of other
    agents as needed.
  • In diabetics CVD and CVD mortality was
    significantly lower in the group with target DBP
    lt 80 mm HG compared lt 85 or 90 mm Hg.

35
Support of BP Recommendations in Diabetic
Nephropathy
  • United Kingdom Prospective Diabetes Study (UKPDS)
  • Usual BP group vs. Low BP group (140-150/80-90).
  • Low BP group tended to have better outcomes with
    regards to microvascular and macrovascular
    complications.
  • No difference between atenolol vs. captopril

36
Systolic Hypertension in the Elderly Program
(SHEP)
  • Patients gt 60 yrs with isolated systolic
    hypertension (SBP 160-219)
  • Stepped care with chlorthalidone. Atenolol added
    as second step.
  • Chlorthalidone decreased incidence of heart
    failure by 49. If there was previous evidence
    of MI by EKG the reduction was 80.
  • Kostis et al JAMA 278 212

37
Systolic Hypertension in the Elderly Program
(SHEP)
  • Patients gt 60 yrs with isolated systolic
    hypertension (SBP 160-219)
  • Stepped care with chlorthalidone. Atenolol added
    as second step.
  • Active therapy decreased CVD events in both
    diabetics and non-diabetics.
  • JAMA (1996) vol. 276

38
Appropriate Blood Pressure Control in Diabetes
(ABCD) Trial (Estacio et al., NEJM 338 645)
  • Compared nisoldipine (CCB) to enalapril (ACE I)
    in type 2 diabetics
  • Aim Determine target BP in type 2 DM
  • Patients Type 2 DM, age 40-74, DBP gt 80 mmHg,
    not on antihypertensives
  • Endpoint Primary- Cr clearance Secondary- CV
    events, retinopathy, urinary albumin
  • Result Among hypertensive, ACE I decreased rate
    of MI (5 fatal and non-fatal MIs in ACE I group
    vs. 25 in CCB group).

39
Hypertension Treatment and CVD in Diabetics With
Renal Disease
  • ABCD (Hypertensives) (Estacio et. al. Diabetes
    Care 23 (suppl 2) B54-64, 2000
  • 2 BP groups (Intensive 132/78 moderate138/86)
  • Nisoldipine vs. Enalapril as initial therapy (470
    pts with 5.3 yrs follow-up).
  • Intensive therapy had lower overall incidence of
    death (5.5 vs. 10.7, p0.037)
  • No difference on progression of retinopathy and
    neuropathy and no difference on in progression of
    renal disease

40
Hypertension Treatment and CVD in Diabetics With
Renal Disease
  • ABCD (Normotensive) (Schrier et. al. KI 61 1086,
    2002)
  • Normotensive, Type 2s (n480, 5.3 yrs f/u)
  • Intensive (Goal DBP decrease of 10 mm Hg,
    achieved 128/75) vs. moderate (Goal DBP 80-89,
    achieved 137/81)
  • Intensive group randomized to nisoldipine vs.
    enalapril
  • Lower blood pressure group (128/75) had less
    progression of retinopathy and lower rates of
    stroke

41
Reduction in Endpoints in NIDDM with the
Angiotensin II Antagonist Losartan Study (RENAAL)
  • International, multicenter, double-blind,
    randomized, placebo controlled study sponsored by
    MERCK
  • Type 2 Diabetics ages 31-70.
  • Urine albumin/ Cr gt 300,Serum Cr 1.3 3.0 mg/dl.
  • Losartan (50mg / dy) or placebo.
  • Losartan lowered first time admits for CHF
  • 20 risk reduction in ESRD or death (p.01)

42
Irbesartan Diabetic Nephropathy Trial (IDNT)
  • Goal Irbesartan vs. Amlopidine or placebo on
    progression of diabetic nephropathy, secondary
    CVD endpoints (13.3 Black)
  • Irbesartan group had 23 lower rate of CHF
    hospitalization compared to placebo.
  • Amlopidine group had 41 lower rate of nonfatal
    myocardial infarction.
  • Higher rate of CHF in amlodipine group vs. other
    groups (?).
  • Trend for lower rate of stroke with amlopidine.

43
Other Studies Examining CVD Outcomes in Diabetics
  • Losartan Intervention for Endpoint Reduction
    (LIFE) (Lancet 3591004)
  • Essential hypertension and LVH Losartan vs.
    atenolol
  • Captopril Prevention Project (CAPPP) (Diabetes
    Care 24253)
  • Essential Hypertension Captopril vs.
    conventional BP Rx (diuretics, b-blockers or
    both)
  • Both favor RAAS blockade in reduction of CVD
    events in diabetics.

44
Trials Demonstrating Risk Reduction in CVD
Outcomes with Lower BP in Diabetics
Crook and Velusamy, Current HTN Reports, 2003
45
Hypertension in Diabetics with Renal Disease
46
Recommendations for Treatment of Blood Pressure
in Patients with Diabetic Kidney Disease
  • Target level of Blood pressure is lt 130 / 80 mm
    Hg
  • Diabetic renal disease and BP gt 130 / 80 mm Hg
    initiate ACE inhibitor or ARB
  • Diabetic renal disease and BP lt 130 / 80 mm Hg
    initiate ACE inhibitor.

47
Blood Pressure Control and Rate of Renal Decline
in Diabetic Nephropathy
  • Parving et al. (1983 Lancet)
  • Ten Type 1 Diabetics followed before (mean of 29
    months) and after initiation of antihypertensives
    (mean 39 months)
  • Antihypertensive agents were metoprolol,
    hydralazine, furosemide or thiazide
  • BP fell from 144/97 mmHg before treatment to
    128/84 mmHg with treatment
  • Albumin excretion rate decreased from 977 mg/min
    before treatment to 433 mg/min with treatment

48
ACE Inhibition in Diabetic Nephropathy
  • Blood pressure determines risk of progression of
    renal disease. Captopril lowers risk among those
    with hypertension.
  • With Doubling of Serum Creatinine

Lewis et. al.
49
Lewis et. al. Relationship Between BP and
Diabetic Nephropathy
50
ARBs and Diabetic Renal Disease
51
Bakris et. al. (2000) 36 646
52
Level of BP and Vascular Complications in Diabetes
UKPDS. BMJ (2000) 321 412
53
ALLHAT Secondary Endpoints ESRD
ALLHAT Collaborative Research Group. JAMA.
20022882981-2997.
54
Antihypertensive Agents and Risk of Diabetes
  • Data from ARIC (Gress, et al. NEJM 342905)
  • ACE inhibitors an Calcium did not increase risk
    for Type 2 diabetes mellitus.
  • Thiazides No increased risk for Type 2 DM
  • b-Blockers 28 increased risk for development
    of type 2 DM compared to those not on
    medications.
  • HOPE Ramipril lowered diabetic risk
  • LIFE Losartan lowered diabetic risk compared to
    atenolol

55
ALLHAT, Diabetic Risk and Treatment of
Hypertension
56
Multiple Agents Usually Required to Achieve BP
Goals in Diabetic Patients
RENAAL (lt140/90)
IRMA2 (lt135/85)
IDNT (lt135/85)
UKPDS
ABCD
MDRD
HOT
AASK
Number of Agents Needed
Adapted, with permission, from Bakris GL, et al.
Am J Kidney Dis. 200036646-661.
57
Other Complications of Diabetic Nephropathy
  • Retinopathy
  • BP control, consider RAAS inhibition
  • Neuropathy
  • BP control, consider RAAS inhibition
  • Anemia
  • Highly prevalent in diabetics
  • May be seen at even moderate reductions in renal
    function
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