Abstract
The metabolic syndrome or cardiovascular dysmetabolic syndrome is characterized by obesity, central obesity,insulin resistance, atherogenic dyslipidemia, and hypertension. The major risk factors leading to this syndromeare physical inactivity and an atherogenic diet and cornerstone clinical feature is abdominal obesity oradiposity. In addition, patients usually have elevated triglycerides, low HDL cholesterol, elevated LDLcholesterol, other abnormal lipid parameters, hypertension, and elevated fasting blood glucose. Impairedfibrinolysis, increased susceptibility to thrombotic events, and raised inflammatory markers are also observed.Given that India has the largest number of subjects with type-2 diabetes in the world it can be extrapolatedthat this country also has the largest number of patients with the metabolic syndrome. Epidemiologicalstudies confirm a high prevalence. Therapeutic approach involves intervention at a macro-level and controlof multiple risk factors using therapeutic lifestyle approaches (diet control and increased physical activity,pharmacotherapy - anti-obesity agents) for control of obesity and visceral obesity, and targeted approach forcontrol of individual risk factors. Pharmacological therapy is a critical step in the management of patientswith metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. Anti-obesitydrugs such as sibutramine and orlistat can be tried to reduce weight and central obesity and jointly controlthe metabolic syndrome components. Other than weight loss, there is no single best therapy and treatmentshould consist of treatment of individual components of the metabolic syndrome. Newer drugs such as theendocannabinoid receptor blocker, rimonabant, appear promising in this regard. Atherogenic dyslipidemiashould be controlled initially with statins if there is an increase in LDL cholesterol. If there are other lipidabnormalities then combination therapy of statin with fibrates, nicotinic acid, or ezetimibe should beconsidered. For insulin resistance, drugs such as thiazolidinediones and renin-angiotensin system blockersare available. Available evidence suggests that angiotensin converting enzyme (ACE) inhibitors andangiotensin receptor blockers (ARBs) may be more beneficial for treatment of hypertension in patients withmetabolic syndrome compared to others as these drugs also prevent development of diabetes. Patients withmetabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothromboticstate and aspirin may be beneficial for primary prevention in these patients. The new developments in thetreatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor (PPAR)agonists and cannabinoid receptor-1 antagonists, will broaden the horizons of the current treatment options.Fixed-dose combination polypharmacy using a single pill is an interesting concept that needs to be evaluatedin long-term prospective trials in such patients. ©

Multifaceted etiology of cardiovascular diseases,especially coronary heart disease, has beenrecognized for a long time1 and clustering of multiplecardiovascular risk factors has been known for at least80 years. Kylin initially reported that hypertension,hyperglycemia and high uric acid levels in the sameindividual predicted increased risk of coronary heartdisease.2 The Framingham Study initially describedimportance of various risk factors for cardiovasculardisease and later concluded that multiple risk factors such as smoking, hypertension, and lipid abnormalitieswere important. Many subsequent prospective studieshave confirmed these findings.

*University of California San Francisco, Fresno, CA, USA.
**Monilek Hospital and Research Centre, Jaipur 302004 India.

Abnormalities of glucose metabolism and diabeteswere added to this risk factor conglomerate later.Although insulin resistance in diabetes was reportedby Himsworth in 1939 in a series of GoulstonianLectures to the Royal College of Physicians in London,3insulin resistance syndrome as a disease entity wasreported in 1988 by Reaven who reported clustering ofmultiple abnormalities of glucose and lipid metabolismand called it syndrome-X or insulin resistancesyndrome.4 He included insulin resistance,hyperglycemia, hypertension, low HDL cholesterol andhigh VLDL triglycerides. He surprisingly missed obesity or visceral obesity from the definition which was lateradded as a crucial abnormality. Various names weresubsequently proposed the latest being the metabolicsyndrome. The cause of the metabolic syndrome remainsobscure. Reaven proposed that insulin resistance wasthe most important abnormality4,5 while Lemieux et alproposed that visceral obesity and hypertriglyceridemicwaist was important.6 Despite the ongoing argumentsamong various groups the ultimate importance of thiscondition is that it helps to identify individuals at highrisk of cardiovascular disease.

Several groups have attempted to develop diagnosticcriteria for diagnosis of metabolic syndrome.7 The firstattempt was made by a World Health Organization(WHO) diabetes group in 1999 who proposed thatinsulin resistance or its surrogates, impaired glucosetolerance or diabetes, as essential components and atleast two of: raised blood pressure, hypertriglyceridemiaand/or low HDL cholesterol, obesity as measured bybody-mass index (BMI) or waist-hip ratio (WHR), andmicroalbuminuria. The European Group for Study ofInsulin Resistance in 1999 then produced a modificationof the WHO criteria excluding people with diabetes andrequiring hyperinsulinemia to be present. Waistcircumference was the cutoff for obesity.

A more pragmatic approach was adopted by the USNational Cholesterol Education Program: AdultTreatment Panel-3 (ATP-3) in 2001 with a focus oncardiovascular disease risk.8 The specific objective wasto facilitate a clinical diagnosis. It was less glucocentricthan earlier definitions and required presence of anythree of the five components: central obesity, raised BP,raised triglycerides, low HDL cholesterol and fastinghyperglycemia. There were problems associated withall these three definitions in terms of applicability,uniformity and positive predictive value. A majorproblem was applicability to different ethnic groups,especially among East Asians and South Asians.7

The International Diabetes Federation has recentlyrevised the guidelines to remedy the ethnic group baseddisparities in the original classification (Table 1).9 Theconsensus was that metabolic syndrome as defined the US National Cholesterol Education Program was apragmatic approach and it was agreed that otherdefinitions unnecessarily highlight diabetes and insulinresistance.8 Central obesity as assessed by waistcircumference was agreed as essential because of thestrong evidence linking waist size with multiplemetabolic syndrome components. The waistcircumference cutoffs were lower for all the ethnicgroups. Although this new definition will misssubstantial number of subjects with impaired glucosetolerance it retains the simplicity of the US NationalCholesterol Education Program’s definition. Currentopinions have varied to whether metabolic syndromeshould be defined to mainly indicate insulin resistance,the metabolic consequences of obesity, risk forcardiovascular disease, or simply a collection ofcoronary risk factors.7 We believe in the latter as it is anetiologically heterogenous condition andtherapeutically involves multi-pronged approach.

The metabolic syndrome is defined as a conditioncharacterized by a set of clinical criteria: obesity, centralobesity, insulin resistance, atherogenic dyslipidemia,and hypertension.7 The major risk factors leading to theepidemic of this syndrome are physical inactivity andan atherogenic diet and cornerstone of the syndrome isabdominal obesity or adiposity.10 In addition, patientsusually have elevated triglycerides, low HDL cholesterol,elevated LDL cholesterol, other abnormal lipidparameters, hypertension, and elevated fasting bloodglucose. Impaired fibrinolysis and increasedsusceptibility to thrombotic events are also observed inthese patients.7 Recent research also reveals thatindividuals who have metabolic syndrome haveincreased levels of inflammatory markers such as, C-reactive protein (CRP) which is now recognized as animportant predictor of cardiovascular risk even beyondthe known classic risk factors.11

In India, both insulin resistance and the metabolic syndrome are widely prevalent.12-16 The Jaipur Heart Watch Studies have reported that in urban Indianpopulations age-adjusted prevalence of metabolicsyndrome was 18.4%in men and 30.9% in women and24.9% overall.15 There is an escalating age-relatedprevalence in both men and women (Fig.1). Diabetes isalready a major epidemic in India and given that Indiahas the largest number of subjects with type-2 diabetesin the world16 it can be extrapolated that this countrywould also have the largest number of patients with themetabolic syndrome. Primary care physicians andcardiologists in community practice are on the front lineswhen it comes to battling the epidemic of metabolicsyndrome.17 The first thing physicians should noticewhen a patient walks into their examining room is thesize of that patient’s size and waistline. This is becauseobesity predisposes individuals to several risk factorsthat cluster and comprise of the metabolic syndrome.18

The metabolic syndrome is associated with increasedrisk of developing both diabetes and cardiovasculardisease.7,17 Risk of diabetes is not surprising as impairedfasting glucose is a component. In the DECODE studyinvolving European men and women subjects with themetabolic syndrome, after exclusion of diabetes, hadincreased risk of all-cause as well as cardiovascularmortality. The overall hazard ratios for men and womenfor cardiovascular mortality were 2.26 and 2.78respectively after adjusting for age, cholesterol andsmoking. In three other prospective studies the relativehazard ratios for cardiovascular disease outcomesranged from 2 to 5. In 10537 NHANES-III participantsthere was a significant association between prevalentmyocardial infarction and stroke and the metabolicsyndrome.7 A series of studies have also found that manymiddle-aged people with the metabolic syndrome are atincreased 10-year absolute risk for cardiovasculardisease.17

Individuals with the metabolic syndrome need to becategorized according to absolute 10-year risk.Individuals with overt coronary heart disease, stroke ordiabetes are in the high risk category and should betreated accordingly. For other individuals theFramingham risk scoring is advised. This assessmenttriages subjects into high risk (10 year risk >20%),moderately high risk (10 year risk 10-20%), and moderaterisk (10 year risk <10%).17 These risk calculations includerisk factors beyond the metabolic syndrome such as age,sex, smoking, and total cholesterol as these risk factorsare important. Studies that estimate the independentinfluence of metabolic syndrome on Framingham riskscores are still in evolution.

The therapeutic goals for and clinicalrecommendations for management of metabolicsyndrome have been defined (Table 2). These includegoals for reducing levels of the abdominal obesity,physical inactivity, atherogenic diet, and smoking.Control of raised blood pressure is crucial. Specific goalsfor modifying blood levels of LDL cholesterol,triglycerides, and high glucose, and control ofproinflammatory and prothrombotic states aresuggested. Therapeutic approach involves interventionat a macro-level and control of multiple risk factors usingtherapeutic lifestyle approaches (diet control andincreased physical activity, pharmacotherapy (anti-obesity agents) for control of obesity and visceral obesity,and targeted approach for control of individual riskfactors (Table 3).7,17,22

LIFESTYLE MODIFICATION

Non-pharmacologic lifestyle management isimportant for obesity control.20,21 In USA it has beenreported that 29% of men and 44% of women describethemselves as trying to lose weight. However, restrictionof calorie intake and increase in physical activity- thecornerstones of obesity management is reported by only20%.20 Many studies demonstrate that obese subjects canlose up to 0.5 kg/week by restricting calories to less than500-1000 kcal below daily requirements.21 Althoughexercise in addition to calorie intake only marginallyincreases the success of calorie intake program but isassociated with many long term benefits. Persons whocombine calorie restriction and exercise with behavioralmodifications should expect to lose 5-10% of pre-intervention weight over a period of four to six months.This weight loss appears small to the patient but resultsin improvement of many obesity related conditionsincluding various abnormal components of the metabolicsyndrome and development of diabetes.21

Both weight reduction and maintenance of a lowerweight are best achieved by a combination of reducedcalorie intake and increased physical activity. Use ofprinciples of behavior change is important. Achievementof target weight loss so as to decrease BMI to less than 23 (Asians) or 25 (Caucasians) through lifestylemodifications will reduce most of the constituent riskfactors as well as the metabolic syndrome.7 Both theFinnish Diabetes Prevention Study23 and the US DiabetesPrevention Program (DPP)24 showed that diet andexercise had a significant effect on reducing theprogression from impaired glucose tolerance to type 2diabetes. The primary goal in DPP was to prevent ordelay the onset of diabetes; the secondary goals were todecrease cardiovascular risk factors, atherosclerosis, andcardiovascular evens. These goals are similar tometabolic syndrome treatment. The DPP enrolled 3234normotensive mostly obese subjects. The subjects wererandomly assigned to intensive lifestyle modification(low energy, low fat diet to induce weight loss with 150 minutes of walking per week), 850 mg of metformin twicedaily, 400 mg of troglitazone daily. or placebo. Thetroglitazone arm was dropped when rare cases of hepatictoxicity were reported from other studies. The remainingtreatment groups showed significant differences in rateof development of new diabetes: 11% per year in placebogroup, 7.8% in metformin roup (-31%), and 4.8% per yearin intensive lifestyle group (-58%). Significantly morepatients achieved normoglycemia in lifestyle group ascompared to metformin group.24 These results supportuse of multiple lifestyle modifications for individualswith the metabolic syndrome.

The available current evidence suggests that the firststep in management of patients with metabolic syndromeshould be focused weight loss and increased physicalactivity. The treatment should be based on two majorcomponents: behavioral change to reduce caloric intakeand an increase in physical activity. A realistic goal forweight reduction should be 7% to 10% over 6 to 12months. This results in decrease in body weight as wellas the insulin resistance.

No particular diet plan or dietary composition hasbeen studied specifically in relation to metabolicsyndrome. The current dietary recommendationsinclude a balanced low energy diet containing fruits,vegetables, whole grains, fish and lean meats whileminimizing fats, salt, simple sugars, and highlyprocessed foods.10 The general dietary recommendationsinclude low intake of saturated fats, trans fats andcholesterol, and diets with low glycemic index. Soyprotein could be more beneficial than animal protein inweight reduction and correction of dyslipidemia.17

Dietary therapies have been studied in relation toatherogenic dyslipidemia that is classical of themetabolic syndrome. Very high carbohydrate intakes canexacerbate this dyslipidemia.25 If the fat content exceeds35% of calories it is difficult to sustain the low intakes ofsaturated fat required to reduce LDL cholesterol. On theother hand if the fat content falls below 25%, triglyceridescan rise and HDL cholesterol levels tend to decline. Toavoid worsening of atherogenic dyslipidemia someinvestigators favor fat intakes in the range of 30-35%and most prefer fat intakes of 25-30% to avoid weightgain.17

Other weight reducing diets such as high-protein low-carbohydrate diets have recently come into vogue.Research documenting the benefits of such high fat/high protein/ low calorie diets is lacking. Stern et alreported that after one year of consumption of low-carbohydrate diet, severely obese patients showed nomore weight reduction than those eating a conventionalweight loss diet.25 A study comparing four types ofweight reducing diets (Atkins, Ornish, Weight Watchersand Zone diets) reported no particular benefit of anyparticular diet on weight loss at one year.26 Dansinger et al randomized 160 individuals to the four diet programs.Overall adherence to any particular program was lowand it was reported that at the end of one year theadherence was only 2-3 points on a 10 point scale. Thediets resulted in a significant reduction in LDLcholesterol but no change was observed in bloodpressure and glucose levels despite a significant weightloss (-2.1 to -3.2 kg weight, -0.7 to -1.4 kg/m2 BMI) in allthe groups. Weight loss was associated with decline infasting insulin levels and total/HDL cholesterol. Thusit is clear that weight loss rather than the diet type ismore important in ameliorating the risk factors of themetabolic syndrome.

The DPP study showed that multiple metabolic riskfactors can be controlled and type 2 diabetes preventedor delayed by keeping weight in control by increasingphysical activity.27,28 The study found that theparticipants who increased their physical activity andlost 5-7% of their body weight (5-10 kg) reduced theirprogression to diabetes by 58% during the course of thestudy.28 Physical activity is associated with successfulweight reduction and these therapeutic lifestyle changescan reduce by half the progression to new-onset diabetesin patients with metabolic syndrome.17 It also reducesoverall cardiovascular risk. Physical activityrecommendations should include practical, regular, andmoderated regimens of exercise, with a daily minimumof 30 to 60 minutes. More exercise adds more benefit.Regular exercise also improves endothelial function andvascular health. Sixty minutes or more of continuous orintermittent aerobic activity, preferably done every daywill promote weight loss and weight maintenance. Thelatter include multiple short (10-15 minute) bouts ofactivity (walking breaks at work, gardening or householdwork), jogging, swimming, biking, golfing, or team sports.An equal balance between aerobic exercise and strengthtraining is advised.

Important issues in lifestyle management includebehavior modification through counseling andadherence promoting techniques. Use of traditionalIndian systems such as yoga and transcendentalmeditation can be important adjunct to lifestyle changesand promote compliance. The Lifestyle Heart Study byOrnish et al29 was the first randomized trialdemonstrating usefulness of comprehensive lifestylechanges along with certain yogic practices inameliorating multiple cardiovascular risk factors (nowknown as metabolic syndrome) and causing regressionof coronary atherosclerosis. In a randomized study in48 patients it was demonstrated that strict dietary control(<10% calories as fat), regular exercises and meditationresulted in significant decrease in weight and variousrisk factors associated with the metabolic syndrome.Amelioration of multiple cardiovascular risk factors has been demonstrated in other studies that have evaluateda similar comprehensive lifestyle modification programincluding yoga,29-32 for example, Manchanda et al31reported significant improvement in multiple metabolicrisk factors and regression of coronary atherosclerosisusing a comprehensive lifestyle change package thatincluded diet control, physical activity and yogatechniques.

Thus, it is clear that a comprehensive approachconsisting of weight reduction, regular physical exerciseand yoga is crucial in control of the insulin resistancestate that characterizes the metabolic syndrome.

PHARMACOLOGICAL TREATMENT

Pharmacological therapy is a critical step in themanagement of patients with metabolic syndrome whenlifestyle modifications fail to achieve the therapeuticgoals (Table 2). Anti-obesity drugs such as sibutramineand orlistat can be tried to reduce weight and centralobesity and jointly control the metabolic syndromecomponents. Other than weight loss, there is no singlebest therapy and treatment should consist of treatmentof individual components of the metabolic syndrome.Newer drugs such as the endocannabinoid receptorblocker, rimonabant, appear promising in this regard.Atherogenic dyslipidemia should be controlled initiallywith statins if there is an increase in low-densitylipoprotein (LDL) cholesterol. If there are otherabnormalities, combination therapy, including fibrates,nicotinic acid, or ezetimibe should be considered. Forinsulin resistance, drugs such as thiazolidinediones andrenin-angiotensin system blockers are available.7,17Available evidence suggests that angiotensin convertingenzyme (ACE) inhibitors and angiotensin receptorblockers (ARBs) may be more beneficial for treatment ofhypertension in patients with metabolic syndromecompared to others as these drugs also preventdevelopment of diabetes.33 Large randomized clinicalstudies of ACE inhibitors and ARBs have shown thatACE inhibitors reduce the incidence of diabetes by 14%to 34% and ARBs reduced the incidence of diabetes by19% to 25%.34 The mechanisms by which this effect takesplace is not clear and a putative mechanism is adifferential effect of ACE inhibition on insulin sensitivityand glucose tolerance. Patients with metabolicsyndrome also have elevations in fibrinogen and othercoagulation factors leading to prothrombotic state andaspirin may be beneficial for primary prevention in thesepatients.7 The new developments in the treatment ofmetabolic syndrome with drugs, such as peroxisomeproliferator-activated receptor (PPAR) agonists andcannabinoid receptor-1 antagonists, will broaden thehorizons of the current treatment options. Fixed-dosecombination polypharmacy using a single pill is aninteresting concept that needs to be evaluated in long-term prospective trials in such patients.

Currently available weight loss drugs possess limitedutility in the management of obesity but maybe useful insome patients. Krejs reported that sibutramine-inducedweight loss and weight maintenance lead to clinicallyrelevant reductions in risk factors associated with themetabolic syndrome.35 Treatment with the drug decreasesvisceral fat, improves lipid levels, decreases glycosylatedhaemoglobin and decreases uric acid concentrations. Inthe ORACARDIA study, 126 subjects with criteriafulfilling metabolic syndrome were evaluated, 94 onorlistat and 34 on a hypocaloric diet.36 At the end of sixmonths of intervention, 91% patients in control grouphad some evidence of the metabolic syndrome ascompared to 65% in orlistat group (p<0.0001). Hseih etal performed a randomized controlled trial in Taiwaninvolving 51 patients on orlistat 360 mg/day and 55control subjects.37 The orlistat group had greater changesin body mass index (BMI), % body fat, waistcircumference, and insulin resistance, C-reactive protein(CRP), leptin and adiponectin levels after one year onthe program as compared to the controls. It wasconcluded that orlistat could effectively manage obesityrelated co-morbidities, especially insulin resistance andatherosclerosis risk. Another study with orlistat,XENDOS, has also reported benefits of orlistat inassociation with lifestyle changes in prevention of type2 diabetes in patients at high risk.38 However, the majorproblem with these currently available anti-obesity drugsis a relatively high rate of adverse side effects leading topoor tolerance and compliance for long term use.

Rimonabant belongs to a new class of drugs whichselectively antagonize cannabinoid type 1 receptors(CB1).39 This novel class of drugs has been reported to beuseful in reduction in bodyweight along with a paralleldecrease in waist circumference and amelioration of themetabolic profile.40 In the RIO-Europe study 1507patients with BMI >30 kg/m2 or BMI >27 kg/m2 withdyslipidemia, hypertension or both were randomized toreceive double blind treatment with placebo, 5 mgrimonabant, or 20 mg rimonabant once daily in additionto a mild hypocaloric diet. Weight loss was significantlygreater in the rimonabant groups as compared to controls.Those on 20 mg/day of the drug also showedsignificantly greater improvements than placebo in waistcircumference, high density lipoprotein (HDL)cholesterol, triglycerides, insulin resistance andprevalence of the metabolic syndrome. It was alsoobserved that in addition to its effects on weight lossrimonabant had significant weight independent effecton lipid parameters.40 Rimonabant also reduced fastinginsulin levels, glucose and CRP.

The RIO-Lipid study examined the effects ofrimonabant on metabolic risk factors, including adiponectin levels, in high-risk patients who areoverweight or obese and have dyslipidemia.41 1036overweight or obese patients (BMI 27-40) with untreateddyslipidemia (high triglyceride levels or cholesterol:HDLratio >4.5 among women and >5 among men) wererandomized to double-blinded therapy with eitherplacebo or rimonabant at a dose of 5 mg or 20 mg dailyfor 12 months in addition to a hypocaloric diet. The ratesof completion of the study were 62.6 percent, 60.3 percent,and 63.9 percent in the placebo group, the groupreceiving 5 mg of rimonabant, and the group receiving20 mg of rimonabant, respectively. The most frequentadverse events resulting in discontinuation of the drugwere depression, anxiety, and nausea. As compared withplacebo, rimonabant at a dose of 20 mg was associatedwith a significant (P<0.001) mean weight loss (-6.7+0.5kg), reduction in waist circumference (-5.8+0.5 cm),increase in HDL cholesterol (+10.0+1.6 percent), andreduction in triglycerides (-13.0+3.5 percent).Rimonabant at a dose of 20 mg also resulted in anincrease in plasma adiponectin levels (57.7 percent,P<0.001).It was concluded that rimonabant significantlyreduces body weight and waist circumference andimproves the profile of several metabolic risk factors inhigh-risk patients who are overweight or obese and havean atherogenic dyslipidemia.

In RIO-North America study42 3045 obese subjectswere randomized into placebo group and to rimonabant5 mg and 20mg. At year 1, the completion rate was 309(51%) patients in the placebo group, 620 (51%) patientsin the 5 mg of rimonabant group, and 673 (55%) patientsin the 20 mg of rimonabant group. Compared with theplacebo group, the 20 mg of rimonabant group producedsignificantly greater mean reductions in weight (–6.3 vs–1.6 kg), waist circumference (–6.1 vs –2.5 cm), and levelof triglycerides (percentage change, –5.3 vs 7.9) and agreater increase in level of HDL cholesterol (percentagechange, 12.6 vs 5.4) (p<0.001). Patients who wereswitched from the 20 mg of rimonabant group to theplacebo group during year 2 experienced weight regainwhile those who continued to receive 20 mg ofrimonabant maintained their weight loss and favorablechanges in cardiometabolic risk factors. More ongoingclinical and mechanistic trials shall be able to answerquestions regarding risk/benefits andpharmacogenomics of this class of drugs.

Liposuction or bariatric surgery are being used forsevere obesity in many developed countries.43 In arandomized trial of liposuction it was reported thatdespite a significant weight loss there was no influenceon lipid profile or other parameters of the metabolicsyndrome. Klein et al studied 15 obese women andevaluated insulin sensitivity of liver, skeletal muscle andadipose tissue as well as inflammatory mediators andother cardiovascular risk factors before and 10-12 weeks after the liposuction procedure.44 Liposuction decreasedthe volume of subcutaneous abdominal adipose tissueby 28-44% and subjects lost 9-10 kg of fat. However,liposuction did not alter the insulin sensitivity of muscle,liver or adipose tissue and also did not alter plasmaconcentrations of CRP, interleukin-6 or TNF-alpha andno change was observed in other coronary risk factorssuch as lipid levels and blood pressure.

Bariatric surgery techniques using laparoscopicadjustable banding of stomach along with Roux-en-Yand other forms of gastric bypass are now favored forsevere and morbid obesity.7 It results in weight loss of25-30% and rapid normalization of glucose handlingand blood pressure in patients with diabetes andhypertension.45 Long-term results are however notavailable and recent reports of substantial mortality andmorbidity of this procedure, especially in the elderly haveraised important safety issues for this procedure.46

A recent American Heart Association and NationalHeart Lung Blood Institute scientific statement highlightsthe importance of control of individual risk factors inmetabolic syndrome.17 This consensus group considersmetabolic syndrome as a clustering of risk factors thatincrease the cardiovascular event risk and suggests amultipronged therapeutic approach. Components of themetabolic control that need control are atherogenicdyslipidemia, elevated blood pressure, elevated fastingglucose, prothrombotic factors, and proinflammatory state.

The lipid abnormalities in the metabolic syndromehave been described as atherogenic dyslipidemia. Thisdefinition was initially proposed by Grundy andincluded borderline high LDL cholesterol andapolipoprotein B, increased small dense LDL particles,raised triglycerides and low HDL cholesterol levels.47 Amajor debate in the field of lipids is whether thetherapeutic approach should focus exclusively on LDLcholesterol reduction or it should be directed atimprovements in LDL cholesterol, triglycerides, andHDL cholesterol simultaneously. The ATP-III guidelinesemphasize that LDL reduction is the primary target inlipid management even in the metabolic syndrome andlow HDL and triglycerides are secondary targets.8Canadian guidelines have adopted both a LDLcholesterol goal of <100 mg/dl and a total/HDLcholesterol ratio of <4.0.48 In keeping with theserecommendations, we would suggest that LDLcholesterol should be lowered to less than 70 mg/dl inall high risk cases with the metabolic syndrome. Thisrecommendation is supported by the recent TNT-Metabolic syndrome study that showed greaterreduction in coronary events in the group that achievedLDL cholesterol levels of 70 mg/dl than group with LDLlevels of about 100 mg/dl.49

The efficacy of statins in reducing LDL cholesterolconcentrations is well established. Studies show thatstatins appear to improve the LDL subfraction profile,possibly by reduction of small dense LDL or by reductionin all LDL subclasses with a shift in LDL particledistribution.50 LDL targets have been defined by variousagencies according to the level of cardiovascular risk. Inmoderate risk subjects the target is <100 mg/dl while inhigh risk subjects it is <70 mg/dl.44 The target LDL levelsin patients with the metabolic syndrome are difficult toachieve by diet or exercise therapy alone and usuallyneed drug therapy, usually a statin. This class of drugsalso reduces all apolipoprotein B containing lipoproteinsand also decreases concentration of CRP.

Combination therapy for dyslipidemias has beensuggested for achieving target LDL and other lipidlevels.51 This is akin to treatment of hypertension anddiabetes where usually two or likely three drugs arerequired to achieve target levels of control. Ezetimibe isa novel cholesterol lowering agent and studies reportwhen combined with any statin in a dose of 10 mg dailywas as effective as the statin monotherapy as the highestdose, e.g., ezetimibe plus 10 mg atorvastatin was aseffective as 80 mg atorvastatin alone. This combinationwas also more effective that statin alone in reducingtriglycerides and apolipoprotein B (ApoB) and inincreasing HDL cholesterol. Statins can also be safelycombined with a fibrate, especially fenofibrate, andniacin to achieve target levels of non-HDL cholesterol,triglycerides and HDL cholesterol.8,51

Fibrates mitigate atherogenic dyslipidemia and areuseful in dyslipidemia of the metabolic syndrome. Incombination with statins they are particularly effectivefor reducing LDL cholesterol as well as triglycerides.However the combination therapy carries someincreased risk for myopathy. The myopathy has beenspecially noted with statin and gemfibrozil combinationdue to pharmacological interaction of statinglucuronidation and increase in level of statins whenused in conjunction. The risk of myopathy is very lowwhen fenofibrate is combined with a statin and the ATP-III has recommended this combination.8

Both statins and fibrates have demonstrated acapacity to reduce primary and secondarycardiovascular event rates in prospective placebo-controlled trials. Clinical trial data with statin-fibratecombination are quite limited. In the Fluvastatin Aloneand in Combination Treatment (FACT) Study, 20 or 40mg of fluvastatin daily was used in combination with400 mg bezafibrate in 167 patients with mixeddyslipidemia over a 6-month follow-up period.Combination therapy was superior and mean changesin lipoproteins from baseline to end-point included a22% increase in HDL cholesterol levels and reductions of 24% and 38% in LDL cholesterol and triglyceridesrespectively.52 Combination therapy was not associatedwith increased risk of myopathy or hepatotoxicity. Anoutcome trial with statin-fibrate therapy is yet to becompleted but one is underway: the Action to ControlCardiovascular Risk in Diabetes trial. This trial isassessing the safety and efficacy of statin monotherapyalone as compared to statin-fibrate combination in 5800patients with diabetes and is expected to be completedby the year 2009.

Fibric acid is a synthetic ligand of the nuclear receptorPPAR-a and promotes oxidation of fatty acids to mediatehypolipidemic action.53 PPAR-a exerts directantiatherogenic action on the vessel wall and improvesendothelial function. Endothelial dysfunction in themetabolic syndrome is characterized by an impairedinsulin stimulated nitric oxide production from theendothelium and decreased blood flow to skeletalmuscle. Fibrates, therefore, may have an action beyondthe hypolipidemic action to decrease the incidence ofcoronary artery disease. However the results of thefenofibrate intervention and event lowering in diabetes(FIELD) study do not confirm the usefulness of fibratesin primary cardiovascular prevention.54 In thismultinational randomized controlled trial 9795participants aged 50-75 years with type 2 diabetes wereevaluated using micronised fenofibrate 200 mg daily(n=4895) or matching placebo (n=4900). After an averagefollow-up of 5 years, fenofibrate did not significantlyreduce the risk of primary outcome of coronary event. Itdid reduce total cardiovascular event mainly due to fewernon-fatal myocardial infarctions andrevascularizations. The authors opined that a high rateof starting statin therapy in patients allocated placebomight have masked a moderately larger treatment benefit.This study questions the usefulness of fenofibrate andother fibrates in primary prevention of cardiovascularevents in high risk subjects with diabetes orcardiovascular diseases and has implications for use offibrates in metabolic syndrome.

Niacin
Niacin raises HDL cholesterol levels and reduces non-HDL cholesterol. Patients with impaired fasting glucose,impaired glucose tolerance or diabetes who are treatedwith nicotinic acid deserve careful monitoring forworsening hyperglycemia.8 Lower doses of niacindecrease this risk. The combination of a statin with alow dose of niacin is a very attractive option in patientswith metabolic syndrome. This combination has beenreported to lower LDL cholesterol, ApoB, triglyceridesand lipoprotein(a) and increase HDL cholesterolsignificantly in an Indian multicentric study.55 In thisopen-label study, 142 patients with mixed dyslipidemiaand LDL cholesterol >130 mg/dl were treated withlovastatin (20 mg) and extended release niacin (375 mg)per day. In the study percent decline in various lipids at 4, 12 and 24 weeks was: total cholesterol 11.8, 18.8 and25.2%, LDL cholesterol 17.0, 28.8 and 38.0%, triglyceride6.8,12.8 and 21.0%, lipoprotein(a) 17.5 , 26.9 and 44.5%respectively (p<0.01). HDL cholesterol and apoA1/apoBincreased by 7.2, 13.1 and 18.2%; and 7.9, 21.9 and 51.6%respectively (p<0.01). Target LDL levels (<100 mg/dl insubjects with manifest coronary heart disease or diabetes;<130 mg/dl in subjects with >2 risk factors) wereachieved in 92 (80.7%) patients. 13 patients (10%) werelost to follow-up and 4 (3%) withdrew because ofdermatological adverse effects- flushing. pruritus andrash. This study showed that low dose niacin is usefultreatment of mixed dyslipidemia as is present in themetabolic syndrome.

Omega-3 fatty acids
Fish oils (omega-3 fatty acids) have been studied intrials after myocardial infarction and have been shownto reduce cardiovascular events and death. They areactivators of PPAR-a system. Fish oils have been used inpatients with diabetes and metabolic syndrome whoneed additional triglyceride lowering.17 In metabolicsyndrome patients, 3 gm of fish oils have been shown todecrease triglycerides by 20%, decrease in ApoBproduction, decrease in postprandial lipemia andmarked reduction in small dense LDL. Extremely highdoses should be avoided to prevent increase in LDLcholesterol levels.

HDL cholesterol modulation
A number of strategies for increasing HDL cholesterolare under evaluation. These include cholesterol estertransfer protein (CETP) inhibition, increasing ApoA1(ApoA1Milano), inhibitors of acyl coenzyme A-cholesterol acyltransferase (ACAT), and others.56Inhibitors of CETP have been shown to increase HDLcholesterol significantly and a study with this novel classof drugs using torcetrapib reported almost 100% increasein HDL cholesterol levels in a controlled study.57Brouseau et al conducted a single-blind placebo-controlled study to examine the effects of torcetrapib in19 subjects with low HDL cholesterol (<40 mg/dl), 9 ofwhom were also treated with atorvastatin 20 mg daily.Treatment with torcetrapib 120 mg daily for four weeksincreased HDL cholesterol by 61% and 46% respectivelyin atorvastatin and non-atorvastatin cohorts and with120 mg twice daily increased it by 106% in both cohorts(p<0.001). It was concluded that torcetrapib was effectivein increasing HDL cholesterol levels significantly. Theeffect of these inhibitors on atherosclerosis progressionas well as clinical significance needs to be evaluated inlarger clinical trials.58

Elevated blood pressure
The pathophysiological mechanisms by whichhypertension is linked so strongly with obesity,particularly central obesity and hyperinsulinemiaremain uncertain. There have been two enduring hypotheses; the first considers that sympathetic systemunderactivity is present in obesity and throughconsequential failed stimulation of thermogenesisprovides a metabolic basis for the obesity and secondconsider that in obesity sympathetic nervous systemover-activation occurs with chronic overeating where itfacilitates energy balance and weight stabilization, butat the cost of adverse consequences attributable tochronic sympathetic stimulation, in particular, elevationin blood pressure.59

Lifestyle changes are of prime importance to reduceelevated blood pressure with a goal to reduce it as muchas possible, ideally >130/85 mm Hg or even >120/80mm Hg. Lifestyle therapies include weight control,increased physical activity, decreased intake of alcohol,sodium restriction and increased consumption of freshfruits and vegetables as in the dietary approaches tostop hypertension (DASH) diet.60 If hypertension cannotbe adequately controlled by lifestyle therapies,antihypertensive drug therapies are usually necessaryto prevent long term adverse effects. Whether findingsof neural pathophysiology of obesity- and centralobesity-related hypertension have any implications fordefining pharmacological treatment is not clear.Sympathetic activation in obese hypertensive patientsseems to contribute both to elevated blood pressure aswell as cardiovascular and metabolic consequences ofthe metabolic syndrome and it is theorized that drugsinhibiting the sympathetic nervous system could beuseful but the evidence of efficacy of central imidazoline-receptor binding agents and peripheral beta-adrenergicblocking agents is not convincing. A diabetogenic effecthas been unequivocally demonstrated for both thiazidediuretics and beta-blockers and at present these drugsmay not be suitable first line therapy in subjects withmetabolic syndrome.

ACE inhibitors
An increasing number of experts support ACEinhibitors as first line therapy in the metabolic syndrome,especially when type 2 diabetes or renal disease ispresent.34,60 Inhibition of renin-angiotensin system withthis class of drugs may lower the risk of diabetes itself asreported in large randomized clinical studies of ACEinhibitors and angiotensin receptor blockers (ARBs).ACE inhibitors reduced the incidence of diabetes by 14-34% and ARBs reduced the incidence of diabetes by 19-25%.34 The mechanisms of action of ACE inhibitors orARBs are not clear and a possible mechanism isimprovement in insulin sensitivity and glucosetolerance. Angiotensin II interferes with postreceptorinsulin signaling and blocking of this action enhanceinsulin sensitivity. This group of drugs also reducesinflammation. In addition these drugs reduce oxidativestress and also improve endothelial function whichwould enhance glucose utilization by skeletal muscledue to increased delivery secondary to improved flow. Small mechanistic studies report that within 2-12 weeksof therapy with ACE inhibitors the insulin sensitivityimproves. ARBs may be used when ACE inhibitors arenot tolerated and have similar beneficial effects inprevention of diabetes.61 However, tailoring ofantihypertensive therapy to pathophysiology cannot bepresently the prime therapeutic principle because of theimperfect knowledge. Clinical considerations such asthe presence of coexisting illnesses are important in drugselection. In general, most experts agree that a drug thatblocks renin-angiotensin system should be one of theinitial therapeutic choice.

Insulin resistance and hyperinsulinemia areassociated with multiple metabolic abnormalities thatare present in the metabolic syndrome.7 These include(a) some degree of glucose intolerance, (b) dyslipidemia-raised triglycerides, low HDL cholesterol, small denseLDL particle diameter and postprandial lipemia, (c)sympathetic nervous system overactivity, renal sodiumretention and hypertension, (d) abnormal uric acidmetabolism with raised plasma uric acid concentrationsand decreased renal uric acid clearance, (e) abnormalhemostasis and raised fibrinogen and plasminogenactivator inhibitor-1, (f) inflammatory milieu with raisedwhite cell count and CRP, and (g) endothelialdysfunction. Decreasing the raised insulin levels bylifestyle changes and pharmacotherapy can revert manyof these abnormalities.

An attractive option in treatment of the metabolicsyndrome might be to begin treatment in individualswith impaired fasting glucose or impaired glucosetolerance before overt hyperglycemia develops. Resultsof recent studies indicate that targeting these individualswith dysglycemia using aggressive lifestyleinterventions or pharmacotherapy can reduce theincidence of diabetes and might reduce thecardiovascular risk. Influence of lifestyle interventionshave been reported above. The Finnish DiabetesPrevention Study23 and the US-DPP24,27,28 showed thatdiet and exercise had a significant effect on reducing theprogression from impaired glucose tolerance to type 2diabetes. In the Finnish study and the DPP personalizedrecommendations about diet and exercise reducedincidence of new onset diabetes by 58% compared to thegroup receiving usual instructions. Similar results havebeen obtained in the Malmo study62,63 and the Da Qingtrial64. Diet and exercise in the Malmo study reduceddiabetes incidence by 50% and at 12 year follow-up thegroup that achieved normoglycemia had similarmortality as normal subjects.63 The Da Qing trialdemonstrated that diet alone, exercise alone or theircombination significantly reduced the incidence ofdiabetes.64

Metformin
Metformin combined with standard lifestyle advicewas one of the treatments evaluated in DPP.24 Althoughmetformin was effective in reducing the incidence ofdiabetes as compared with placebo (31% reduction,p<0.01), it was not as effective as intensive lifestyleintervention. Metformin was less effective than lifestylechanges in improving cardiovascular risk factors.65 Morestudies are required with metformin in the context ofmetabolic syndrome.

Acarbose
Acarbose, an inhibitor of a-glucosidase slows thedigestion of carbohydrates in the intestine and reducedpostprandial glucose levels. The Study to Prevent Non-Insulin Dependent Mellitus (STOP-NIDDM) was arandomized trial to evaluate whether acarbose wouldprevent development of type 2 in subjects with impairedglucose tolerance.66 In the acarbose group as comparedto placebo group significantly less developed diabetes(32% vs 42%, p=0.0015) and probability of reverting tonormal glucose tolerance was significantly greater. Therewas also a reduction in risk of developing cardiovascular events.

PPAR- and PPAR- agonistsThiazolidinedione drugs such as troglitazone,rosiglitazone and pioglitazone enhance insulinsensitivity. In an early randomized study withtroglitazone (now withdrawn) in 266 Hispanic womenwith post gestational diabetes, it was found to reduceincidence of diabetes by 55% (p=0.009) and also to alterthe natural course of diabetes.67 Troglitazone has alsobeen studied in the DPP and patients with impairedglucose tolerance and have been shown to be effective inprevention of diabetes but have not been demonstratedto reduce cardiovascular risk.27 Pioglitazone has beenshown to reduce multiple components of metabolicsyndrome such as high blood pressure, high bloodglucose and triglycerides in addition to a decrease inurinary albumin/creatinine ratio.68

Thiazolidinedione drugs such as troglitazone,rosiglitazone and pioglitazone enhance insulinsensitivity. In an early randomized study withtroglitazone (now withdrawn) in 266 Hispanic womenwith post gestational diabetes, it was found to reduceincidence of diabetes by 55% (p=0.009) and also to alterthe natural course of diabetes.67 Troglitazone has alsobeen studied in the DPP and patients with impairedglucose tolerance and have been shown to be effective inprevention of diabetes but have not been demonstratedto reduce cardiovascular risk.27 Pioglitazone has beenshown to reduce multiple components of metabolicsyndrome such as high blood pressure, high bloodglucose and triglycerides in addition to a decrease inurinary albumin/creatinine ratio.68

The PROACTIVE study evaluated secondaryprevention of macrovascular events in patients with type2 diabetes using pioglitazone in a randomizedcontrolled trial.69 These investigators evaluated 5238patients with type 2 diabetes who had evidence ofmacrovascular disease at baseline and randomized 2605subjects to 15 to 45 mg of pioglitazone and 2633 toplacebo. Primary endpoint was a composite of all-causemortality, non-fatal myocardial infarction, stroke, acutecoronary syndrome, endovascular or surgicalintervention in coronary or leg arteries, and above-ankleamputation. The composite endpoint was notsignificantly different in the two groups but pioglitazonereduced composite of all-cause mortality, non-fatalmyocardial infarction and stroke (hazard ratio 0.84,confidence intervals 0.72-0.89, p=0.027). It wasconcluded that pioglitazone may be useful in prevention of cardiovascular events in high risk patients with type2 diabetes although the usefulness of this approach inmetabolic syndrome or impaired glucose tolerancesubjects is not clear. However, use of this group of drugshas not been recommended for treatment of metabolicsyndrome by a consensus group.17

Preclinical trials with dual PPAR blockade haveshown promising results in ameliorating insulinresistance and diabetic hyperglycemia.70 Cardiovascularrisk factor improvements have to be confirmed in clinicaltrial setting. Combination therapy of PPAR blockade withother strategies is also being evaluated. There are threemajor trials using combination therapies currently inprogress examining the effect of rosiglitazone/ramipril(the DREAM study), nateglinide/valsartan (theNAVIGATOR study) and pioglitazone (the ACT-NOWstudy) on the development of diabetes in impairedglucose tolerance subjects as a primary outcome. Thereare studies for prevention of diabetes as secondaryoutcomes of which the ONTARGET-TRANSCEND studyis examining telmisartan with or without ramipril in avery large study. The evidence is overwhelming:progression of insulin resistance to diabetes can beprevented or delayed in high risk population throughlifestyle modification and/or pharmacologicalinterventions.

Early insulin therapy
An interesting hypothesis is of prevention of ß-cellfatigue in context of insulin resistance. The ORIGINstudy is testing glargine insulin in patients withimpaired glucose tolerance.71 The ORIGIN is a large,international, multicentre trial investigating in high riskpeople with impaired glucose tolerance or early diabetes,whether insulin replacement therapy targeting fastingnormoglycaemia with insulin glargine reduces the riskof long-term cardiovascular events more than standardapproaches to dysglycaemia. The study commenced in2003 and is expected to conclude in the year 2009.

Subjects with the metabolic syndrome have increasedlevels of fibrinogen, plasminogen activator inhibitor-1(PAI-1), and other coagulation factors. They also have aproinflammatory state characterized by elevatedcytokines- tumor necrosis factor and interleukin-6, andacute phase reactants such as CRP and fibrinogen. Forprimary prevention the only long–term approach tocounter the thrombotic state is low dose aspirin or otheranti-platelet agents.7,17 Aspirin is widely recommendedin patients with established cardiovascular diseasesalthough its role in prevention of events in diabetes isnot well established. In metabolic syndrome patientswith a high risk of future cardiovascular events, aspirinin a dose of 75-150 mg/day is an attractive therapeuticoption to lower vascular events.72 It is also important tonote that renin-angiotensin system inhibition alsoreduces PAI-1 levels and inflammatory cytokines and thus potentially reduces risk of increased thromboticevents in patients with metabolic syndrome.34

An elevated CRP level of >3 mg/dl (in absence ofother detectable causes) is a useful marker ofproinflammatory state. Finding of an elevated levelsupports the need for lifestyle changes. Weight reductionleads to a decrease in CRP levels and also mitigates otherinflammatory factors. No drugs that act exclusively viathis mechanism are available for reducingcardiovascular risk. However, several drugs used to treatother metabolic risk factors in the metabolic syndromehave been reported to reduce CRP levels. These drugsgroups are statins, nicotinic acid, fibrates, ACE inhibitorsor ARBs, and thiazolidinediones but isolated regularuse of these drugs to reduce the inflammatory markershas not yet been demonstrated to result in improvedclinical outcomes.

Wald and Law have suggested a polypharmacyconcept to prevent cardiovascular disease.73 Acombination “polypill” has been suggested that containsthree antihypertensives (thiazide, beta-blocker and ACEinhibitor), a statin, aspirin, and folic acid in low dosesbased on current clinical evidence. It has beenhypothesized that such a combination if given toeveryone more than 55 years of age in Britain wouldprevent 88% (84-91%) of heart attacks and 80% (71-87%)strokes. This combination highlights the need formultifactorial interventions in prevention ofcardiovascular diseases and underscores the clinicalimportance of the metabolic syndrome. Such acombination approach has yet to be formally evaluatedalthough a retrospective analysis has reported significantbenefits. In a British general practice open prospectivecohort evaluation of 1.18 million patients and using anested case-control design, 2266 incident coronary heartdisease death cases were matched to 9064 controls.74 Itwas observed that a combination of aspirin, statin andbeta-blocker improves survival. Drug combinationsassociated with the greatest reduction in all causemortality were statins, aspirin and beta blockers (-83%)while a combination of statin, aspirin, beta blocker andACE inhibitor reduced mortality by 75%. Economicissues in such a combination therapy in developingcountries should be resolved as polypharmacy can leadto a massive burden.75

The use of combination pharmacotherapy assuggested by the polypill authors has been reviewed bya US expert panel.76 It was concluded that thecombination therapy as suggested by Wald and Lawmay prove to be effective but may also have side effectsand poor adherence, which may be greater or lesser thanother preventive approaches. It has also been suggestedthat randomized trials are needed to evaluate thistherapy although the study design is uncertain. Minoritygroups and people with low socioeconomic status in the US may be especially suitable for such therapies giventhe high prevalence of obesity and related cardiovascularrisk factors in these groups but a large number ofquestions need to be answered in this context (Table 3).

We believe that the polypill concept is especiallysuitable for the management of metabolic syndrome. Theissues to be addressed include the evidence-based useof such a combination pill in primary or secondaryprevention and cost-effectiveness and assessment of itsimpact on cardiovascular healthful behaviors. Suchcombinations (2, 3 and 4 drug combos) are alreadyavailable in India and some other developing countriesbut issues related to long-term safety and benefits needsto be addressed in a properly designed multifactorialrandomized clinical trials. Ethical issues involved alsoneed to be clarified before undertaking such a study.

The metabolic syndrome is an important public healthproblem in South Asians in their homeland andworldwide. It has also emerged as an important issue indeveloped countries. This epidemic has been fuelled byescalating epidemic of obesity. A strong correlation ofvarious measures of obesity (adiposity) such as bodymass index, waist size and waist hip ratio with variouscomponents of the metabolic syndrome is observed inIndian studies19 showing that obesity management andweight optimization should be the primary target oftherapy in these individuals.

Lifestyle interventions are crucial in this regard.Interventions targeted to reduce obesity and adiposityare effective in reducing overall cardiovascular risk andpositively modify the metabolic syndrome parameters.Increased physical activity is the single most usefulintervention to modify global cardiovascular risk byaffecting all the components of the metabolic syndrome(obesity, atherogenic dyslipidemia, insulin resistanceand high blood pressure). Diet modification and controlleads to control of obesity, lipids and blood pressure.Yoga-based interventions can have positive influenceson mind-body relationships and improve compliance tolifestyle changes.

Pharmacological interventions to specifically targetall the risk factors are limited. Obesity modulation offersthe best strategy and newer drugs such as the novelcannabinoid receptor blocking agent, rimonabant, offersmuch promise as it improves most of the components ofmetabolic syndrome. Focus on individual risk factormodification involves a multipronged strategy to controlborderline high LDL cholesterol (statins, statin-ezetimibecombination), high triglycerides (fibrates, fibrate-statincombination, omega-3 fatty acids), low HDL cholesterol(niacin, fibrates, torcetrapib, ApoA1 Milano), high bloodpressure (ACE inhibitors, ARBs, ß-blockers, and others),and insulin resistance (metformin, acarbose,thiazolidinediones). Combination polypharmacy and use of polypill-like combinations is an attractive optionin control of the overall risk factors of the metabolicsyndrome. This strategy needs to be formally evaluatedin settings of randomized controlled trials. Until thattime population based lifestyle interventions are crucialand best evidence-based approaches in South Asianpopulations.76,77 The time has come to aggressivelymarket cardiovascular and other chronic diseasesprevention strategies in India and other developing countries.

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