1. ΜΕΤΑΒΟΛΙΚΟ ΣΥΝΔΡΟΜΟ. ΥΠΕΡΤΑΣΗ ΚΑΙ ΔΥΣΛΙΠΙΔΑΙΜΙΑ
Δημήτριος Ρίχτερ, MD, FESC, FAHA
- Διευθυντής Καρδιολογικής Κλινικής Ευρωκλινικής Αθηνών
Αντιπρόεδρος ΕΚΟΜΕΝ
- Γενικός Γραμματέας Ελληνικής Εταιρείας Λιπιδιολογίας.
- Μέλος ΔΣ ΕΛΙΚΑΡ

2. NCEP ATP III: The Metabolic Syndrome
Recommends a diagnosis when ³3 of these risk factors are present
Risk Factor
Defining Level
Abdominal obesity (Waist circumference)
Men Women
>102 cm (>40 in) >88 cm (>35 in) TG
³150 mg/dL (1.7 mmol/L)
The diagnosis of the Metabolic Syndrome, as defined by the NCEP ATP III guidelines, is established when 3 or more of the above risk determinants are present.1 The Metabolic Syndrome is a secondary target of risk-reduction therapy, after the primary target of LDL-C reduction.
The Metabolic Syndrome is associated with a constellation of lipid and non-lipid risk factors of metabolic origin, and include abdominal obesity, atherogenic dyslipidaemia, hypertension, insulin resistance (with or without glucose intolerance), and prothrombic and proinflammatory states.
NCEP ATP III provides a clinically useful definition of the Metabolic Syndrome because of the measurement of fasting glucose, rather than insulin resistance as seen in the WHO definition.
Reference
1. National Cholesterol Education Program, Adult Treatment Panel III, JAMA 2001:285;2486–2497.
HDL-C
Men Women
<40 mg/dL (1.0 mmol/L) <50 mg/dL (1.3 mmol/L)
Blood pressure
³130/³85 mmHg
Fasting glucose
³110 mg/dL (6.0 mmol/L)
Adapted from NCEP, Adult Treatment Panel III, JAMA 2001:285;2486–2497.

3. PREVALENCE OF METS IN GREECE
Mets-Greece study (Athyros et al) adults.
Prevalence 22.8%. Similar men and women. Increasing with age ( 4,7% 18-29y, 44,2% >60y).
62% 3 components, 28% 4, 10% all 5.
74th EAS Congress, Seville, April 2004
ATTICA study (Panagiotakos et al) adults.
Prevalence 19,8%. Men 25,2%, women 14,6%.
Prevalence increased with age.
Am Heart J 2004; 147:

4. The presence of the Metabolic Syndrome is associated with increased CHD, CVD and total mortality
In a recently published analysis from the Kuopio Ischaemic Heart Disease Risk Factor Study of a male cohort of 1209 subject followed for almost 12 years, it was clearly shown that the metabolic syndrome is associated with a statistically increased risk for CHD, CVD, and total mortality, using either the ATP III or the WHO definition of the metabolic syndrome.
Unadjusted Kaplan-Meier hazard curves for men with and without the Metabolic Syndrome based on factor analysis. Median follow-up was 11.6 ( ) years. Relative risks were determined by age-adjusted Cox proportional hazards regression analysis.
Lakka HM et al, J Am Med Assoc 2002;288:

5. ©2004 PPS®
Association of MI* With the Metabolic Syndrome and Individual Components
Odds Ratio 95% CI P Value
Metabolic syndrome <0.0001
Syndrome components
Abdominal obesity
High triglycerides
Low HDL-C
Hypertension
Insulin resistance†
*Self-reported.
†Fasting plasma glucose ³110 mg/dL.
Ninomiya JK et al. Circulation. 2004;109:42-46.

6. ©2004 PPS®
Association of Stroke* With the Metabolic Syndrome and Individual Components
Odds Ratio 95% CI P Value
Metabolic syndrome
Syndrome components
Abdominal obesity
High triglycerides
Low HDL-C
Hypertension
Insulin resistance†
*Self-reported.
†Fasting plasma glucose ³110 mg/dL.
Ninomiya JK et al. Circulation. 2004;109:42-46.

7. Major causes of death in USA 1990 and 2000
Mokdad AH et al. JAMA 2004

9. Risk of AMI associated with risk factors in the overall population
% Cont % Cases
OR (99% IC) adj age, sex, smoking
OR (99% IC) adj for all
ApoB/ApoA-1 (5 v 1)
20.0
33.5
3.87 (3.39, 4.42)
3.25 (2.81, 3.76)
Smoking
26.8
45.2
2.95 (2.72, 3.20)
2.87 (2.58, 3.19)
Diabetes
7.5
18.4
3.08 (2.77, 3.42)
2.37 (2.07, 2.71)
Hypertension
21.9
39.0
2.48 (2.30, 2.68)
1.91 (1.74, 2.10)
Abd Obesity (3 v 1)
33.3
46.3
2.22 (2.03, 2.42)
1.62 (1.45, 1.80)
Psychosocial -
2.51 (2.15, 2.93)
2.67 (2.21, 3.22)
Veg et fruits DIE
42.4
35.8
0.70 (0.64, 0.77)
0.70 (0.62, 0.79)
Exercise
19.3
14.3
0.72 (0.65, 0.79)
0.86 (0.76, 0.97)
Alcohol intake
24.5
24.0
0.79 (0.73, 0.86)
0.91 (0.82, 1.02)
Yusuf S et al, Lancet 2004

10. Declining HDL-C in the Population
Women
Men
1.5
1.4
1.3
1.2
1.1
0.0
>12,000 respondents to a biennial population survey in the Pawtucket Heart Health Program
Between 1981 and 1993, mmol/L (3.1 mg/dL) decline
Adjusted for other risk factor changes
1.3
1.2
1.1
1.0
0.0
Nonsmokers
Nonsmokers
Smokers
Smokers
1.5
1.4
1.3
1.2
1.1
0.0
Alcohol
1.3
1.2
1.1
1.0
0.0
Alcohol
HDL-C (mmol/L)
No Alcohol
No Alcohol
1.5
1.4
1.3
1.2
1.1
0.0
BMI <22.9
1.3
1.2
1.1
1.0
0.0
BMI <24.5
Slide 6. Declining HDL-C in the population
Current population trends in HDL-C show declining levels for both men and women across strata of other cardiovascular risk factors. In a 12-year population survey from the Pawtucket Heart Health Program, the mean population level of HDL-C declined 3 mg/dL. This is consistent with the growing problem with central obesity and insulin resistance and increasing prevalence of non–insulin dependent diabetes mellitus (type 2).
Reference:
Derby CA, Feldman HA, Bausserman LL, Parker DR, Gans KM, Carleton RA. HDL cholesterol: trends in two southeastern New England communities, Ann Epidemiol 1998;8:84-91.
BMI 27.6
BMI 27.9
'83-84
'87-89
'92-93
'85-86
'81-82
'89-90
'83-84
'87-89
'92-93
'85-86
'81-82
'89-90
Reprinted from Ann Epidemiol, Vol. 8, Derby CA et al., , copyright 1998, with permission from Elsevier. 10

13. Treatment of obesity Modest weight loss can be effective
 ~ kcal/day restriction
 energy expenditure as tolerated
Monitor blood pressure with anorectic drugs
Treat CHD, LVH and RVH risk factors aggressively
lipids, blood pressure, diabetes, hypertension
obstructive sleep apnea and respiratory problems
Poirier et al, Circulation 2006

17. Finnish Diabetes Prevention Study: Treating the IGT
Finnish Diabetes Prevention Study: Treating the IGT* Patient With Lifestyle Changes
Study Design
522 middle-aged, overweight† subjects
172 men, 350 women with IGT
BMI 31 kg/m2
mean age: 55 years
mean duration: 3.2 years
intervention group: individualized counseling
reducing weight, total intake of fat and saturated fat
increasing intake of fiber, physical activity
*Plasma glucose concentration of 140 to 200 mg/dL.
†BMI 25 kg/m2.
IGT=impaired glucose tolerance; BMI=body mass index.
Tuomilehto J et al. N Engl J Med. 2001;344:

18. Finnish Diabetes Prevention Study: Reduction in Risk for Diabetes*
23% 25
(n=257) 20 15
Diabetes (%)
11% 10
(n=265) 5
Intervention
Control
*P<0.001; 4-year results
Tuomilehto J et al. N Engl J Med. 2001;344:

20. Bariatric surgery and mortality
Prospective study
SOS study
N=4047 patients
10.9 yrs follow-up
Information: 99.9%
Sjostrom L et al, NEJM 2007

21. SOS: Mortality reduction with weight-loss surgery14
Deaths:
Control: 129 (6.3%)
Surgery: 101 (5.0%)
Unadjusted HR 0.76
( ), P = 0.04
Adjusted HR 0.71*
( ), P = 0.01 12
Control 10
Cumulative
mortality
(%) 8 6
Surgery 4 2 2 4 6 8 10 12 14 16
Years
*Adjusted for age, sex, risk factors
Sjöström L et al. N Engl J Med. 2007;357:

22. SOS: Causes of death Surgery (n) Controls Cardiovascular condition 4353
Cardiac
Myocardial infarction
Heart failure
Sudden death 13 2 20 25 5 14
Stroke 6
Other 3
Noncardiovascular condition 58 76
Cancer/meningioma
29/0
47/1
Infection 12
Thromboembolic disease 7 18
Total mortality
101
129
Sjöström L et al. N Engl J Med. 2007;357:

23. 2007 Guidelines for the Management of Arterial Hypertension
European Society of Hypertension European Society of Cardiology
Journal of Hypertension 2007;25:

24. Initiation of antihypertensive treatment
Other risk factors, OD or disease
Normal
SBP or DBP 80-84
High normal
SBP or DBP 85-89
Grade 1 HT
SBP or DBP 90-99
Grade 2 HT
SBP or DBP
Grade 3 HT SBP ≥180 or DBP ≥110
No other risk factors
No BP intervention
Lifestyle changes for several months then drug treatment if BP uncontrolled
Lifestyle changes for several weeks then drug treatment if BP uncontrolled
Lifestyle changes + immediate drug treatment
1-2 risk factors
Lifestyle changes
3 or more risk factors, MS, OD or diabetes
Lifestyle changes and consider drug treatment
Lifestyle changes + drug treatment
Diabetes
Established CV or renal disease

25. The Metabolic Syndrome
Subjects with the metabolic syndrome also have a higher prevalence of microalbuminuria, left ventricular hypertrophy and arterial stiffness than those without the metabolic syndrome. Their cardiovascular risk is high and the chance of developing diabetes markedly increased
In patients with a metabolic syndrome diagnostic procedures should include a more in-depth assessment of subclinical organ damage. Measuring ambulatory and home BP is also desirable

26. The Metabolic Syndrome
In all individuals with metabolic syndrome individuals intense lifestyle measures should be adopted. When there is hypertension drug treatment should start with a drug unlikely to facilitate onset to diabetes. Therefore, a blocker of the renin-angiotensin system should be used followed, if needed, by the addition of a calcium antagonist or a low-dose thiazide diuretic. It appears desirable to bring BP to the normal range
Lack of evidence from specific clinical trials prevents firm recommendations on use of antihypertensive drugs in all metabolic syndrome subjects with a high normal BP. There is some evidence that blocking the renin-angiotensin system may also delay incident hypertension

27. Hypertension Guidelines: ESH/ESC 2013

28. Definitions and classification of office blood pressure levels (mmHg)
Category
Systolic
Diastolic
Optimal
< 120
And
< 80
Normal
And/or
80-84
High normal
85-89
Grade 1 hypertension
90-99
Grade 2 hypertension
Grade 3 hypertension
> = 180
> = 110
Isolated systolic hypertension
>= 140
and
< 90

29. BP Goals all be treated to <140/90 mm Hg
Except : diabetes (<85 mm Hg diastolic)
In patients near 80 years age, the systolic blood-pressure target should be 140 to 150 mm Hg, but physicians can go lower than 140 mm Hg if the patient is fit and healthy-mentally & physically

31. Life style changes Salt
A reduction to 5 g per day can decrease systolic blood pressure about 1 to 2 mm Hg in normotensive individuals and 4 to 5 mm Hg in hypertensive patients, he said.
Wt loss
Losing about 5 kg can reduce systolic blood pressure by as much as 4 mm Hg, aerobic endurance training
can reduce systolic blood pressure 7 mm Hg

32. When to start drug Rx
Consider BP level and correlate with overall risk:
cardiovascular risk factors
overt cardiovascular disease
asymptomatic organ damage
diabetes
chronic kidney disease.

34. Asymptomatic Target Organ Damage (TOD)
Pulse pressure ( in the elderly) >= 60 mmHg
Electrocardiograhic LVH( Sokolow-Lyon index > 3.5 mV; RaVL > 1.` mV; Cornell voltage duration product> 244 mV* ms), or
Echocardiographic LVH [ LVM index: men > 115 g/m2; women > 95 g/m2 (BSA)]a
Carotid wall thickening (IMT > 0.9 mm) or plaque
Carotid- femoral PWV > 10 m/s
Ankle- brachial index < 0.9
CKD with Egfr ml/min/1.73 m2 (BSA)
Microalbuminuria ( mg/24 h), or albumin- creatinine ratio( mg/g; mg/mmol) (preferentially on morning spot urine) √ √

36. Combination Rx
For patients at high risk for cardiovascular events or those with a markedly high baseline blood pressure
In those at low or moderate risk for cardiovascular events or with mildly elevated blood pressure, a single starting agent is preferred.
For a high-risk individual, you can't play around with one drug after another, trying to control blood pressure

37. Drugs to be preferred in specific conditions

38. Compelling and possible contra-indications to the use of antihypertensive drugs

39. Effects of lipid-lowering therapy on CHD events in statin trials
Secondary 25 4S - P
Prevention
Primary 20
Prevention 4S - S
Simvastatin
LIPID - P
Patients with CHD event (%) 15
CARE - P
Pravastatin
HPS - P
Lovastatin 10
LIPID - S
WOSCOPS - P
Atorvastatin
CARE - S
The introduction of statins has had a dramatic impact on the treatment of atherosclerosis and the prevention of cardiovascular events. Data from many placebo-controlled trials show a clear association between the degree of LDL-C reduction and the degree of clinical benefit.1
By lowering lipid levels and reducing the risk of CHD, statins are among the most effective agents to reduce morbidity and mortality available to clinical practice.
Kastelein JJP. The future of best practice. Atherosclerosis. 1999; (Suppl 1):S17-S21.
WOSCOPS - S
HPS - S
ASCOT - P *
S=statin treated 5
ASCOT - S *
P=placebo treated
AFCAPS - P
AFCAPS - S
*Extrapolated to 5 years 90
110
130
150
170
190
210
LDL-C (mg/dL)
Modified from Kastelein JJP. Atherosclerosis. 1999;143(Suppl 1): S17-S21.

40. Metabolic Syndrome Subgroup
TNT Study Design: Post-Hoc Analysis of Patients With Metabolic Syndrome
Metabolic syndrome was based on the updated NCEP ATP III definition,1 and was defined as 3 of the following prior to open-label run-in:
Waist circumference: Men 40 inches (102 cm); Women 35 inches (88 cm)*
Triglycerides 150 mg/dL (1.7 mmol/L)
HDL-C: Men <40 mg/dL (<1.0 mmol/L); Women <50 mg/dL (<1.3 mmol/L)
Blood pressure 130/85 mm Hg
Fasting glucose 100 mg/dL (5.6 mmol/L)
Atorvastatin 10 mg
Open-label run-in
8 weeks
1-8 weeks
Screening and wash-out
Atorvastatin 10 mg
LDL-C target: 100 mg/dL (2.6 mmol/L)
Median follow-up = 4.9 years
Atorvastatin 80 mg
LDL-C target: 75 mg/dL (1.9 mmol/L)
Double-blind period n=5584
n=2764
n=2820
Baseline
Of 10,001 patients enrolled in the TNT trial, 5584 (56%) met the criteria for metabolic syndrome at screening.1
*BMI 28 substituted for waist circumference
1Grundy SM et al. Circulation. 2005;112:
Reference
1. Deedwania P, Barter P, Carmena R, et al, for the Treating to New Targets Investigators. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet. 2006;368:

41. Metabolic Syndrome Subgroup
Time to First Major Cardiovascular Event in Patients with Metabolic Syndrome (MetS)
All metabolic syndrome
Atorvastatin 10 mg (n=2820)
Atorvastatin 80 mg (n=2764)
HR = 0.71 (95% CI: 0.61, 0.84) P<.0001
Metabolic syndrome, no diabetes
Atorvastatin 10 mg (n=2191)
Atorvastatin 80 mg (n=2162)
HR = 0.70 (95% CI: 0.57, 0.84) P=.0002
Cumulative incidence of major cardiovascular events*
In the subgroup of metabolic syndrome patients without diabetes at screening, 178 (8.2%) receiving atorvastatin 80 mg and 225 (11.6%) receiving atorvastatin 10 mg had a primary event (30% relative risk reduction, P=.0002).1
*Coronary heart disease death, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, fatal or nonfatal stroke
Time (years)
Deedwania P et al. Lancet. 2006;368:
Reference
1. Deedwania P, Barter P, Carmena R, et al, for the Treating to New Targets Investigators. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet. 2006;368:

42. Metabolic Syndrome Subgroup
First Major Cardiovascular Event in Patients With Metabolic Syndrome: Summary
End point
No. of patients (%)
Atorvastatin 10 mg (n=2820)
Atorvastatin 80 mg (n=2764)
Major cardiovascular event*
367 (13.0)
262 (9.5)
CHD death
66 (2.3)
46 (1.7)
Nonfatal non–PR MI
201 (7.1)
139 (5.0)
Resuscitated cardiac arrest
6 (0.2)
10 (0.4)
Fatal/Nonfatal stroke
94 (3.3)
67 (2.4)
After a median follow-up of 4.9 years, 262 patients (9.5%) with metabolic syndrome receiving 80 mg and 367 (13%) receiving atorvastatin had a primary event.1
*HR = 0.71 (95% CI: 0.61, 0.84)
P<.0001
Data on file, Pfizer Inc, New York, NY.
Reference
1. Deedwania P, Barter P, Carmena R, et al, for the Treating to New Targets Investigators. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet. 2006;368:

43. Metabolic Syndrome Subgroup
Secondary Event Rates in Patients With Metabolic Syndrome (MetS) and Overall
Event rate (MetS) 10 mg 80 mg
Event rate (overall) 10 mg 80 mg
Any CV event 37.6% 30.9%
33.5% 28.1%
Major coronary 9.9% 7.3%
8.3% 6.7%
Any coronary 29.8% 23.3%
26.5% 21.6%
Cerebrovascular 6.0% 4.5%
5.0% 3.9%
CHF with hosp. 4.2% 3.1%
3.3% 2.4%
Treatment effect in patients with metabolic syndrome was consistent with the overall TNT study group.
Consistent with the overall population, in patients with metabolic syndrome there was no significant difference between the treatments for all-cause mortality.1
PAD 6.5% 6.3%
5.6% 5.5%
All-cause mortality 6.3% 6.2%
5.6% 5.7%
Atorvastatin 80 mg better
Atorvastatin 10 mg better
Deedwania P et al. Lancet. 2006;368:
Reference
1. Deedwania P, Barter P, Carmena R, et al, for the Treating to New Targets Investigators. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet. 2006;368:

51. Treating HDL: Nonpharmacologic Methods7 4 1 -2
Exercise overrated
HDL only when TG high
HDL only with intense, frequent exercise
Alcohol
Raises TG
Affects CETP activity
Modest HDL changes
Smoking cessation
Weight loss
P=0.015
Frequent, intense exercise
Changes in HDL-C Concentration (mg/dL)
Infrequent
exercise
Slide 7. Treating HDL: Nonpharmacologic methods
Efforts to increase HDL-C include both nonpharmacologic and pharmacologic means. Although most favorable cardiovascular risk interventions may lead to increased HDL-C levels, exercise is commonly recommended. While exercise is very important as a general cardiovascular risk intervention, it has only limited efficacy in increasing HDL-C levels, being modestly effective only in the setting of elevated triglycerides and in response to frequent and intense exercise. Additional abbreviation on slide: CETP= cholesteryl ester transfer protein.
References:
Couillard C, Despres JP, Lamarche B, et al. Effects of endurance exercise training on plasma HDL cholesterol levels depend on levels of triglycerides: evidence from men of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study. Arterioscler Thromb Vasc Biol 2001;21:
Kraus WE, Houmard JA, Duscha BD, et al. Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med 2002;347:
Control
Moderate
Intense
Couillard C et al. Arterioscler Thromb Vasc Biol 2001;21: | Kraus WE et al. N Engl J Med 2002;347: Copyright 2002 Massachusetts Medical Society. All rights reserved.

52. HDL-C Response to Exercise
Kokkinos et al1 studied the relationship between exercise and HDL-C in 2,906 healthy, nonsmoking men. They found that there was a dose-response relationship between miles run per week and increasing HDL-C levels. Most of the increases in HDL-C were noted in men who ran 7 to 14 miles a week, a distance and level of effort equivalent to moderate jogging or brisk walking 30 minutes daily, 3 to 5 times per week.
Savage et al2 found that women had greater improvement in HDL-C with cardiac rehabilitation than men, even though changes in fitness and body composition were similar. Women showed improvement regardless of baseline HDL-C, while only men with low HDL-C at baseline showed an increase in HDL-C.
Kokkinos PF, Holland JC, Narayan P, Colleran JA, Dotson CO, Papademetriou V. Miles run per week and high-density lipoprotein cholesterol levels in healthy, middle-aged men: a dose-response relationship. Arch Intern Med. 1995;155:
Savage PD, Brochu M, Ades PA. Gender alters the high-density lipoprotein cholesterol response to cardiac rehabilitation. J Cardiopulm Rehabil. 2004;24:

53. Lipids and Exercise Duration of exercise effect on lipids
TG increase delays for several hours after exercise and this effect can persist for hours or several days when exercise is prolonged and intense.
Usually HDL begins to rise after >10 weeks of exercise
Single exercise sessions reduce postprandial hyperlipidemia but have no other effect on lipids.
After exercise cessation lipids return on original values
The longer the exercise program lasted the longer the favorable lipid profile remains after exercise cessation.

54. Smoking Cessation Increases HDL-C Level
In study by Moffatt, smokers had HDL-C levels 15–20% lower than nonsmokers (P < 0.05).1
PROCAM showed less of an effect of smoking on HDL-C (7% lower than nonsmokers).2
HDL-C levels returned to normal within 30–60 days after smoking cessation.1
In eight women who smoked > 1 packs per day for 5 years, HDL-C levels increased from 51 to 64 mg/dL after quitting for 60 days.1
Smoking Cessation Increases HDL-C Level
Moffat evaluated the effects of smoking cessation in 26 women who had smoked at least 20 cigarettes per day for the preceding 5 years. Twelve subjects stopped smoking for 60 days (ex-smokers); six stopped smoking for 30 days and then resumed smoking for an additional 30 days (re-smokers); and eight subjects continued to smoke for the entire 60 days (smokers). Ten women who had never smoked served as controls (nonsmokers). Before smoking cessation, all three smoker groups had high-density lipoprotein cholesterol (HDL-C) levels that were 15–20% (P < 0.05) lower than those of the nonsmokers. (Other studies, however, have shown less of an effect of smoking on HDL-C levels, e.g., the Münster Heart Study [PROCAM], in which mean HDL-C levels were reduced by 6.4% in male smokers and by 6.7% in female smokers versus nonsmokers.) In ex-smokers, HDL-C levels increased by 5.7 mg/dL by day 30 and by an additional 6.8 mg/dL by day 60, reaching 63.9 mg/dL. In contrast, HDL-C levels in re-smokers returned to precessation values (50.7 mg/dL) by day 60 (P < 0.05).
References:
Moffatt RJ. Effects of cessation of smoking on serum lipids and high density lipoprotein-cholesterol. Atherosclerosis. 1988;74:85–89.
Cullen P, Schulte H, Assmann G. Smoking, lipoproteins, and coronary heart disease risk: data from the Münster Heart Study. Eur Heart J. 1998;19:1632–1641.
1. Moffatt RJ. Atherosclerosis 1988;74:85–89
2. Cullen P et al. Eur Heart J 1998;19:1632–1641

55. Weight and HDL-C
Inverse correlation between body weight and HDL-C is consistently observed in both men and women.
For every 3 kg of weight loss, HDL-C levels increase 1 mg/dL.
Weight and HDL-C In 1988, the National Cholesterol Education Program’s Panel Report identified obesity (i.e.,  30% overweight) as a factor for clinicians to consider when evaluating cholesterol concentrations and determining treatment. Even mild to moderate excess weight is associated with an increased risk of coronary heart disease. Dattilo and Kris-Etherton conducted a meta-analysis of 70 studies (published between 1966 and 1989) to examine the effects of weight loss by dieting on lipids and lipoproteins. They found a consistent linear association between weight loss and high-density lipoprotein cholesterol (HDL-C) concentrations in both men and women. For every 3 kg (7 lb) of weight loss, HDL-C levels increased 1 mg/dL when weight reduction was maintained.
References:
Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988;148:36–69.
Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of obesity and risk of coronary heart disease in women. N Engl J Med. 1990;322:882–889.
Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr. 1992;56:320–328.
Dattilo AM, Kris-Etherton PM. Am J Clin Nutr 1992;56:320–328

56. Caloric Restriction Acutely Lowers HDL-C Level
Trials of very-low-calorie diets show that HDL-C levels decrease by 2–12 mg/dL during acute caloric restriction.
After 12 wks, HDL-C returned to pretreatment range, and this trend was still apparent after 1 year.
Therefore, benefits of weight-loss programs should not be assessed during acute caloric restriction.
Caloric Restriction Acutely Lowers HDL-C Level
Trials of very-low-calorie diets show that high-density lipoprotein cholesterol (HDL-C) levels decrease by 2–12 mg/dL during acute caloric restriction. For example, Rössner and Björvell reported significant (P < 0.05) reductions in HDL-C concentrations after 6 weeks of weight loss in 118 grossly obese patients (mean weight in 46 men: 137 kg; mean weight in 72 women: 111 kg). After 12 weeks, however, HDL-C returned to the pretreatment range in both men and women, and this trend was still apparent after 1 year in 15 obese patients who continued to lose weight (weight at baseline: 120 kg; weight at Week 6: 105 kg; and weight at Week 52+: 100 kg). These data indicate that the HDL-C benefits of weight-loss programs should not be assessed during acute caloric restriction, since it may be expected that lipoprotein metabolism will differ in a catabolic early stage compared with a later stable situation at a lower body weight.
Reference:
Rössner S, Björvell H. Early and late effects of weight loss on lipoprotein metabolism in severe obesity. Atherosclerosis. 1987;64:125–130.
Rössner S et al. Atherosclerosis 1987;64:125–130

57. Alcohol Increases HDL-C Level
Alcohol increases HDL-C level in a dose-dependent manner.
Half bottle of wine per day (39 g alcohol) for 6 weeks significantly increased mean HDL-C level by 7 mg/dL in 12 healthy subjects.1
Wine intake did not significantly affect Total-C, Total-TG, or LDL-C.1
One beer per day (13.5 g alcohol) for 6 weeks significantly increased mean HDL-C level by 2 mg/dL in 20 healthy subjects.2
Beer intake did not significantly affect LDL-C, VLDL-C, TG, or apolipoproteins.
Alcohol Increases HDL-C Level
Moderate alcohol intake has been associated with a decreased risk of cardiovascular disease, which may be mediated by high-density lipoprotein cholesterol (HDL-C). Evidence indicates that alcohol intake increases HDL-C concentrations. For example, Thornton and colleagues showed that consumption of half a bottle of white wine (39 g alcohol) per day for 6 weeks significantly (P < 0.01) increased mean HDL-C levels––from 41 to 48 mg/dL––in 12 healthy, normolipidemic subjects (nine women and three men). None of the subjects was taking medication, and none smoked tobacco. The subjects’ wine intake did not significantly change total plasma cholesterol (Total-C), total triglyceride (Total-TG), or low-density lipoprotein cholesterol (LDL-C) concentrations. However, one must consider the calories added to the diet by alcohol use. The 39 g of alcohol consumed per day for 42 days in this study represent a total of 11,466 additional calories––the equivalent of 3 lbs of additonal weight (11,466 cal ÷ 3,600 cal/lb) over 6 weeks, or approximately 27 lbs per year! A more moderate alcohol intake was described by McConnell et al. In this study, 20 healthy nonsmokers (11 men and 9 women; aged 23–51 years) completed a 10-week program of controlled alcohol consumption, which consisted of 2 weeks of alcohol abstention; 6 weeks of alcohol use (one 12-ounce Samuel Adams Boston Lager––13.5 g of ethyl alcohol––each evening); and 2 additional weeks of abstention. Compared with the mean abstention level, the mean HDL-C level significantly (P = 0.03) increased 2 mg/dL (from 52 to 54 mg/dL) after consumption of a single, daily alcoholic beverage for 6 weeks. LDL-C, very-low-density-lipoprotein cholesterol (VLDL-C), TG, and apolipoprotein levels were not significantly changed.
References:
Stason WB, Neff RK, Miettinen OS, Hershel J. Alcohol consumption and non-fatal myocardial infarction. Am J Epidemiol. 1976;104:603–608.
Yano K, Rhoads GG, Kagan A. Coffee, alcohol, and risk of coronary heart disease among Japanese men living in Hawaii. N Engl J Med. 1977;287:405–409.
Miller NE. The evidence for the antiatherogenicity of high-density lipoprotein in man. Lipids. 1978;13:914–919.
Thornton J, Symes C, Heaton K. Moderate alcohol intake reduces bile cholesterol and raises HDL cholesterol. Lancet. 1983;ii:819–822.
McConnell MV, Vavouranakis I, Wu LL, Vaughan DE, Ridker PM. Effects of a single, daily alcoholic beverage on lipid hemostatic markers of cardiovascular risk. Am J Cardiol. 1997;80:1226–1228.
1. Thornton J et al. Lancet 1983;ii:819–822
2. McConnell MV et al. Am J Cardiol 1997;80:1226–1228

60. HDL-C Response to Pharmacological Intervention
Because all of the available drugs that increase HDL-C levels have significant effects on other lipoproteins, it has not been possible to prove, in clinical trials, the benefit of raising HDL-C in isolation.1 However, because of the known correlation of low HDL-C levels with increased CAD risk, the magnitude of the HDL-C elevation achievable with pharmacological treatments has become a point of interest in many trials of lipid-altering therapy. This slide shows the range of HDL-C elevations that have been observed with various lipid-modifying agents, used alone or in combination.1-4
1. Belalcazar LM, Ballantyne CM. Defining specific goals of therapy in treating dyslipidemia in the patient with low high-density lipoprotein cholesterol. Prog Cardiovasc Dis. 1998;41:
2. Hesberger M, von Eckardstein A. Low high-density lipoprotein cholesterol: physiological background, clinical importance and drug treatment. Drugs. 2003;63:
3. Goerdt C, Keith M, Rubins HB. Effects of phenytoin on plasma high-density lipoprotein cholesterol levels in men with low levels of high-density lipoprotein cholesterol. J Clin Pharmacol. 1995;35:
4. Miller M, Burgan RG, Osterlund L, Segrest JP, Garber DW. A prospective, randomized trial of phenytoin in nonepileptic subjects with reduced HDL cholesterol. Arterioscler Thromb Vasc Biol. 1995;15:

61. ACCORD Study Design Overall ACCORD Glycemia Trial: 10,251 participants
Lipid Trial: 5,518 in Lipid Trial
2765 randomized to fenofibrate
2753 randomized to placebo
Primary Outcome: First occurrence of a major cardiovascular event (nonfatal MI, nonfatal stroke, cardiovascular death)
87% power to detect a 20% reduction in event rate, assuming placebo rate of 2.4%/yr and 5.6 yrs follow-up in participants without events. 61

62. ACCORD Lipid Trial Eligibility
Stable Type 2 Diabetes >3 months
HbA1c 7.5% to 11%
High risk of CVD events = clinical or subclinical disease or 2+ risk factors
Age (limited to <80 years after Vanguard)
≥ 40 yrs with history of clinical CVD (secondary prevention)
≥ 55 yrs otherwise
Lipids
60 < LDL-C < 180 mg/dl
HDL-C < 55 mg/dl for women/Blacks; < 50 mg/dl otherwise
Triglycerides < 750 mg/dl if on no therapy; < 400 mg/dl otherwise
No contraindication to either fenofibrate or simvastatin 62

63. Baseline Characteristics
Mean or %
Age (yrs) 62
Total Cholesterol (mg/dl)
175
Women % 31
LDL-C (mg/dl)
101
Race / Ethnicity
HDL-C (mg/dl) 38
White % 68
Triglyceride (mg/dl)*
162
Black % 15
Blood pressure (mm Hg)
134/74
Hispanic % 7
Serum creatinine (mg/dl)
0.9
Secondary prevent % 37
Current smoking %
DM duration (yrs)* 9
On a statin % 60
A1c (%) *
8.3
On another LLA % 8
BMI (kg/m2) 32
On Insulin % 33
* Median values 63 63

64. 64

65. Primary Outcome 291 2.24 310 2.41 0.92 (0.79 - 1.08) 0.32 Rate (%/yr)
HR (95% CI)
P Value
Primary Outcome:
Major Fatal or Nonfatal
Cardiovascular Event
291
2.24
310
2.41
0.92
( )
0.32
Fenofibrate
Placebo
(N=2765)
(N=2753)
N of
Events 65

66. Prespecified Secondary Outcomes66