The concerns about new onset diabetes

1
The concerns about new onset diabetes With
various antihypertensive medications Should not
be a major determining factor In the choice of
initial therapy.
2
Past History Attempts to minimize benefits of
therapy with diuretics or diuretics/B-blockers S
tatement 1) Reduced strokes and heart failure
but minimal effect on CHD events - result of
effects on lipids Proven false 2) Poorly
tolerated - Proven false 3) Increased ectopy -
sudden death - Proven false 4) Use did not result
in regression of LVH - Proven false
3
The Present Statement New onset diabetes (NOD)
is increased with diuretics - should reconsider
use of these agents as initial therapy Fact NOD
increased by about 1 compared to placebo or
CCBs and 1- 3.5 compared to ACE-Is but Fact
Long-term outcome not affected CVD events
reduced to as great or greater extent as other Rx
4
Incidence of New Onset Diabetes with Various
Medications. How significant is it?
5
Effects of High-Dose Diuretic Therapy Compared
To Control or Placebo on Glucose Metabolism
Study Yrs Serum Glucose
(mg/dL) Hyperglycemia or Diabetes
Oslo 5 No difference D/Pl No
data EWPHE Increase of 6.6 , D/Pl MRC
3-4 Excess of 6 new cases/1000 pt
yrs HAPPY HDFP 5 1.6
(57/3,563) SHEP 1 Difference of 5, D/Pl No diff
new onset diabetes Rx/C MRFIT 6 Exces
s of 5 (SI) diuretics vs (UC) no
diuretics
Diuretics compared with placebo Fasting
glucose gt110 mg/dL
Cleve Clin J Med 19936027-37
6
Incidence of New Onset Diabetes in the 3-8 Year
Hypertension Treatment Trials
Yrs New
Absolute Trial Duration
Onset Diabetes Difference
UC or D/B-Bl
I. ACE-I compared to conventional Rx
ACE-I
CAPPP ACE-I/B-Bl/D 6.1
6.5 7.5 1.0 STOP-2
ACE-I/B-Bl/D 6 4.7
4.9 0.2 ANBP-2
ACE-I/ 4
4.5 6.6 2.1 ALLHAT
ACE-I/D 4.9 8.1
11.6 3.5 II. CCB compared
to conventional Rx CCB
NORDIL CCB/B-Bl/D 4.5 4.3
4.9 0.6 ALLHAT CCB/D
4.9 9.8 11.6
1.8 INVEST CCB/B-Bl 4.0 6.2
7.3 1.1
INSIGHT CCB/D 3.5 5.4
7.0 1.6 STOP-2 CCB/B/Bl/D
6 4.8 4.9 0.1
7
Incidence of New Onset Diabetes in the 3-8 Year
Hypertension Treatment Trials
Yrs New
Absolute Trial Duration
Onset Diabetes Difference

• III. ARB vs other Rx ARB
  Other Rx
• VALUE ARB/CCB 4.2
  13.1 16.4 3.3
• LIFE ARB/B-Bl
  4.8 6.0 8.0
  2.0
• SCOPE ARB/UC 5
  4.3 5.3 1.0
• CHARM ARB/other Rx
  3 6.0 7.4
  1.4
• IV. ACE-I vs CCB ACE CCB
• ALLHAT ACE-I/CCB 4.9
  8.1 9.8
  1.7

Approximate overall difference ACE or ARB vs
D/B-Bl 2.0 ACE/CCB 2.0 CCB vs D/B-Bl 1.5
8
Many clinical trial results demonstrate that

• Fewer cases of new onset diabetes occur if an ACE
  or an ARB is included in therapy
• Diabetic patients, especially those with
  proteinuria, have a better outcome if an ACE or
  an ARB is included in therapy

IDNT, RENAAL, LIFE, HOPE, CAPPP, AASK, VALUE,
ALLHAT
9
Combined CVD Subgroup Comparisons
P .04 for interaction
10
Conclusions

• Among non diabetics, incidence of fasting glucose
  ??126 mg/dL at 4 years was 1.8 higher in
  chlorthalidone vs amlodipine, and 3.5 higher in
  chlorthalidone vs lisinopril.
• Overall, metabolic differences did not translate
  into more adverse cardiovascular events, or into
  higher all-cause mortality, with chlorthalidone.

11
Risk of Hyperglycemia with Use of
Antihypertensive Drugs

Thiazide Central antiadrenergic agents
Peripheral antiadrenergic agents
ACE inhibitors
B-Blockers Calcium
channel blockers
Vasodilators gt1 Agent without
thiazide gt1 Agent with thiazide
0.5 1 1.5 2 2.5 3
Decreased Risk
Increased Risk
Adjusted ORs and 95CI
12
In a large prospective survey, it was concluded
that subjects with hypertension who were taking
thiazide diuretics were not at greater risk for
the subsequent development of diabetes than were
subjects with hypertension who were not
receiving any antihypertensive therapy. However,
subjects with hypertension who were taking
B-blockers had a 28 higher risk of subsequent
diabetes.
Gress, et al. NEJM 2000342905-12
13
Conclusions Concern about the risk of
diabetes should not discourage physicians from
prescribing thiazide diuretics to nondiabetic
adults who have hypertension. The use of
B-blockers appears to increase the risk of
diabetes, but this adverse effect must be weighed
against the proven benefits of B-blockers in
reducing the risk of cardiovascular events.
Gress, et al. NEJM 2000342905-12
14
Results of Tight Blood Pressure Control Compared
with Less-Tight BP Control in the UKPDS Study
Risk Reduction ()
Any diabetes related end- point
Diabetes related death
Stroke
Micro vascular endpoints
Retinopathy progression
Deterior- ation of vision
Heart failure
BMJ 1998317703-713
15

• The ALPINE Study (392
  patients)
• Candesartan felodipine (71) compared to
  HCTZ
• Atenolol (84) (mean dose 68 mg/day, 50 on 100
  mg/day)
• Baseline BMI - 28 kg/m2
• SBP more in HCTZ group
• 12 mos. - no difference in cholesterol or LDL
  levels
• Significant difference in HDL and triglycerides
• 8 new diabetics in HCTZ vs 1 in C groups
• Metabolic syndrome - 18 HCTZ vs 5 C

The Antihypertensive Treatment and Lipid Profile
in the North of Sweden Efficacy Evaluation
J Hypertens 2003211563-74
16

• Prognostic Significance of New Diabetes
• in Treated Hypertensive Subjects
• 795 untreated hypertensives - follow-up - median
  6.0 Years
• New onset diabetes (NOD) - 5.8
• Plasma glucose and diuretic Rx at follow-up visit
  (but not B-blockers)
• were predictive of NOD
• Relative risk of CV event 2.92 NOD
• 3.57 patients with pre Rx diabetes
• Baseline non diabetic patients who developed
  diabetes
• SBP and DBP higher
• more LVH
• glucose levels higher
• 1 FG 42 vs 6 who did not develop NOD

Verdecchia, Hypertens 200443963-968
(observational cohort study)
17
Cardiovascular Events inTreated Hypertensive
Subjects
4.70
3.90
Rate of events (per 100 patient years)
.97
Verdecchia, Hypertens 200443963-968
18
It is important to remark that the occurrence
of new diabetes was an independent predictor of
cardiovascular risk, whereas the use of
diuretics, albeit predictive of new diabetes,
did not show any independent relation with
subsequent cardiovascular events.
Verdecchia, Hypertens 200443963-968
19
Morbidity and Mortality in Diabetic and
Nondiabetic Subjects in the Systolic Hypertension
in the Elderly Program
Reduction in risk () in treated compared with
placebo groups
Fatal or nonfatal MI, SCD, CABG, or angioplasty
All-cause mortality
Nonfatal and fatal MI
Therapy low-dose diuretic with B-blocker added
if necessary n 4736 subjects gt60 years of age
Curb KD. et al. JAMA 19962761886-1892
20
Objective

• To assess the long term (14.3 years) mortality
  of Systolic
• Hypertension in Elderly Program (SHEP)
  participants by
• diabetes status
• No diabetes
• Diabetes at Baseline
• New onset diabetes (during SHEP)

From Kostis, et al
21
Results-6 CV death ()
SHEP-X
14.3 Year Follow-up
PLACEBO
ACTIVE
From Kostis et al
22
Conclusions

• Chlorthalidone based treatment of hypertension
  results in improved long-term outcomes.
• The diabetes related to chlorthalidone therapy
  has better prognosis than diabetes at baseline.
• The benefit of chlorthalidone-based therapy on
  long-term total and CV mortality is most
  pronounced in hypertensive patients with diabetes.

From Kostis, et al
23
Intensive control of blood pressure reduces
cardiovascular morbidity and mortality in
diabetic patients regardless of whether low-
dose diuretics, B-blockers, angiotensin-
converting enzyme inhibitors, or calcium
antagonists are used as first-line treatment.
Grossman, MesserliArch Intern Med
2000?602447-2452
24
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25
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26
Effect of DM on Mortality
SHEP-X
13.4 Year Follow-up
From Kostis et al
27
Hypertension Detection and Follow-Up Program
Results in Diabetic Subjects
Nondiabetics
Diabetics
5-yr all-cause 17 lower No difference mortality
in SC group between SC and RC
groups Patients with DBPs 90-104 22.2
lower 20.5 lower in mm Hg (466 in SC group SC
group patients)
1079 patients with history of diabetes or
fasting blood sugar gt 140 mg/dL Although
the relative decrease in mortality was similar in
the diabetic subjects, the baseline absolute
risk was greater in diabetic subjects and
absolute benefits were greater in those
individuals.
28
Plasma glucose levels at entry and
diuretic treatment on follow-up were
independent predictors of new diabetes but"
while the occurrence of new diabetes was an
independent predictor of cardiovascular risk, the
use of diuretics, albeit predictive of new
diabetes, did not show any independent relation
with the subsequent cardiovascular events.
Verdecchia, Hypertens 200443963-968
29
AHT Age 65
Amlodipine/Chlorthalidone
Relative Risk and 95 Confidence Intervals
0.50 1 2
Favors Amlodipine Favors
Chlorthalidone
05/15/03
30
AHT Age 65
Lisinopril/Chlorthalidone
Relative Risk and 95 Confidence Intervals


0.50 1 2
Favors Lisinopril Favors
Chlorthalidone
05/15/03
31
AHT Age 75
Amlodipine/Chlorthalidone
Relative Risk and 95 Confidence Intervals
0.50 1 2
Favors Amlodipine
Favors Chlorthalidone
05/11/03
32
AHT Age 75
Lisinopril/Chlorthalidone
Relative Risk and 95 Confidence Intervals
0.50 1 2
Favors Lisinopril Favors
Chlorthalidone
05/11/03
33
Systolic Hypertension in the Elderly Program
Influence of Diabetes on Cardiovascular Event
Rates
7-Yr Incidence of CV Events ()
34
Cardiovascular Events in Diabetics in the
Hypertension Optimal Treatment Study
CV Events/1000 Patient-Years
Major CV Events
Myocardial Infarctions
CV Mortality
CV events were reduced to a greater degree in
diabetics who achieved the lowest levels of
diastolic blood pressure Hansson L, et al.
Lancet 19983511755-1762
35
Cumulative 5-Year Rates (1000 Patient Years) of
Cardiovascular Events in the Systolic
Hypertension in the Elderly program
Active Active Therapy
Placebo Therapy Placebo Major CHD
events 9.2 16 6.9
7.6 Nonfatal MI or fatal CHD 7.7
13.1 5.1 5.7 Nonfatal and fatal
strokes 9.7 14.4
4.4 7.5 Major
cerebrovascular disease events 21.4
31.5 13.3 10.4
Placebo-treated diabetic patients had about 2-3
times the risk of a cardiovascular event as
placebo-treated nondiabetics
36
Systolic Hypertension in the Elderly
Trial Results in Diabetics

• Blood pressure changes - difference between
  therapy
• and placebo -9/-4 mm Hg
• In the placebo subjects, the rate of events in
  diabetics was
• twice that in nondiabetics. Rate of events
  became equal in
• treated diabetics compared with nondiabetics
• Therapy compared with placebo
• - Reduction of 63 in CV events
• - Reduction of 69 in strokes
• - Reduction of 70 in CV mortality

Absolute benefit was 36 compared with 8 CV
events/100 patient years that were prevented in
diabetics and nondiabetics, respectively.
37
Significant Differences in Outcomes in the
Clinical Trials
Heart Failure Other Rx Compared to
Diuretics/B-Blockers LA Nifedipine
2x INSIGHT Amlodipine
1.4x ALLHAT Verapamil (high risk)
1.3x CONVINCE
38
Results of Different Levels of Blood Pressure
Control in Hypertensive Patients with Type 2
Diabetes B-Blocker compared with ACE
Inhibitor-Based Treatment Program

• Better control of blood pressure compared with
  less aggressive treatment in 8.4-year follow-up
  of 1148 subjects (achieved blood pressure of
  144/82 mm Hg compared with 154/87 mm Hg)
• Reduced risk of
• Stroke (44)
• Fatal strokes (58)
• Death related to diabetes (32)
• Heart failure (56)
• Fatal and nonfatal coronary heart disease events
  (21) (trend but not significant)

• No difference in outcome between a
  captopril-based and an atenolol-
• based treatment program

UKPDS . BMJ 1998317703-713