Transcript Blood Pressure Response (mm Hg)

GO! Diabetes
Residency
Train the Trainer Program
Cardiovascular Disease
Prevention
Blood Pressure, Dyslipidemia,
Antiplatelet Therapy
Diabetes and Hypertension
Key Questions
•
•
•
•
•
•
Why should we pay so much attention?
What parameters?
Non Drug Recommendations
Which drugs and how many?
Should recent studies change goals?
What about resistant cases?
Diabetes and Hypertension
Why?
• Volume Expansion
– Increased insulin levels
• Higher sympathetic activity
– Increased glucose level
• Increased sodium resorption with hyperglycemia
• Decreased arterial compliance
• Obesity
UKPDS Blood Pressure Study:
Tight vs. Less Tight Control
• 1148 type 2 patients
• BP lowered to avg. 144/82 (controls-154/87); 9 yr follow-up
Endpoint
Risk Reduction(%) P Value
Any diabetes related endpoint
Diabetes related deaths
Heart failure
Stroke
Myocardial infarction
Microvascular disease
UKPDS. BMJ. 317: 703-713. 1998.
24
32
56
44
21
37
0.0046
0.019
0.0043
0.013
NS
0.0092
UKPDS Kaplan-Meier Plots of Proportion of Patients
Who Died of Disease Related to Diabetes
Patients with events (%)
Less tight blood pressure control
Captopril
P=0.28
Atenolol
0
No. of patients at risk:
1
2
3
4
5
6
7
Years from randomization
383
328
172
Captopril
400
346
303
154
Atenolol
358
UKPDS Group. BMJ. 1998;317:713–720.
Reprinted with permission from the BMJ Publishing Group.
8
9
HOT Trial: Effect Of Diastolic Target On
CVD Events - 4 Years
30
48%
Diabetic Patients
n=1,501; P=0.016
Risk
Reduction
24.4
Non-Diabetic Patients
n=18,790; P=NS
18.6
20
Events/
1000
Pt-Yrs
11.9
10
9.9
10.0
<90
<85
9.3
0
<90
Lancet 1998;351:1755
<85
<80
<80
Published online March 14, 2010
Mean # Meds
Intensive:
Standard:
3.2
1.9
3.4
2.1
3.5
2.2
3.4
2.3
Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2
ACCORD BP
Trial design: Type 2 diabetics were randomized to systolic BP <120 mm Hg (n = 2,362) vs.
systolic BP <140 mm Hg (n = 2,371). Mean follow-up was 4.7 years.
Results
• Systolic BP at 1 year: 119 mm Hg in intensive
group vs. 134 mm Hg in standard group
% per year
4
2
(p = 0.20)
1.9
2.1
• CV mortality, MI, or stroke: 1.9%/yr vs.
2.1%/yr, respectively
• CV mortality: 1.3%/yr vs. 1.2%/yr (p = 0.55),
respectively
• Serious adverse events: 3.3% vs. 1.3% (p <
0.001), respectively, due to increase in
hypokalemia and serum creatinine
Conclusions
• Goal systolic BP <120 mm Hg was not
superior to a goal systolic BP <140 mm Hg
0
CV mortality,
MI, or stroke
mace
Systolic BP
<120 mm Hg
Systolic BP
<140 mm Hg
• Similar incidence of CV outcomes in both
groups; however, more adverse events in the
intensive group
Diabetes Treatment Goals
for Blood Pressure
•Control blood pressure
– 130/80 mmHg for most patients
– 125/75 mmHg for patients who have proteinuria
>1 g/day and renal insufficiency
•Reduce the risk of end-organ failure
•Reduce the risk of cardiovascular events
– Myocardial infarction
– Cardiovascular death
•Delay or prevent the progression to heart failure
JNC 7 Report. JAMA 2003;289:2560; Bakris GL et al. Am J Kidney Dis 2000;36:646
ADA. Diabetes Care 2010;33(suppl 1)
ADA Guidelines for the
Treatment of Hypertension
• Initial therapy
– Lifestyle modification
– Smoking cessation
– Weight reduction
– Increase physical
activity
– Sodium restriction
• Pharmacologic therapy
– ACEI/ARB, thiazide, βblocker, CCB
– Multiple drugs generally
required
Goal of therapy
BP <130/80 mmHg
Diabetes Care 2010;33 (Suppl 1)
Number of Medications to Achieve Goal
BP In 5 Trials of DM and/or Renal Disease
UKPDS (<150/85 mmHg)
2.7
ABCD (<75 mmHg DBP)
2.8
MDRD (<92 mmHg MAP)
3.6
HOT (<80 mmHg DBP)
3.3
AASK (<92 mmHg MAP)
3.8
0
1
2
3
Number Of BP Meds
Bakris. J Clin Hypertens 1999;1:141
4
Clinical Trials Of
Anti-Hypertensive
Agents In Diabetes
UKPDS: ACE Inhibitor Vs -Blocker
Aggregate Clinical Endpoints
Relative Risk & 95% CI
RR
P
Any diabetes-related endpoint
1.10
0.43
Diabetes-related deaths
1.27
0.28
All-cause mortality
1.14
0.44
Myocardial infarction
1.20
0.35
Microvascular disease
1.29
0.30
Stroke
1.12
0.74
0.5
Favors
ACE Inhibitor
UKPDS Group. BMJ 1998;317:713
1
2
Favors
-Blocker
ABCD, CAPPP, FACET
and UKPDS Meta-Analysis
• To assess whether ACE inhibitors are superior to other agents in
the prevention of cardiovascular events in hypertensive type 2
diabetics
• Review and meta-analysis of randomized controlled trials of
patients treated with ACEIs or other agents, followed for 2
years, with adjudicated cardiovascular events
• 4 trials eligible
– ABCD (n=470) compared enalapril with nisoldipine
– CAPPP (n=572) compared captopril with diuretic or betablockers
– FACET (n=380) compared fosinopril with amlodipine
– UKPDS (n=758) compared captopril with atenolol
Pahor M, et al. Diabetes Care. 2000;23:888-892.
Relative Risk Reduction With ACEIs
in ABCD, CAPPP and FACET
Acute
Myocardial
Infarction
Cardiovascular
Event
All-cause
Mortality
Stroke
NS
P=0.01
P<0.001
P<0.001
Pahor M, et al. Diabetes Care. 2000;23:888-892.
Superior Drugs? Variable
Results
Vs Placebo
UKPDS:
ABCD:
FACET:
LIFE:
CONSENSUS:
ALLHAT:
ALLHAT:
ALLHAT:
AUSTRALIAN:
Thiazide, ACE, CCB, BB
BB = ACE
ACE > CCB
ACE + CCB > ACE > CCB
ARB > BB
ACE > ARB
Thiazide > ARB
Thiazide ≥ ACE
Thiazide ≥ CCB
ACE > Thiazide
Which Class Of Agents Should Be
Added Second-Line?
• Thiazide diuretics
– Complementary mechanism to ACEs or ARBs
– ALLHAT showed benefit
– Particularly effective in African American patients
– BUT slightly higher deterioration of glucose metabolism
• Beta blockers
– Good evidence of benefit particularly for those with coronary
heart disease or congestive heart failure
– BUT mechanism of action may not complement
ACEs or ARBs
Treatment Algorithm - Hypertension
BP >130/80 mmHg
Lifestyle Intervention
Smoking Cessation
Quarterly to
semiannual
follow-up
SBP <130 and DBP <80?
Yes
No
Coronary Disease
β-blocker
Monthly to
quarterly
follow-up
Albuminuria/CVD Risk Factors
Thiazide
ACE/ARB
Virtually all two drug combinations should include a thiazide diuretic
The third drug could (should) be a calcium channel blocker
In the setting of kidney disease and significant proteinuria, consider combined ACE/ARB therapy
In the setting of kidney or heart disease, consider adding a furosemide bid or torsemide
Additional BP Recommendations
• Lower blood pressure gradually in the elderly
• If unable to achieve goal, don’t hesitate to discuss with peers
• Check for orthostasis in some patients when clinically indicated
• If angiotensin modifying drugs or diuretics are used, monitor renal function
and potassium
• Use as many medicines as necessary to achieve blood
pressure target
– 130/80 mmHg
– 125/75 mmHg if proteinuria is found
• Begin with an angiotensin modifying drug
• Add a thiazide in African American patients
• Add a Beta blocker in patients with heart disease
ADA. Diabetes Care 2010;33(Suppl1):29
Causes Of Resistant Hypertension
 Improper blood pressure measurement
 Excess sodium intake
 Inadequate diuretic therapy
 Medication
– Inadequate doses
– Drug actions and interactions (e.g. nonsteroidal
anti-inflammatory drugs (NSAIDs), illicit drugs,
sympathomimetics, oral contraceptives)
– Over-the-counter (OTC) drugs and herbal supplements
 Excess alcohol intake
 Identifiable causes of hypertension
Effect of Low-Dose Spironolactone on
Resistant Hypertension
Diastolic Blood Pressure
Blood Pressure Response (mm
Hg)
Blood Pressure Response (mm
Hg)
Systolic Blood Pressure
African-Americans (n = 45)
Whites (n = 31)
Reprinted by permission from Macmillan Publishers Ltd: Nishizaka MK, et al. Am J
Hypertens. 2003;16:925-930, copyright 2003.
Lipid Goals for Diabetics
American Diabetes Association
LDL <100 mg/dL
(<70 mg/dL in patients at “highest risk”)
HDL >40 mg/dL (>50 mg/dL in females)
TG <150 mg/dL
National Cholesterol Education Program
LDL <100 mg/dL
(<70 mg/dL in patients at “highest risk”)
Non-HDL <130 mg/dL
Primary and Secondary
Prevention of CVD - Statins
Study
CVD
Prevention
Statin Dose vs. comparator
Relative Risk
Reduction
Absolute Risk
Reduction
4S DM
2o
Simvastatin 20-40 vs.. placebo
50%
42%
Aspen
2o
Atorvastatin 10 vs.. placebo
34%
12.7%
HPS-DM
2o
Simvastatin 40 mg vs. placebo
17%
7.5%
CARE-DM
2o
Pravastatin 40 mg vs. placebo
13%
5.4%
TNT-DM
2o
Atorvastatin 80 mg vs. 10mg
18%
4.7%
HPS-DM
1o
Simvastatin 40 mg vs. placebo
34%
6.0%
CARDS
1o
Atorvastatin 10 mg vs. placebo
35%
4.0%
ASPEN
1o
Atorvastatin 10 mg vs. placebo
19%
1.9%
ASCOT-DM
1o
Atorvastatin 10 mg vs. placebo
8%
0.9%
Statins:
Primary And Secondary Prevention
25
4S
20
% With
CVD
Event
15
CARE
PROVE-IT
10
TNT
5
HPS
(estimated)
0
50
70
90
LIPID
HPS
(estimated)
WOSCOPS
CARDS
AFCAPS
110
130
150
LDL-C (mg/dL)
Adapted from Illingworth. Med Clin North Am 2000;84:23
and LaRosa. N Engl J Med 2005;352 (e-pub)
and Colhoun. Lancet 2004;364:685
170
190
210
ACCORD Lipid Protocol
• All participants on open-labeled simvastatin, 20 to 40 mg/day
– Simvastatin dose complied with lipid guidelines
• Patients randomized to double-blind placebo or fenofibrate, 54 to
160mg/day. Observed Follow-up: 4 to 8 years (mean 4.7 years).
Dosing based upon eGFR level
• ACCORD Lipid does not support use of the combinationof
fenofibrate and simvastatin, compared to simvastatin alone, to
reduce CVD events in the majority of patients with T2DM who
are at high risk for CVD
ADA Standards 2010
Dyslipidemia
• Lipid profile every 1-2 years
• Lipid Goals
– Primary Goal
• LDL<100 (30-40% reduction)
– Secondary Goals
• HDL>50
• Triglycerides<150
ADA Standards 2010
Dyslipidemia
• Statin Usage
– Primary Prevention
• Age 40 with 1 additional risk factor
– Secondary Prevention
• With overt CVD
• Reduce LDL 30-40%
• LDL<70 is option for highest risk individuals
ADA Standards 2010
Dyslipidemia
• High triglycerides (>200) and Low HDL (<40)
– Achieve LDL goals first
– Isolated low HDL (triglycerides < 200)
• Consider Niacin first
– Low HDL with high triglycerides
• Fibrates
• If combining with statin use fenofibrate (less risk
of rhabdomyolysis) or niacin
Statin-Fibrate Combination Therapy:
Pharmacokinetic Interactions
Atorvastatin
Pravastatin
Fluvastatin
Simvastatin
Cerivastatin
Rosuvastatin
Gemfibrozil
Not available
 in Cmax by 2-fold
No effect
 Cmax by 112%
 Cmax by 2 to 3-fold
 in Cmax by 2-fold
Fenofibrate
Not available
No effect
Not available
No effect
No effect
No effect
Cmax =peak concentration
Pan W-J et al. J Clin Pharmacol 2000;40:316; Backman JT et al. Clin Pharmacol Ther 2000;68:122
Kyrklund C et al. Clin Pharmacol Ther 2001;69:340; Backman JT et al. Clin Pharmacol Ther
2002;72:685; Davidson MH. Am J Cardiol. 2002;90(suppl):50K; Prueksaritanont T et al. Drug
Metab Dispos 2002;30:1280; Martin PD et al. Clin Ther 2003;25:459
Anti-platelet Therapy
ADA Standards
• Recommendations for Aspirin
– ASA 75-162 mg/day for 2o prevention
– ASA 75-162 mg/day for 1o prevention
• 10 year risk > 10%
– Men > 50 yrs old with additional CV risk factor
– Women > 60 yr old with additional CV risk factor
– Not recommended ages < 21 (Reye’s syndrome)
• Clopidogrel
– Very high risk diabetics; intolerance to ASA
60 yo type 2 DM
• Meds
– Metformin 1 gm bid
– Insulin glargine 25 units q hs
– Lisinopril 20 mg daily
• Pertinent Data
– HbA1C 7.0%
– BP 155/82
– microalbumin elevated
– LDL 150 HDL 36
Creatinine 1.3 triglycerides 182
• What should be done to reduce his CV risk?
65 yom type 2 DM with resistant
hypertension
• BP 162/86
Pulse 55
Weight 225
• PMH: gout and chronic kidney disease
• Meds
– Ramipril 10 mg daily
– Atenolol 50 mg daily
– Amlodipine 5 mg daily
– Metformin 1 gm bid
• Labs
– Creatinine 1.8 Lytes normal HgbA1C 6.8%
• What medicine changes would you suggest?
Which of the following lipid-lowering agents can
worsen glycemic control?
20%
20%
20%
20%
20%
1.
2.
3.
4.
5.
Colestipol (Colestid)
Ezetimibe (Zetia)
Gemfibrozil (Lopid)
Nicotinic acid (Niacin)
Atorvastatin (Lipitor)
0
10
Case Study
•32 year-old African American male presents for evaluation of poorly controlled
diabetes. His diabetes was diagnosed after presenting with DKA at age 22
years during rehabilitation from a MVA with spinal cord injury that ended
football career
– Current medications include insulin 70/30 65 units bid
•FHx Early vascular disease
•PE
• Height 70"
• Weight 245 lb • BP 162/92, 102
Labs:
Renal function and lytes normal
Chol 245
LDL 165
HbA1C 8.0%
HDL 30 Triglycerides 190
Urine microalbumin elevated
•Questions What should be done to lower his CV risk?
Questions?