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).

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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.
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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.
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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.

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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.

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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.

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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.

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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

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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

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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).

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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.

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Trials Demonstrating Risk Reduction in CVD
Outcomes with Lower BP in Diabetics
Crook and Velusamy, Current HTN Reports, 2003
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Hypertension in Diabetics with Renal Disease
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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.
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Lewis et. al. Relationship Between BP and
Diabetic Nephropathy
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ARBs and Diabetic Renal Disease
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Bakris et. al. (2000) 36 646
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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.
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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