Download Metabolic Syndrome

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Aub Guru Hai, Mein Nahin
Sab Andhiyara Mit Gaya‚
Jab Deepak Dekhya Mahin
When "I“, the Ego, was with me, then I couldn’t
realize the almighty within; Now, the Almighty "is"
ever with me and there is no place for this Ego.
All the darkness (illusion) within me is mitigated,
on realizing the light (illumination) within.
SK
www.drsarma.in
Diabetic Hypertension
The Two Terrorists
THE ENORMITY OF THE
PROBLEM - COMPOUNDED
How Common is this Duo?
HTN is twice as common in DM
New onset DM is 2.5 times in HTN
20 to 40% of IGT pts have HTN
40 to 50% of Type 2 DM have HTN
Only 1/4 of HTN in DM is controlled
DM + HTN –  CV Risk 3 fold
What Causes HTN in DM
• Metabolic Syndrome – Mainly IR, ED,  BG
• Excessive RAAS activity is the main mechanism
• HTN due to nephropathy in T2DM – GS - KWL
• Renal scarring - Recurrent pyelonephritis
• Endocrine causes for both HTN & DM
– Cushing’s, Conn’s, Pheochromo, Acromegaly
• Coincidental – DM on existing HTN
• Diabetogenic antihypertensive drugs (D and B)
• Drugs causing both HTN & DM – OCP, CS
Each Perpetuates the Other
DIABETES
HYPERTENSION
Relative Risk of DM + HTN
Diabetes + HTN versus Diabetes
• Neuropathy
1.6
• Nephropathy
2.0
• Retinopathy
2.0
• Stroke
4.0
• CHD
3.0
• Mortality
2.0
Difficulties of HTN in DM
• Systolic HTN more common in DM
• S-HTN is a stronger predictor of CVE
• 65% of T2DM have S-HTN
• S-HTN is more difficult to control
• Depression is more in DM – Adherence Rx
• ‘Clinician Inertia’ is a big problem
• Glycemic control only is the focus – No VP
The Compound Jeopardy !!
Insulin Resistance
Obesity
MS with HT associated
2x
Diabetes
4x
CAD, CKD, PAD, CVD – All same
Reilly MP et al – Circulation 2003; 108: 1546-1551
THE DASAVATARAM AND
THE VISWA ROOPAM
IR,  Insulin
Dyslipidemia
IGT, IFG
ED, Vessel
Increased
CV Risk
Pro Thrombotic
Hypertension
Visceral obesity
Pro Inflammatory
Perpetuating Circus
Diabetes
 BP
CKD
ED
 Lipids
CAD
The Devastating Conspiracy
DM
HT
CAD
CKD
RF for Nephropathy in DM
Dysglycemia
and HTN
AT gene
Tobacco
ACE gene
Na/Li pump
CKD
Progression of DM - Nephropathy
Type 2 DM with
No Albuminuria
Type 2 DM with
Microalbuminuria
Type 2 DM with
Macroalbuminuria
Type 2 DM with
  GFR and ESRD
ACR < 30
30 – 300
> 300
eGFR < 30
Nephropathy in DM
Years after onset of DM
Outcomes of DM Nephropathy
CVE
• Prevention
• Management
Diabetic
Nephropathy
ESRD
• Early Detection
• Prevent worsening
THE EVIDENCE BASE
DM + HT IS DANGEROUS
Top 3 Countries for Diabetes
60
1995
2025
Millions of Cases
50
40
30
20
10
0
India
China
Data from King H et al. Diabetes Care. 1998;21:1414-1431.
US
CV Mortality Risk
CV Mortality Risk Doubles with
Each 20/10 mm Hg BP Increment
8
7
6
5
4
3
2
1
0
115/75
135/85
155/95
SBP/DBP (mm Hg)
Lewington S, et al. Lancet. 2002; 60:1903-1913.JNC VII. JAMA. 2003.
175/105
SBP & CV Mortality in T2DM
CV Mortality rate per
10,000 person-yr
250
Nondiabetic
Diabetic
200
150
100
50
0
<120
120-139
140-159
160-179
SBP (mm Hg)
Stamler J et al. Diabetes Care. 1993;16:434-444.
180-199
≥200
Metabolic Syndrome and Age
33% of Indian Adults Have Metabolic Syndrome
45
40
Men (n=4265)
Women (n=4559)
35
30
25
20
15
10
5
0
20-29
30-39
40-49
Adapted from: Ford ES, et al. JAMA. 2002;287:356-359.
50-59
60-69
?
70
Age in yr
HOT Study – Imp. of DBP
Events/1000 pt-years
25
DM
non-DM
20
15
10
5
0
<90
<85
Target diastolic BP
Lancet 1998; 351: 1755–62
<80
5-Year Cumulative Event Rates for All
Major Cardiovascular Events (%)
SHEP – DM and CVE Rates
35
30
Active treatment
RR .66, 95% Cl .46 - .94
Placebo
25
20
RR .66, 95% Cl .55 - .79
15
10
5
0
Nondiabetes
Curb JD, et al. JAMA. 1996;276:1886-1892.
Diabetes
Mortality and Morbidity in DM
SHEP
SYST-EUR
SHEP
-25
Rate in Placebo Group*
Mortality
-55
35.6
45.1
63.0
57.6
28.8
26.6
32.2
21.3
-34
CV Endpoints
-22
-59
Stroke
-73
SYST-EUR
-56
Coronary
-57
Active Better
-100%
-50%
*Number of endpoints / 1000 patient years
0
50%
Placebo Better
HOT – Diabetic Hypertension
90 mmHg
Myocardial Infarction
80 mmHg
Major CV Events
Stroke
CV Mortality
Total Mortality
0
Lancet 1998; 351: 1755–62
|
|
|
|
1
2
3
4
BP v/s Glucose Control
0 -
Stroke
Any DM
End Point
DM Death
Reduction in Risk (%)
-10 -
-20 -30 Tight Glucose Control
-40 -50 -
UKPDS. BMJ. 1998:317;703-712.
Tight BP Control
*P < 0.05
Microvascular
Complications
Hypertension & DM Mortality
Captopril
(UKPDS)
Atenolol
(UKPDS)
Diuretic
(SHEP)
Nitrendipine
(Syst-Eur)
Nitrendipine
(Syst-China)
0%
20%
40%
60%
80%
100%
STENO-2 Study in DM – Event 
1. Nephropathy
 56%
2. Proliferative retinopathy
 55%
3. Cardiovascular events
 59%
4. Total Mortality
 40%
%  in Complications with intensive Rx
NEJM 2003; 358:580
SOLVD: Enalapril – Reduction
in New-Onset Diabetes
36
Absolute risk reduction in
development of diabetes
30
24
No. of New
Diabetes
Cases
18
P <.0001
12
6
0
Placebo
Vermes E et al. Circulation. 2003;107:1291-1296.
Enalapril
SOLVD: Enalapril – Reduction
in New-Onset Diabetes in IFG
Patients With IFG at Baseline (n = 55)
% Diabetes-Free
100
Enalapril
45% risk reduction
P < 0.0001
75
50
Placebo
25
0
1
2
3
Time (y)
Vermes E et al. Circulation. 2003;107:1291-1296.
4
5
Events/1000 Patient-Years
LIFE Study: Results
30
25
P <.05
Atenolol
Losartan
25% decrease in RR
20
15
P <.001
10
5
0
Primary Endpoint: CV Death, MI,
and Stroke
Dahlöf B et al. Lancet. 2002;359:995-1003.
New Cases of Diabetes
ALLHAT: Incidence of New-Onset
Diabetes at 4 Years
P .001
P = .04
15
11.6%
9.8%
10
8.1%
%
5
0
Chlorthalidone
Amlodipine
Lisinopril
ALLHAT Officers and Coordinators. JAMA. 2002;288:2981-2997.
THE EVIDENCE BASE
MANAGEMENT GUIDE
Risk Reduction for CAD and CKD
Dysglycemia
Hypertension
Dyslipidemia
Risk Reduction for CAD and CKD
Na &
K
SFA
UFA
CHO
GL
Mandatory Clinical Actions
BP check – Goal < 130/80, WC, BMI
MAU/ACR on spot urine < 30, LVH
Serum creatinine – eGFR > 90 ml/min
Screen for MS and RF for CAD, ABI, Eye
HbA1c, Full lipid profile, Lp(a), hs-CRP
HTN – Lifestyle modifications
• Regular 30’ of moderately intense exercise
• No tobacco and minimizing alcohol
• Na restriction to < 6 g of Nacl per day
• Avoiding high salt foods – pickles, savouries
• Four adult family – 6 x 30 x 4 = 720 g (500 g)
• Use of K containing foods – fruits, vegetables
• Weight reduction – goal ideal weight
• Reducing coffee consumption
HTN – Lifestyle modifications
Weight Reduction
• 5-20 mmHg/10kg
DASH diet eating
• 8-14 mmHg
Sodium Restriction
• 2-8 mmHg
Physical Activity
• 4-9 mmHg
Alcohol Abstinence
• 2-4 mmHg
All put together
• 20-55 mmHg
DASH Diet Plan
Type of Food
Servings (1600 K cal)
Grains (whole grains)
6 per day
Vegetables
3 per day
Fruits (not tinned juices)
4 per day
Low fat milk
2 per day
Lean meat, poultry
3 per day
Nuts, seeds (dry roast, soak)
3 per week
Fats and oils
2 per day
Sweets and pastries
0 per day
Salt at table & salted foods
None
Benefit of Quitting Smoking in HTN
 CAD incidence (%) over 5 years
# Cigarettes/day
Men
Women
10
19
24
20
34
40
40
57
64
BP Targets in DM
Ideal Blood Pressure
Without proteinuria
< 130/80
With proteinuria
< 125/75
Goal BP maximum for DM
< 130/80
Almost all DM pts require > 1 drug for HTN
Identify the co-morbidity – CAD, CKD, CVD
ADA Guidelines on Rx. of HTN with DM
Systolic
Diastolic
Goal (mmHg)
<130
<80
Behavioral therapy alone
(maximum 3 months) TLC
130–139
80–89
Behavioral therapy +
pharmacologic treatment
140
90
Arauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82.
THE EVIDENCE BASE FOR
MANAGEMENT OPTIONS
Management Options
NDHP - CCBs
Diuretics
MNT
ACEi, ARB
Exercise
New BB
Choice of Drug Rx for HTN
Younger than 55 years
ACEi or ARB (A)
Older than 55 years
Diuretic (D) or CCB (C)
A + D or C
A+D+C
A + D + C + new
or 
blocker
HTN Rx. Algorithm in DM
BP > 130/80 (2 readings)
>140/90/MAU/TOD
No TOD / MAU
TLC cont.
ACE/ARB + TLC 1 M
Yes
Goal BP 130/80
Yes
Add LD Diuretic
1 Month
No
Yes
Add Verapamil
1 Month
No
Yes
Sub Amlodepine
1 Month
No
Yes
Add new B /
1 Month
No
Diabetes Spectrum 2004, Vol. 5, # 3, 103-108
No
?
Physiological RAAS Effects
Renin Angiotensin Aldosterone System
The RAAS Blockade
Ang I
ACE
ACEi
+
+
Ang II
Non-ACE
Pathways
AT1 Receptor
AT2 Receptor
Aldosterone
MRA
Renal Injury
and Proteinuria
Progressive Diabetic Nephropathy
ARB
Adverse Renal and CV
Effects of Aldosterone
Aldosterone
•Glomerulosclerosis
•Interstitial Fibrosis
•Proteinuria Brand
•Renal Failure
•LVH
•Endothelial
•Cardiac Fibrosis Dysfunction
•LV Dysfunction
name:
Eplirestat
•Inflammation
•Heart Failure
•Oxidative Stress
MRA – Eplerenone
ACEi or ARB – A must for VP
• Antihypertensive, vasoprotective,
anti-thrombotic and anti-inflammatory
• Inevitable in DM more so in DM + HT/CVD
• Reduce CV events, Reduce atherosclerosis
• Reduce renal disease - a strong CV risk factor
• Metabolically ‘friendly’ drugs in DM
• They prevent new onset DM, Nephropathy
• Well-tolerated with few side effects
ACE inhibitor or ARB
• Renal impairment – These improve
e-GFR, microalbuminuria or proteinuria
• LV dysfunction (along with new  blocker)
• Previous MI (along with new  blocker)
• Contraindicated in pregnancy
• Relative contraindications
- Bilateral renal artery stenosis
- Severe renal impairment (Cr > 3.0)
- Monitor renal function
- Angioedema, ACEi cough
Vascular Protection in DM
1. Atorvastatin (Lipid management)
2. ASA (Acetyl Salicylic Acid) – (enteric
coated)
3. ACE inhibitors or ARBs
4. A1c control (Glycemic control)
5. Blood pressure goal (<130/80)
6. Control of Nephropathy, Proteinuria (MAU)
7. Cigarette smoking cessation
8. Weight and waist management
9. Physical Activity – at least 2 km/d x 5 d
# of Antihypertensive Agents
Needed to Achieve Target BP
Trial
Target BP (mm Hg) 1
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
IDNT
No. of antihypertensive agents
2
3
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
Bakris GL et al. Am J Kidney Dis. 2000;36:646-661; Lewis EJ et al. N Engl J Med.
2001;345:851-860. Cushman WC et al. J Clin Hypertens. 2002;4:393-404.
4
JNC 7 – Antihypertensive Agents
Based on Favorable Outcome Data From Clinical Trials
CHF
Diuretic
BB
ACEI
ARB















Post-MI
CAD Risk

Diabetes Mellitus

Nephropathy
Stroke Prevention


Chobanian AV et al. JAMA. 2003;289:2560–2572.
CCB
AA


Other Effects of HTN Drugs
Drug Class
Dysglycemia
Dyslipidemia


CCBs


Diuretics


 Blockers


 Blockers


ACEi and ARB
DM + Co-morbidity
DM + Co-morbidity
Primary Drug
Add on Drug Rx.
DM alone
ACEi low dose
BP & ACR watch
DM + HT  LVH
ACEi or ARB
D + C + New B
DM + MAU/AU
ARB, (ACEi)
Indap + Carve
DM + CAD/MI
ACEi (ARB)
Carve / New B
DM + CHF
ACEi or ARB
D + AA + B
-Blockers and their Effects
1,
1
ISA
2
,
1
Name of
B
Receptor
Acebutolol
1
ISA
Yes
Comment
Not Good
Penbutolol
1,
2
Yes
Bad
Pindolol
1,
2
Yes
Bad
Propranolol
1,
2
No
No Good
Nadolol
1,
2
No
No Good
Timolol
1,
2
No
No Good
No
No
No
OK
Very Good
Excellent
No
No
No
Excellent
Emergency
CHF, IHD
Atenolol
Metoprolol
Nebivolol
Bisoprolol
Labetalol
Carvedilol
1
1
1
1
,
,
1,
2
1,
2
Advantages of Carvedilol
Neutral on Glycemic control
Improves IR and MS, Lipid Neutral
Add on to RAAS blockade in DM
Improves MAU / ACR and ED
First
blocker approved for CHF
GEMINI trial and OPTIMIZE-HF Study
Ideal anti HTN drug in DM
•
•
•
•
•
•
•
•
•
•
Must decrease blood pressure to  130/80
Must reduce the RAAS activity, improve ED
Must prevent, improve or arrest proteinuria
Must prevent and protect from CAD, CKD, CHF
Must be favourable on glycemic control
Must improve the dyslipidemia – not worsen it
Must not worsen peripheral arterial disease
Must improve ED and not cause impotence
Must not decrease eGFR and  serum creatinine
Must not raise uric acid, serum potassium
What should We take home ?
 ‘Clinician Inertia’ for HTN in DM must be overcome
 HTN in DM is serious; So manage aggressively
 TLC, Lipid control, Glycemic targets – VP is a must
 HTN Rx. delays or arrests CVD, CKD, PAD, CVD
 ACEi or ARBs are the main stay of Rx -  RAAS
 Postural hypotension, DAN are important in Rx
 MAU/ACR must for all DM – Predict CAD, CKD
 Typically 2 or more drugs are needed for HTN Rx.
 New
B, Carvedilol, CCBs are add-on drugs
Amaedhya poornam, krimi raasi samkulam,
Swaabhava gandham, asaucham, adhruvam |
Sareeram, mootra pureesha bhaajanam
Ramanti moodha, viramanti pandithaa |
Full of filth, ridden with all bacteria and worms,
Naturally stinking, unclean to the core & perishable,
This body of ours, is drenched in excreta & secreta,
Only the fools engross in it, but the wise shun it.
VC by ASA