Metabolic Syndrome

1
Jab Mein Thaa, Tab Guru Nahin Aub Guru Hai,
Mein Nahin Sab Andhiyara Mit Gaya Jab Deepak
Dekhya Mahin When "I, the Ego, was with me,
then I couldnt 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
2
Diabetic Hypertension

• Dr. R.V.S.N. Sarma.,
• M.D., M.Sc., (Canada)

3
The Two Terrorists
4
The ENORMITY of the problem - compounded
5
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
6
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
• Cushings, Conns, Pheochromo, Acromegaly
• Coincidental DM on existing HTN
• Diabetogenic antihypertensive drugs (D and B)
• Drugs causing both HTN DM OCP, CS

7
Each Perpetuates the Other
8
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

9
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

10
The Compound Jeopardy !!
Insulin Resistance
Diabetes
Obesity
MS with HT associated
2 x
4 x
CAD, CKD, PAD, CVD All same
Reilly MP et al Circulation 2003 108 1546-1551
11
The DASAVATARAM andTHE viswa roopam
12
IR, ? Insulin
IGT, IFG
Dyslipidemia
Increased CV Risk
Hypertension
ED, Vessel
Visceral obesity
Pro Thrombotic
Pro Inflammatory
13
Perpetuating Circus
Diabetes
? BP
CKD
ED
? Lipids
CAD
14
The Devastating Conspiracy
15
RF for Nephropathy in DM
16
Progression of DM - Nephropathy
17
Nephropathy in DM
Years after onset of DM
18
Outcomes of DM Nephropathy
Diabetic Nephropathy
19
The EVIDENCE BASEDM HT is dangerous
20
Top 3 Countries for Diabetes
Data from King H et al. Diabetes Care.
1998211414-1431.
21
CV Mortality Risk Doubles withEach 20/10 mm Hg
BP Increment
CV Mortality Risk
8
7
6
5
4
3
2
1
0
115/75
135/85
155/95
175/105
SBP/DBP (mm Hg)
Lewington S, et al. Lancet. 2002
601903-1913.JNC VII. JAMA. 2003.
22
SBP CV Mortality in T2DM
250
Nondiabetic Diabetic
CV Mortality rate per 10,000 person-yr
200
150
100
50
0
lt120
120-139
140-159
160-179
180-199
200
SBP (mm Hg)
Stamler J et al. Diabetes Care. 199316434-444.
23
Metabolic Syndrome and Age
33 of Indian Adults Have Metabolic Syndrome
Prevalence,
Age in yr
Adapted from Ford ES, et al. JAMA.
2002287356-359.
24
HOT Study Imp. of DBP
Lancet 1998 351 175562
25
SHEP DM and CVE Rates
35
Active treatment
RR .66, 95 Cl .46 - .94
Placebo
30
25
20
5-Year Cumulative Event Rates for All Major
Cardiovascular Events ()
RR .66, 95 Cl .55 - .79
15
10
5
0
Diabetes
Nondiabetes
Curb JD, et al. JAMA. 19962761886-1892.
26
Mortality and Morbidity in DM
SHEP
SYST-EUR
SYST-EUR
SHEP
-25
Rate in Placebo Group
Mortality
35.6
45.1
-55
-34
CV Endpoints
63.0
57.6
-22
-59
26.6
Stroke
28.8
-56
-73
21.3
32.2
Coronary
-57
Placebo Better
Active Better
50
-100
-50
0
Number of endpoints / 1000 patient years
27
HOT Diabetic Hypertension
90 mmHg
Myocardial Infarction
80 mmHg
Major CV Events
Stroke
CV Mortality
Total Mortality




0
1
2
3
4
Lancet 1998 351 175562
28
BP v/s Glucose Control
Any DM
Microvascular

Stroke
End Point
DM Death
Complications
0 -
-10 -
-20 -
Reduction in Risk ()
-30 -
Tight Glucose Control
-40 -
Tight BP Control
P lt 0.05
-50 -
UKPDS. BMJ. 1998317703-712.
29
Hypertension DM Mortality
Captopril (UKPDS) Atenolol (UKPDS) Diuretic (
SHEP) Nitrendipine (Syst-Eur) Nitrendipine
(Syst-China)
0
20
40
60
80
100
30
STENO-2 Study in DM Event ?

• Nephropathy ? 56
• Proliferative retinopathy ? 55
• Cardiovascular events ? 59
• Total Mortality ? 40
• ? in Complications with intensive Rx

NEJM 2003 358580
31
SOLVD Enalapril Reductionin New-Onset Diabetes
Absolute risk reduction in development of
diabetes
No. of New Diabetes Cases
P lt.0001
Vermes E et al. Circulation. 20031071291-1296.
32
SOLVD Enalapril Reductionin New-Onset
Diabetes in IFG
Patients With IFG at Baseline (n 55)
100
Enalapril
Diabetes-Free
45 risk reduction P lt 0.0001
75
50
Placebo
25
0
1
2
3
4
5
Time (y)
Vermes E et al. Circulation. 20031071291-1296.
33
LIFE Study Results
P lt.05
25 decrease in RR
P lt.001
Dahlöf B et al. Lancet. 2002359995-1003.
34
ALLHAT Incidence of New-Onset Diabetes at 4 Years
P ?.001
P .04
11.6
9.8
8.1

Chlorthalidone
Amlodipine
Lisinopril
ALLHAT Officers and Coordinators. JAMA.
20022882981-2997.
35
The EVIDENCE BASEMANAGEMENT Guide
36
Risk Reduction for CAD and CKD
Management of Components
Dysglycemia
Hypertension
Dyslipidemia
37
Risk Reduction for CAD and CKD
Management of Components
?CHO ?GL
?Na ?K
?SFA ?UFA
S
S
O
38
Mandatory Clinical Actions
39
HTN Lifestyle modifications

• Regular 30 of moderately intense exercise
• No tobacco and minimizing alcohol
• Na restriction to lt 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

40
HTN Lifestyle modifications
41
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
42
Benefit of Quitting Smoking in HTN
? CAD incidence () over 5 years
Cigarettes/day Men Women
10 19 24
20 34 40
40 57 64
43
BP Targets in DM

• Ideal Blood Pressure
• Without proteinuria lt 130/80
• With proteinuria lt 125/75
• Goal BP maximum for DM lt 130/80
• Almost all DM pts require gt 1 drug for HTN
• Identify the co-morbidity CAD, CKD, CVD

44
ADA Guidelines on Rx. of HTN with DM

• Systolic Diastolic
• Goal (mmHg) lt130 lt80
• Behavioral therapy alone 130139 8089
• (maximum 3 months) TLC
• Behavioral therapy ?140 ?90
• pharmacologic treatment

Arauz-Pacheco C et al. Diabetes Care.
200326(suppl)S80S82.
45
The EVIDENCE BASE FORMANAGEMENT OPTIONS
46
Management Options
NDHP - CCBs
Diuretics
MNT
ACEi, ARB
Exercise
New BB
47
Choice of Drug Rx for HTN
Younger than 55 years
Older than 55 years
1
ACEi or ARB (A)
Diuretic (D) or CCB (C)
2
A D or C
3
A D C
4
A D C new ? or ?? blocker
48
HTN Rx. Algorithm in DM
BP gt 130/80 (2 readings)
No TOD / MAU
gt140/90/MAU/TOD
ACE/ARB TLC 1 M
TLC cont.
Yes
No
Yes
Add LD Diuretic
No
1 Month
Add Verapamil
Yes
No
1 Month
Sub Amlodepine
Yes
1 Month
No
Add new ?B /??
No
Yes
1 Month
?
Diabetes Spectrum 2004, Vol. 5, 3, 103-108
49
Physiological RAAS Effects
50
Renin Angiotensin Aldosterone System
51
The RAAS Blockade
Ang I
Non-ACE Pathways
ACE
Ang II
ACEi
ARB

AT2 Receptor
Aldosterone

Renal Injury and Proteinuria
Progressive Diabetic Nephropathy
52
Adverse Renal and CVEffects of Aldosterone
Aldosterone

• Glomerulosclerosis
• Interstitial Fibrosis
• Proteinuria
• Renal Failure

• LVH
• Cardiac Fibrosis
• LV Dysfunction
• Heart Failure

• Endothelial
• Dysfunction
• Inflammation
• Oxidative Stress

MRA Eplerenone Brand name Eplirestat








53
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

54
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 gt 3.0)
• - Monitor renal function
• - Angioedema, ACEi cough

55
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 (lt130/80)
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

56
of Antihypertensive Agents Needed to Achieve
Target BP
No. of antihypertensive agents
Target BP (mm Hg)
Trial
1
2
3
4
UKPDS DBP lt85
ABCD DBP lt75
MDRD MAP lt92
HOT DBP lt80
AASK MAP lt92
IDNT SBP lt135/DBP lt85
ALLHAT SBP lt140/DBP lt90
Bakris GL et al. Am J Kidney Dis.
200036646-661 Lewis EJ et al. N Engl J Med.
2001345851-860. Cushman WC et al. J Clin
Hypertens. 20024393-404.
57
JNC 7 Antihypertensive Agents
Based on Favorable Outcome Data From Clinical
Trials
BB
ACEI
ARB
CCB
AA
Diuretic
CHF Post-MI CAD Risk Diabetes Mellitus Nephropathy
Stroke Prevention
? ? ?
? ? ?
? ?
? ?
? ? ? ? ?
? ? ? ?
?
?
Chobanian AV et al. JAMA. 200328925602572.
58
Other Effects of HTN Drugs
Drug Class Dysglycemia Dyslipidemia
ACEi and ARB ? ? ? ?
CCBs ? ?
Diuretics ? ?
? Blockers ? ? ?
? Blockers ? ?
59
DM Co-morbidity
DM Co-morbidity
Primary Drug
Add on Drug Rx.
DM alone DM HT ? LVH DM MAU/AU DM CAD/MI DM
CHF
ACEi low dose ACEi or ARB ARB, (ACEi) ACEi
(ARB) ACEi or ARB
BP ACR watch D C New ?B Indap Carve
Carve / New ?B D AA ?B
ACEi ARB extra benefit ? CCBs NDHP (Vera,
Dil) - DHP
60
? -Blockers and their Effects
61
Name of ? B Receptor ISA Comment
Acebutolol ?1 Yes 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
Atenolol ?1 No OK
Metoprolol ?1 No Very Good
Nebivolol ?1 No Excellent
Bisoprolol ?1 No Excellent
Labetalol ?, ?1, ?2 No Emergency
Carvedilol ?, ?1, ?2 No CHF, IHD
62
Advantages of Carvedilol
GEMINI trial and OPTIMIZE-HF Study
63
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

64
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

65
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