Treatment dm dyslipidemia

review

article

Diabetes, Obesity and Metabolism 13: 313–325, 2011.© 2011 Blackwell Publishing Ltdreview article

Therapies for diabetic dyslipidaemiaD. S. H. Bell1, F. Al Badarin2 & J. H. O’Keefe, Jr21Department of Endocrinology, University of Alabama, Birmingham, AL, USA2Saint Luke’s Cardiovascular Consultants/Mid America Heart and Vascular Institute, University of Missouri-Kansas City, Kansas City, MO, USA

Correction of diabetic dyslipidaemia in diabetic patients is the most important factor in reducing cardiac risk. Diabetic dyslipidaemia ischaracterized by elevated triglycerides, low total high-density lipoprotein (HDL) and small dense low-density lipoprotein (LDL) particles. Themost important therapeutic goal in diabetic dyslipidaemia is correction of the non-HDL-cholesterol (HDL-C) level. Glycaemic control withparticular attention to postprandial glucose control plays a role not only in improving dyslipidaemia but also in lowering cardiac events.Pioglitazone is particularly effective for improving the manifestations of diabetic dyslipidaemia, in addition to its favorable effects on systemicinflammation and hyperglycaemia. Use of statins in addition to lifestyle change is recommended in most if not all type 2 diabetic patientsand the goal should be to lower the LDL to a level recommended for the patient with existing cardiovascular disease (CVD) (non-HDL-C level<100 mg/dl). In addition, therapies for normalization of HDL and triglyceride levels should be deployed. Most patients with type 2 diabetes(T2D) will require combining a lipid-lowering therapy with therapeutic lifestyle changes to achieve optimal lipid levels. Combinations usuallyinclude two or more of the following: a statin, nicotinic acid, omega-3 fats and bile acid sequestrants (BASs). Fibrates may also be of usein diabetic patients with persistently elevated triglycerides and depressed HDL-C levels, although their role in lowering adverse CV events isquestionable.Keywords: cardiovascular disease, diabetes mellitus, dyslipidaemia, lipid-lowering therapy, thiazolidinediones, type 2 diabetes

Date submitted 6 July 2010; date of first decision 16 August 2010; date of final acceptance 17 November 2010

Modifiable Cardiac Risk Factors in theDiabetic PatientDiabetes mellitus (DM) is a major risk factor for cardiovasculardisease (CVD). According to the National cholesterol educationprogram (NCEP) and adult treatment panel III (ATPIII)recommendations, patients with diabetes are in a high-risk category for cardiovascular (CV) events [1,2] anddiabetes is now considered a coronary heart disease (CHD)equivalent [3].

Diabetic patients have high prevalence of concomitantCV risk factors (hypertension, smoking and truncal obe-sity) [4]. In addition, the biochemical and metabolic derange-ments that accompany DM lead to abnormal oxidativestress, impaired endothelial function, increased fibrinogenand platelet activation and chronic low-grade inflamma-tion, all of which are known to promote plaque for-mation and atherogenesis [5–7]. Furthermore, DM predis-poses to atherogenic lipid abnormalities including elevatedlow-density lipoprotein-cholesterol (LDL-C), greater num-ber of smaller LDL particles, low high-density lipoprotein-cholesterol (HDL-C) and high triglycerides [8,9]. There-fore, an aggressive approach to controlling CVD risk fac-tors, especially dyslipidaemia, is essential in all diabeticsubjects.

Correspondence to: Dr. David S. H. Bell, University of Alabama and SouthsideEndocrinology, 1020 26th Street South, Room 204, Birmingham, AL 35205, USA.E-mail: [email protected]; [email protected]

Diabetic DyslipidaemiaData from the Framingham study indicate that a low HDLlevel accompanied by an elevated triglyceride level is twiceas common among patients with type 2 diabetes (T2D)compared to non-diabetic patients, while concentrations ofcalculated LDL and total cholesterol do not differ [10]. Thelowering of total HDL levels in patients with T2D is mainlybecause of a decrease in the concentration of the larger morecardioprotective HDL particles, with the smaller more denseand less cardioprotective HDL particles predominating [11].The low HDL, high triglyceride pattern is also characteristicof individuals with prediabetes or the metabolic syndrome(MetSyn), regardless of race, ethnicity and gender. It shouldbe noted that in the Framingham study, the diabetic AfricanAmericans’ lipid pattern was more commonly that of a lowHDL accompanied by a high calculated LDL level with only19% (compared with 50% of those of European origin) havinghypertriglyceridaemia [12].

Because of resistance to the action of insulin on the adipocyte(particularly the peritoneal adipocyte), free fatty acid (FFA)levels are elevated [13]. Increased delivery of FFAs to theliver promotes hepatic production of triglycerides which arepackaged in ApoB-containing very low-density lipoproteins(VLDLs). The presence of increased VLDL increases theavailable substrate for cholesterol ester transfer protein (CETP)which enhances the exchange of triglycerides for cholesterolfrom the HDL to the LDL particles increasing the triglyceridecontent of both particles.

review article DIABETES, OBESITY AND METABOLISM

The increased triglyceride content of both the LDL andHDL particles causes increased activity of the enzyme hepaticlipase which results in an increased production of both smalldense LDL and small dense HDL particles. Small dense LDLparticles are more atherogenic because these particles, especiallywhen glycated, are more easily oxidized and ‘picked up’by the scavenger receptor on the macrophage which has amuch greater affinity for oxidized LDL than for non-oxidizedLDL [14]. Macrophages therefore facilitate the transportationof these particles through the intima to the subintimal spaceand media of the artery where the process of atherogenesis isinitiated and accelerated by these highly atherogenic particles.The concentration of small dense LDL particles is increasednot only with diabetes and the MetSyn but also with cigarettesmoking, hypertension and the presence of a low HDL-C level.In addition to facilitating the passage of monocytes throughthe arterial wall, oxidized LDL is also cytotoxic and damagesthe endothelium [15].

Small dense HDL particles are more easily cleared by thekidney with more apo-A being filtered and metabolized renally,which results in a shorter life span of this particle, andaccounts for the lower HDL levels typically seen in patientswith insulin resistance and/or diabetes [16]. Small dense HDLparticles are also twofold to threefold less effective than thelarger HDL particle in reverse cholesterol transport. Thisis mainly attributed to the lower concentrations of ApoEand lecithin-cholesterol acyltransferase (LCAT) in small denseHDL particles. Furthermore, these particles have decreasedanti-inflammatory and antioxidant properties [17]. Therefore,small dense HDL particles are potentially less cardioprotectivethan larger HDL particles which are inferred almost entirelyfrom epidemiological and clinical associations.

Goals of the Lipid-lowering Therapyin the Diabetic PatientCalculated LDL

The Friedewald calculation for serum LDL-C levels is almostuniversally utilized. However, in the insulin-resistant ordiabetic patient this calculation may be inaccurate becauseit underestimates the number of LDL particles as well as theatherogenic potential of these particles.

The most logical solution to the problem of an underes-timated LDL level, utilizing the Friedewald calculation, is todirectly measure the ApoB levels (one per LDL particle) orto directly measure the number of LDL particles. However,measurement of ApoB is preferable because ApoB is also acomponent of the other important atherogenic particles (inter-mediate density lipoproteins, remnant lipoproteins and smalldense VLDL particles).

The use of non-HDL-C, a surrogate for the number ofApoB-containing atherogenic particles, was shown to be a bet-ter predictor of cardiac events than LDL-C [18], particularlyin patients with DM, insulin resistance and/or hypertriglyceri-daemia [19]. The non-HDL-C level is recommended by ATPIIIto be utilized as a secondary target in the hypertriglyceridaemiasubject where the calculated LDL is invariably falsely low [1]. In

addition, non-HDL-C is also more convenient for the patientbecause it can be measured in the non-fasting state. The goalsfor non-HDL-C are 30 mg/dl higher than those of the calcu-lated LDL, so that if the goal for LDL is 100 mg/dl then thegoal for non-HDL-C is 130 mg/dl and if the goal for LDL is70 mg/dl then the goal for non-HDL-C is 100 mg/dl [1].

Recently, it has been proposed that in the general populationlipid screening should be performed in the non-fasting statewith only a total cholesterol and HDL being measured. Thisopinion is based on a study of a European population whereit was shown that independent of the calculated LDL levels,patients with higher non-HDL-C levels were at an increasedrisk of CHD [20]. In addition, two large trials of statintherapy, treating to new targets (TNT) [21] and incrementaldecreases in endpoints through aggressive lipid-lowering(IDEAL) trial [22], have also shown that levels of non-HDL-Cand ApoB are more closely associated with CV outcomesthan calculated LDL levels. However, data documenting thattargeting non-HDL-C leads to better outcomes than targetingLDL-C levels is still lacking.

Therapy of Diabetic Dyslipidaemia

Based on the UK prospective diabetes study (UKPDS), themost powerful risk factor for cardiac events in the diabeticpatient is an elevated LDL, closely followed by a decreasedHDL level. These lipid risk factors are followed in order by theother independent risk factors including HbA1c, systolic bloodpressure and cigarette smoking [23].

Thus, while the therapy of diabetic dyslipidaemia is extremelyimportant, it should not be performed in isolation and shouldbe accompanied by aggressive therapy of both hyperglycaemiaand hypertension, using evidence-based therapies such as drugsand therapeutic lifestyle changes (diet, weight loss, exercise,smoking cessation, etc).

Glycaemic Control and Diabetic Dyslipidaemia

Glycaemic control is the first and most important step incontrolling dyslipidaemia, which can result in a significantimprovement in lipid levels particularly in patients withhypertriglycaeridemia, where lowering of the triglyceride levelis usually accompanied by an increase in the HDL level. Inaddition, with correction of hyperglycaemia the LDL particlesize may be increased, and if pioglitazone or insulin is utilized,a decrease in the number of LDL particles may occur as well.

Of more importance than overall glycaemic control is thecontrol of postprandial hyperglycaemia. Varying degrees ofpostprandial hyperglycaemia are invariably present in diabeticpatients, especially when treated with drugs with minimaleffect on postprandial hyperglycaemia, such as basal insulinand metformin.

Triglyceride-rich lipoproteins (TRLs) derived from theintestine have been shown to be increased with insulinresistance not only in the preprandial state but importantlyalso in the postprandial state. Elevated TRLs are also associatedwith increased cardiac events. In particular, the productionrate of ApoB 48 containing particles is increased with bothinsulin resistance and T2D. Enterocytes, which are similar

314 Bell et al. Volume 13 No. 4 April 2011

DIABETES, OBESITY AND METABOLISM review articleto hepatocytes, overproduce ApoB 48 which facilitates theabsorption of ingested fat thereby enriching the assemblyand secretion of TRLs which contributes to postprandialhyperlipidemia [24].

Postprandial hyperglycaemia is accompanied by postpran-dial hyperlipidemia (characterized by elevated postmeal levelsof triglycerides and fatty acids) and the combination of post-prandial hyperglycaemia and postprandial hyperlipidemia hasbeen labelled ‘postprandial dysmetabolism’ [25]. Postprandialdysmetabolism is an insulin-resistant inflammatory state char-acterized by increased cytokine levels, decreased fibrinolysisbecause of increased PAI1 activity and increased oxidativestress leading to endothelial dysfunction [26]. The increasedinflammation within the plaque that occurs with postpran-dial dysmetabolism increases the risk of a cardiac event andit has been shown that postprandial glucose fluctuations aremore likely to trigger oxidative stress than chronic sustainedhyperglycaemia (figure 1) [27,28].

In multiple population studies, postprandial glucose levelshave been associated with CHD and mortality. In theHOORN [29], DECODE [30], Whitehall, Helsinki policemenand Paris protective studies, which in aggregate included over45 000 subjects, an elevated 2-h glucose was associated with

Figure 1. Postprandial—the immediate deleterious effects of a mealcontaining 75 g of glucose and 700 kcal/m2 of whipping cream in 20diabetic subjects. Within 2–4 h glucose and triglyceride levels double,causing immediate oxidant stress (nitrotyrosine), inflammation C-reactiveprotein (CRP), resulting in deterioration in endothelial function (FMD% = percent flow-mediated dilatation). Adapted with permission fromRef. [28].

Figure 2. Postprandial glucose and athero progression—patients withnormal glucose tolerance who had a postprandial glucose level of<87 mg/dlhad coronary regression. The remaining patients had coronary progressionin proportion to the increase in postprandial glucose. Adapted withpermission from Ref. [28].

increased cardiac events and mortality [31]. In the Honolulustudy of over 6000 men, the 1-h postprandial glucose level wasassociated with cardiac events and mortality [32].

In a study of non-diabetic females with normal glucosetolerance and coronary artery disease, coronary angiographywas performed at baseline after 3 years [33]. The lower the2-h glucose level on a baseline glucose tolerance test, the lessthe progression of coronary atherosclerotic burden over thecourse of the 3-year study. Indeed, if the 2-h glucose waslesser than 86 mg/dl there was regression in the coronaryatheroma volume (figure 2) [33]. Therefore, even in this studyof individuals with postmeal glucose excursions within thenormal range, the higher the postprandial glucose rose, thegreater was the rate of atheroma formation. Similarly, in astudy of individuals with normal fasting and 2-h glucose levels,higher CV mortality was seen among those with higher 2-hglucose levels (closer to 140 mg/dl) [34].

The DECODE study showed that mortality could not bepredicted from the fasting glucose level but could be predictedfrom the postprandial glucose level, which was also shown tobe an independent risk factor for mortality [30]. The STOP-NIDDM study, a blinded placebo-controlled study of 1429individuals with impaired glucose tolerance, assessed whetherthe α-glucosidase inhibitor, acarbose, could slowdown theprogression to T2D [35]. While conversion to diabetes wassignificantly decreased by 25%, the relative risk of a CVevent decreased by 49%. Subsequently, the phase 3 studiesof acarbose were re-examined for CV events and it was foundthat compared to placebo and other diabetic medications therisk of having a myocardial infarction (MI) was decreasedby 64% and the risk of any CV event decreased by 35% withacarbose [36]. Additionally, acarbose decreased carotid intima-medial thickening (CIMT) by 50%—a benefit that dissipatedwhen acarbose was discontinued [37]. Acarbose, though itseffects on α-glucosidase and lipase, reduces both postprandialglucose and lipid levels. Thiazolidinediones (TZDs), bylimiting intestinal lipid absorption, which is increased inthe MetSyn, also reduce both postprandial hyperglycaemiaand hyperlipidemia. While postprandial glucose is not

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lowered by metformin or basal insulin, it is lowered bysulfonylureas, incretin mimetics, DPP4 inhibitors, pramlintideand short-acting insulin [38]. However, to date, only theα-glucosidase inhibitors and TZDs have been shown toreduce both postprandial hyperglycaemia and postprandialhyperlipidemia [39].

The nateglinide and valsartan in impaired glucose toleranceoutcomes research (NAVIGATOR) trial showed that nateglin-ide, a sulfonylurea-like agent that lowers postprandial glucose,proved ineffective at halting progression from impaired glucosetolerance to overt T2DM and also had no significant impacton reducing CV events. However, nateglinide, for uncertainreasons, did not lower the postglucose challenge glucose levelsfor the patients in the NAVIGATOR trial [40].

TZDs and Diabetic Dyslipidaemia

A head-to-head randomized clinical trial comparing maximaldoses of pioglitazone and rosiglitazone showed that whileboth of these drugs were equally effective at lowering theHbA1c, pioglitazone was superior to rosiglitazone in increasingboth the HDL and the LDL particle sizes [41]. Paradoxically,while pioglitazone decreased triglycerides by 12%, rosiglitazoneincreased triglycerides by 14.9%. However, a finding of muchgreater importance was that pioglitazone reduced the numberof LDL particles by 51% while rosiglitazone increased thisnumber by 111%, resulting in lesser increases in calculatedLDL and ApoB levels with pioglitazone. Rosiglitazone hasbeen shown to be ineffective at lowering atherosclerotic plaqueburden in the carotid and coronary arteries and has beeneffectively removed from the US and European markets due toconcerns about its CV safety [42].

These differences in lipid levels, especially the differencein LDL particle numbers, could explain the differences inaccumulation of coronary artery atheroma and cardiac eventsseen with these drugs. However, other factors may be involvedbecause a total of 23 genes have been shown to be expressedwith either rosiglitazone or pioglitazone; of these, 5 genes areexclusively expressed by rosiglitazone and 12 genes exclusivelyby pioglitazone [43].

In contrast, in the pioglitazone effect on regression ofintravascular sonographic coronary obstruction retrospectiveevaluation (PERISCOPE) study, pioglitazone when comparedwith glimepiride significantly reduced the percentage ofatheroma volume (the primary endpoint) as well as atheromathickness [44]. Of note, the reduction in the atheroma volumeachieved with pioglitazone in PERISCOPE compared favorablywith that achieved by the strongest of the statin cholesterol-lowering drugs [45].

In the PROACTIVE study, the addition of pioglitazone toexisting diabetic therapies resulted in significant decreases inthe principle secondary combined endpoint of MI, stroke anddeath (figure 3). Furthermore, decreases in the recurrenceof MI and stroke were also shown [46,47]. The primarycomposite endpoint which included criteria for peripheralvascular disease was not significantly decreased, probablybecause of the inclusion of subjects with peripheral vasculardisease who showed no improvement in cardiac events withpioglitazone [47,48]. However, even in this group, the trend

Figure 3. Proactive trial—PROactive: significant difference in principalsecondary endpoint (death, MI or stroke; pioglitazone vs. placebo: HR 0.84;95% CI 0.72–0.98). HR, heart rate; MI, myocardial infarction. Adaptedwith permission from Ref. [124].

towards less CV events could have become significant witha longer duration of the study because the termination ofthe study was based on the number of events which wassurprisingly high and resulted in the study lasting for only3.4 years. In addition, a retrospective subanalysis of the studyshowed that there was no significant improvement in CV eventswhen statins or β-blockers were being utilized. However, forany study to show an additional improvement in cardiacevents in the diabetic patient who was utilizing maximalrisk-reducing therapies would entail the inclusion of verylarge numbers of subjects and would therefore be impracticaland cost-prohibitive. The major side effect of pioglitazone inPROACTIVE, especially when used with insulin, was fluidretention and non-fatal heart failure [49].

Lifestyle Changes and Diabetic Dyslipidaemia

Lifestyle factors including dietary changes, increased physicalactivity, weight loss and smoking cessation may help diabeticpatients reach their therapeutic goals. Cessation of smoking,exercise and weight loss is particularly beneficial in elevatingHDL levels.

The benefits of regular exercise, in addition to an improvedlipid profile, include weight loss, decreased abdominal fat,reduced inflammation, increased insulin sensitivity, decreasedblood pressure levels and improved endothelial function. TheADA recommends 150 min of aerobic physical activity perweek accompanied by resistance training up to three times perweek [50]. Exercise duration correlates strongly with reductionsin triglycerides and weight and increases in HDL levels.Significant improvements in HDL require at least 20 min ofdaily exercise; 40–60 min of exercise daily will produce betterresults. Aerobic exercise appears to raise HDL better thanstrength training or stretching exercises [51,52].

Diet

The ADA recommends weight loss in overweight patients, asaturated fat intake of less than 7% of total calories, minimaltrans-fat intake, reduced cholesterol intake, a carbohydrateintake limited to 130 g/day and fiber intake of at least 14 g


DIABETES, OBESITY AND METABOLISM review articleper thousand calories [50]. ATPIII also focuses on weight loss,reduced fat intake, reduced carbohydrate intake in additionto an increase in calories derived from monounsaturated orpolyunsaturated fats [1].

Investigators from the Framingham Heart study found thata diet consistent with the fundamentals of the Mediterranean-style diet appears to prevent development of the T2D andMetSyn. Specifically, a diet high in vegetables, fruits, nuts,omega-3 fatty acids, olive oil and whole grains but lowin refined carbohydrates, saturated fats and trans fats wasassociated with reduced risks for T2D, including lowerlevels of insulin resistance, abdominal obesity, fasting glucoseand triglycerides, and improvements in HDL-C levels andendothelial function [53].

A more recent epidemiological study of 23 500 Greek adultsreported that the intake of vegetables, fruits, nuts, legumes, andolive oil, and drinking light-to-moderate amounts of alcohol,while minimizing the consumption of fatty meats and avoidingexcessive alcohol intake was linked to improved longevity. Theproportion of the overall improvement in longevity attributableto each of the specific components of the Mediterraneandiet was as follows: moderate ethanol consumption 24%, lowconsumption of meat 17%, high vegetable consumption 16%,high fruit and nut consumption 11%, high monounsaturatedto saturated lipid ratio 11% and high legume consumption10% [54]. Overall, those individuals who adhered to theMediterranean dietary principles most closely were 25% lesslikely to die during the course of the study [54].

A trial of patients with newly diagnosed T2D randomizedthem to either a Mediterranean diet or a low-fat AmericanHeart Association (AHA) diet. After 4 years, only 44% of newlydiagnosed diabetic patients randomized to the Mediterraneandiet vs. 70% of those randomized to the low-fat AHA dietrequired glucose-lowering drug therapy for control of theirdiabetes. Individuals following the Mediterranean diet alsoshowed greater improvement in several CV risk factors [55].

An epidemiological study of over 13 000 people found thatthose who followed a Mediterranean-style diet were less likelyto develop new-onset diabetes. The benefits were especiallypronounced in those who were at higher risk of developingT2D because of issues such as MetSyn, excess weight, familyhistory and blood pressure. Study participants with the bestadherence to the Mediterranean dietary principles had >50%decrease in the risk of developing diabetes during 4.4 yearsfollow-up [56].

In summary, following the traditional Mediterranean-stylediet results in a lower risk of developing T2D, better controlof blood glucose in individuals with T2D and a substantiallylower need to resort to glucose-lowering drug therapy. TheMediterranean-style diet has also been shown to improvemultiple CV risk factors.

Principles of the Mediterranean Diet

• A high intake of fruits, vegetables, beans, nuts, seeds andcereal grains

• Olive oil preferred for cooking and dressings• Moderate amounts of fish and seafood but modest intake of

meat

• Low-to-moderate amounts of non-fat or low-fat dairy• Light-to-moderate daily consumption of wine, typically with

meals• Preference for local, seasonal, produce• Physically active lifestyle, usually incorporated into activities

of daily life

Testosterone Replacement Therapy and DiabeticDyslipidaemia

It has been estimated that as many as 50% of type 2diabetic males have hypogonadotropic hypogonadism [57].This is because the excess peritoneal fat associated with theMetSyn and T2D is associated with increased activity of theenzyme aromatase which results in an increased conversion oftestosterone to estrogen (mainly estradiol). Increased estrogenlevels at the level of the hypothalamus suppress the release ofgonadotropin-releasing hormone which in turn decreases therelease of gonadotropins (particularly luteinizing hormone)from the anterior pituitary gland resulting in a decreasedproduction of testosterone from the Leydig cells of the testicles.Low testosterone levels have been associated with insulinresistance, higher PAI1 and fibrinogen levels, increased FFAand triglyceride levels and lower HDL levels [58]. Increasedoxidative stress, endothelial dysfunction, increased CIMT andincreased CV events and mortality have also been associatedwith low testosterone levels.

Testosterone replacement therapy in testosterone-deficientsubjects lowers insulin resistance and results in lowering oftriglyceride and elevation of HDL levels and improved oxidativestress and endothelial function [59]. It has been estimated thatfor each 5.3 nmol/l elevation in serum testosterone levels therisk of an MI may decrease by 57% [60]. However, the safetyand clinical benefit of routine testosterone replacement inhypogonadal men with MetSyn are currently unknown. Indeed,a recent randomized study of testosterone dermal gel to assessleg strength which improved with testosterone was abandonedbecause of a greater number of cardiac adverse events in thetestosterone group [61,62]. Routine testosterone replacementin hypogonadal men with MetSyn cannot be recommendedand further prospective studies evaluating the safety and clinicalbenefit of testosterone replacement are needed.

Therapies that may Worsen Diabetic Dyslipidaemia

Drugs commonly utilized for hormone replacement therapyand hypertension may worsen hyperlipidemia. Hypertrigly-caeridemia, often at levels that may cause pancreatitis andenough pancreatic damage to cause diabetes, is associated withthe utilization of oral postmenopausal estrogen replacementtherapy in vulnerable individuals [63]. Drugs that increaseinsulin resistance not only result in an increase in triglyceridesbut also a lowering of HDL levels and the development ofsmaller more dense and more atherogenic LDL particles. Use ofthiazide diuretics, first and second generation β-blockers (butnot vasodilating β-blockers such as carvedilol and nebivolol)increases insulin resistance and adversely affect the lipid profileof the insulin-resistant or diabetic patient. However, ethanoland drugs such as blockers of the renin-angiotensin system



(RAS), both of which reduce insulin resistance, have beenshown to increase total HDL (mainly smaller HDL particles)and increase the LDL particle size [64]. The use of bile acidsequestrants (BASs) may induce hypertriglyceridaemia [65].However, with colesevelam it does not appear to cause signifi-cant hypertriglyceridaemia [66].

Statin (HMG-CoA-Reductase Inhibitor) Therapyin the Diabetic Patient

Statins are recommended by the ADA as an addition to lifestyletherapy for all diabetic patients with CVD and for those withoutknown CVD who are over the age of 40 and have an additionalCV risk factor (family history of heart disease, cigarette smokingor hypertension) [50]. Even without risk factors, statins shouldbe considered for those diabetic patients without known CVDwho are under the age of 40 and who have a calculated LDL ofover 100 mg/dl [50]. Statins mainly lower LDL levels but alsoraise HDL levels and may increase LDL particle size. In addition,statins lower highly sensitive C-reactive protein (hsCRP) (amarker of inflammation which is strongly associated with theMetSyn, diabetes and CV disease).

In the diabetic patient, statins may worsen glycaemic controland in the prediabetic patient increase the risk of developmentof T2D. Rosuvastatin has, in the JUPITER trial [67], been shownto increase both the HbA1c and the incidence of reportednew-onset diabetes. Alternatively, in the West of Scotlandstudy [68] the incidence of diabetes was decreased by 30% withpravastatin. A meta-analysis of mega trials suggested that, withthe exception of pravastatin, the statins appear to modestlyincrease the risk of new diabetes (approximately by 9%), withsimvastatin showing the highest risk [69]. A more recent meta-analysis showed that treating 255 patients with a statin for4 years would result in one extra case of diabetes [70]. Becausein the JUPITER trial the HbA1c but not the fasting glucose wasincreased [67], it is likely that statins (with the exception ofpravastatin) increase postprandial glucose. Indeed, atorvastatinhas been shown to both increase insulin levels and HbA1c [69].Overall, the risk (6–13%) of developing diabetes with the useof statin is not a major liability when compared with the potentcardioprotective effects of statins, even in those who developnew diabetes while on the statin [71].

Subgroup analyses of several major statin trials haveexamined whether statins had as much of an effect onimproving CV outcomes in the diabetic patient compared withthe non-diabetic patient. In the Heart Protection study [72],daily administration of 40 mg of simvastatin resulted in a22% reduction of CV events in all diabetic subjects and indiabetic subjects without known CVD a 33% reduction. Ameta-analysis of 14 statin trials which included 18 686 diabeticsubjects showed that with an average 39 mg/dl reduction inLDL, over 4.3 years all-cause mortality was decreased by 9%and major cardiac events by 21% [73].

Subgroup analyses of major statin trials have also shown thatachieving lower LDL levels in diabetic subjects was associatedwith a greater lowering of CV events. In the pravastatin oratorvastatin evaluation and infection therapy (PROVE-IT) andthe TNT trials, diabetic subjects treated with atorvastatin 80 mg

daily achieved a 25% reduction in CV events. In PROVE-IT,only 38% of diabetic patients achieved the combined goal ofan LDL lesser than 70 mg/dl and an hsCRP level of lesser than2 mg/l, but if both these goals were achieved there was a furtherreduction in CV events of 34% [74].

In the JUPITER trial, where patients with diabetes wereexcluded, 41% of the subjects had the clinical features ofMetSyn. With rosuvastatin 20 mg daily, a similar reduction inCV events was achieved in MetSyn subjects as was achieved innon-MetSyn subjects [67]. In addition, subjects with impairedfasting glucose had similar reductions in CV events withrosuvastatin as those with normal fasting glucose levels.Importantly, the development of new T2D did not negatethe statin-conferred reduction in adverse CV events noted inthose patients randomized to rosuvastatin in the JUPITERtrial [67].

There have been three large-blinded and placebo-controlledstudies with atorvastatin 10 mg daily, which have beenrestricted to diabetic subjects. Neither the die deutsche diabetesdialyse studies (4D) of hemodialysis patients with diabetes [75]nor the atorvastatin for prevention of CHD endpoints innon-insulin-dependent DM (ASPEN) [76] showed significantreductions in CV events because of the advance stages ofatherosclerosis in these subjects. In contrast, the collaborativeatorvastatin diabetes study (CARDS) showed not only adecrease in LDL and an increase in HDL, but also an increasein LDL particle size and a 37% reduction in CV events [77](figure 4).

Prior to the availability of statins, the POSCH studyof subjects with familial hypercholesterolemia showed thatthe LDL level was significantly lowered by small bowelbypass surgery [78]. In spite of significant LDL lowering,an improvement in CV events did not occur over the first5 postsurgical years, but after 5 years positive differences incardiac events began to appear and by 12 years these differencesbecame statistically significant with a 35% reduction. Becausethe protective effect of statins on cardiac events in mostclinical trials begins to appear within 3–6 months, this earlier

Figure 4. The CARDS Trial, significant reduction in the primary endpoint(acute CHD events, coronary revascularization or stroke). Atorvastatin alsoresulted in a 48% relative risk reduction for stroke, p = 0.016, and a 47%relative risk reduction for non-fatal MI, p = 0.0178. CHD, coronaryheart disease; MI, myocardial infarction. Adapted with permission fromRef. [77].


DIABETES, OBESITY AND METABOLISM review articleimprovement cannot be related to LDL lowering and isprobably because of the pleiotropic effects of statins.

The pleiotropic effects of statins include lowering ofplasma viscosity, decreased generation of thrombin anddecreased platelet aggregation [79]. Most importantly, statinsalso decrease inflammation, both systemically and within theatheromatous plaque [80]. The decrease in systemic inflamma-tion lowers oxidative stress and improves endothelial function.Within the atheromatous plaque a decrease in inflammationpromotes a more stable fibrous plaque by reducing the elabo-ration of collagenases and metalloproteinase’s by white bloodcells, thereby lowering the likelihood of plaque rupture. Statinsalso increase angiogenesis and the formation of collateral ves-sels and thus reduce ischaemia severity in the setting of acuteand chronic coronary artery occlusions [81].

Subjects with diabetes and/or the MetSyn almost invari-ably have elevated hsCRP levels because excess macrophage-infiltrated peritoneal fat produces Interleukin 6 which stim-ulates hepatic production of CRP. In the setting of bacterialinfections, CRP is protective by adhering to the wall of thepneumococcus bacteria where it combined with complementto damage the bacterial cell membrane and activate the immunesystem [82]. While CRP is beneficial during an acute infection,chronically elevated CRP levels are detrimental, mainly becauseCRP binds to oxidized LDL particles. Therefore, when oxidizedLDL levels are high, as occurs in both the diabetic and insulin-resistant patients, CRP not only accelerates the growth of theatheromatous plaque but also increases inflammation withinthe atheroma and increases the risk of plaque rupture and CVevents.

Lowering of inflammation, with drugs other than statins, hasbeen shown to decrease CV events, and decreasing inflamma-tion as a result of statin therapy has been associated with reducedrisks for some non-cardiac diseases. For example, the use ofmethotrexate in patients with rheumatoid arthritis has beenshown to decrease cardiac events by as much as 40–60% andveterans admitted to hospital with septicemia have a higher sur-vival rate if they have been taking a statin [83]. In the PROVE-ITstudy, lowering of LDL and hsCRP to goal were equally effectivein lowering cardiac events, and when both goals were achievedthe reduction in CV events was maximized [84]. In the PROVE-IT, subjects with the higher CRP levels had all the characteristicsof the MetSyn, i.e. higher levels of glucose, triglyceride andblood pressures with a higher BMI and a lower HDL [85].Therefore, in the type 2 diabetic patient where hsCRP is almostinvariably elevated, statins and doses of statins that maximallylower both LDL and hsCRP should be utilized. In the JUPITERtrial, those subjects on rosuvastatin who achieved LDL levels<70 mg/dl and CRP levels <1.0 experienced a 79% reductionin adverse CV events during the randomized trial [67].

However, it may be that rather than being a treatment target,CRP may simply be another risk factor that strengthens thecase for statin therapy. If indeed this is the case, then the use ofCRP is superfluous in a diabetic patient where statin therapyis generally indicated regardless. Because of the expected highlevels of inflammation and CV risk in diabetic patients, maximalstatin therapy as utilized in the REVERSAL [86], TNT [87],PROVE-IT [88] and JUPITER [67] trials should be utilized.

Niacin

The key components of diabetic dyslipidaemia are improvedwith niacin therapy with both LDL and triglyceride levels beinglowered and both total HDL levels and HDL and LDL particlesizes being increased. In addition, niacin (2 g/day) can lowerlipoprotein (a) levels by 25% [89–91]. In practice, the use ofniacin is limited by its side effects, particularly that of cutaneousflushing. This side effect is mediated through the interaction ofprostaglandin D2 with the DP1 receptor in the skin [92].The use of extended-release preparations and/or patienteducation may improve compliance. Taking an extended-release preparation with apple sauce or psyllium (metamucil)and an aspirin can decrease the frequency and severityof flushing. Combining niacin with laropiprant, a potentprostaglandin receptor antagonist, is a safe and promisingoption to improve patients’ tolerability of niacin [93] and isbeing tested in a large outcome-based clinical trial [94].

Another side effect of niacin is an increase in insulinresistance, which is usually short-lived, so that over the longterm the effect on glycaemic control is minimal. For example,in the arterial disease multiple intervention trial (ADMIT) [95]and the assessment of diabetes control and evaluation of theefficacy of niaspan trial (ADVENT) [96], niacin was utilizedwithout significant long-term increases in glucose levels.

Niacin was utilized in the double-blind coronary drugproject (CDP) which was a study of men who had had anMI and of whom 40% had impaired fasting glucose and/orimpaired glucose tolerance [97]. In this study, while the primaryendpoint of all-cause mortality was not significantly reducedwith niacin, after 6.2 years non-fatal MI was decreased by26% and transient ischemic attacks or strokes by 24%, inspite of a poor adherence due to troublesome side effects.However, 9 years after the termination of the study there was aresidual 10.2% decrease (58.2 vs. 52.0%) in all-cause mortalitywhich was largely because of a decrease in death from CVD,suggesting that niacin therapy may have residual long-lastingbenefits [98].

While the use of niacin in the CDP study resulted in modestincreases in both fasting and 1-h postprandial glucose levels,the need for initiation of insulin or the addition of an oralantidiabetic agent was no greater in the niacin group than itwas in the placebo group [97]. In addition, in those who diddevelop a fasting glucose of more than 126 mg/dl, there was asignificant 57% reduction in MI after 6 years, which was similarto those whose fasting glucose remained in ranges lesser than126 mg/dl, suggesting that niacin may be even more effectivein the insulin-resistant or diabetic subject, probably becauseof niacin’s ability to elevate HDL levels. Therefore, in spiteof poor compliance and short-term worsening of glycaemiccontrol, niacin significantly reduces cardiac events in both thediabetic and insulin-resistant patients and thus should be usedmore frequently utilized in these cohorts [99].

Fibrates

Fibrates, through stimulating the activity of lipoprotein lipase,reduce both triglyceride levels and the levels of the TRLsthrough decreased hepatic production of VLDL [100]. As a



result, there is an increase in HDL levels and an increase in LDLparticle size [101]. Other cardioprotective properties of fibratesinclude the ability to lower hsCRP and inflammation [102].This, in conjunction with an improvement in the level of theatherogenic TRLs and HDL levels, might result in a reductionin CV events.

The Helsinki Heart study [103] utilized gemfibrozil at adose of 1200 mg daily, in men who had a non-HDL-C levelof more than 200 mg/dl. The greatest lowering of cardiacevents occurred when the baseline triglyceride level exceeded200 mg/dl and was accompanied by a low LDL-to-HDLratio. Compared with placebo, cardiac events were decreasedby 71% in this group who had all the characteristics ofthe insulin resistance (metabolic) syndrome. The veteransaffairs high-density lipoprotein-cholesterol intervention trial(VA-HIT) [104] also utilized gemfibrozil at a dose of 1200 mgdaily in men with known CVD, an HDL lesser than 40 mg/dland a calculated LDL lesser than 140 mg/dl. In a subgroupanalysis of the VA-HIT of those subjects with diabetes,gemfibrozil reduced cardiac events by 32% and in those withinsulin resistance (defined as non-diabetic subjects with anelevated fasting hyperinsulinemia) by 35% [105].

In prospective placebo-controlled studies of diabeticsubjects, fibrates have been shown to be inconsistent in theirability to decrease the progression of coronary atherosclerosisand/or decrease cardiac events. With fenofibrate beingadministered in a dose of 200 mg daily, in the diabetesatherosclerosis intervention study (DIAS) [106] there was,after 3 years, significantly less progression of coronary arterydisease as measured by the minimal coronary artery lumendiameter. In the DIAS study, however, the primary endpoint ofa decrease in mean segment diameter did not reach statisticalsignificance. Similarly, in the fenofibrate intervention and eventlowering in diabetes (FIELD) study [107], daily administrationof 200 mg fenofibrate did not significantly change the primaryendpoint of non-fatal MI or death related to CHD. However,in the FIELD study, there was a significant 24% reductionin non-fatal MI and a significant 11% decrease in CVevents as well as improvements in albuminuria and diabeticretinopathy as was later documented with fenofibrate in theACCORD study of type 2 diabetic subjects. Fenofibrate alsonon-significantly increased total mortality, mortality related tocoronary artery disease and the incidence of acute pancreatitisand pulmonary embolism. The FIELD study was confoundedby a greater use of statins in the placebo group which mayaccount for the less than expected improvement in CV events.Again, the greatest CV benefit of fenofibrate was seen in patientswho had the characteristic lipid profile (high triglyceride andlow HDL) of the MetSyn.

In the action to control cardiovascular risk in diabetes(ACCORD) trial [108], the investigators examined the effectsof combination lipid therapy in 5518 patients with T2D. Theaddition of fenofibrate to simvastatin vs. simvastatin plusplacebo did not reduce the risk CV events (fatal CV events,non-fatal MI or non-fatal stroke) (figure 5). There was a trendtowards the benefit of fenofibrate in the cohort of patients withhigh triglyceride and low HDL levels. After a mean follow-upof 4.7 years, the annualized rates of the primary endpoint were

Figure 5. In the ACCORD lipid trial, fenofibrate did not significantlyimprove the primary outcome. Adapted with permission from Ref. [108].

2.2 and 2.4 events per year, respectively, in the two treatmentarms (p-value 0.32). Also, there was no statistically significantdifference between the two treatments among the secondaryendpoints.

Omega-3 Fatty Acids

Omega-3 fatty acids at high doses, 3–5 g of eicosapentanoicacid (EPA) + docasahexanoic acid (DHA) per day, effectivelylower triglyceride levels [109], while concurrently increasingcalculated LDL levels which is probably because of an increase inparticle size rather than an increase in particle numbers [110].The decrease in mortality that has been shown with omega-3 fats appears to be in part because of an antiarrhythmiceffect. Recently, omega-3 fats have also been shown todecelerate telomere shortening which is a marker of biologicalaging [111].

In diabetic subjects, daily administration of 3.6 g ofEPA + DHA has been shown to decrease triglyceride levelsby 28%, increase HDL levels by 7% and not to have aneffect on ApoB or LDL-concentrations in spite of decreases inthe ApoB component of VLDL and an increased conversionof VLDL to LDL [112]. In the COMBOS trial, the use ofomega-3 fats (3.6 g of EPA + DHA) was tested in subjectswith hypertriglyceridaemia. In this randomized trial, thenon-HDL-C was decreased by an additional 9% when omega-3fats were added to simvastatin 40 mg compared with 2.2%when placebo was added to 40 mg of simvastatin daily [113].In addition, triglycerides were lowered by 30% with thecombination compared to 6% with simvastatin alone andHDL-C was increased by 3.4% with the combination.

A subgroup analysis of the Gruppo Italiano per lo Studiodella Infarto Miocardico (GISSI-Prevenzione) showed thattotal mortality was decreased by 28% with 1 g of omega-3fats in diabetic subjects which compared favorably with non-diabetic subjects where omega-3 fats decreased mortality by18% [114]. In another subgroup analysis from the JapanEPA lipid intervention study (JELIS), subjects who had thecharacteristics of the MetSyn (defined as a high triglyceride


DIABETES, OBESITY AND METABOLISM review article

Figure 6. In the JELIS trial, supplementation with omega-3 fatty acidsreduced the primary endpoint of major coronary events particularly wellin those patients with impaired glucose metabolism (IGM) as comparedto those with normal glucose (NG) levels. Adapted with permission fromRef. [116].

to HDL ratio) had a 71% increased risk of a CV eventwhich was decreased by 53% with the daily combination ofEPA (1800 mg) and a statin [115,116] (figure 6). In addition,even with the lower daily intake of 250 mg of omega-3 fatsdaily, diabetic subjects showed a 17% reduction in mortalityand a 36% reduction in mortality related to coronary arterydisease [116].

In addition, to their beneficial effects on lipid levels, omega-3 fats have other non-LDL-dependent benefits, includingreduced heart rate and blood pressure and antithromboticeffects which protect against ischemic stroke and non-fatal MI.However, the most important cardioprotective effect of omega-3 fats may be their antiarrhythmic properties, protecting fromboth atrial and ventricular fibrillation, the incidences of whichare increased in the diabetic patient [117].

Bile Acid Sequestrants

Historically, BASs have been used where statins are nottolerated or untested and/or associated with safety concerns(fertile women and children). These agents have a non-systemic action; BASs are not absorbed out of the lumenof the intestine. They work to lower cholesterol, by decreasingthe reabsorption of bile acids resulting in a compensatoryincrease in the hepatic production of bile acids, decreasingintracellular cholesterol and increasing the utilization ofcholesterol and depletion of the LDL pool. However, BASscan also increase triglyceride levels, cause gastrointestinalsymptoms (particularly constipation) and are associated withan increased prevalence of cholelithiasis. A more modernBAS, colesevelam, has been chemically altered to improve therelative affinity of binding of bile acids and thus has a muchlower incidence of these side effects [66,118]. While it carriesa warning of induction of severe hypertriglyceridaemia, this isgenerally only an issue for patients with elevated triglyceridesat baseline [66,118].

BASs are considered as second-line therapy for loweringLDL levels and are most commonly utilized in combinationtherapy. While not as potent as statins in the lowering of

LDL levels, BASs, at least in one trial, may be equally effectiveat lowering cardiac events. This is because for every 1% theLDL is lowered by a statin there is a 1% lowering of car-diac events, whereas for every 1% the LDL is lowered witha BAS there is a 2% decrease in cardiac events [119]. Addi-tional advantages of BASs are their beneficial effects on glucosemetabolism (improvement in fasting, postprandial glucoseas well as HbA1c) and reductions in systemic inflammation(BASs lower CRP by about 20–25%). Because many statinsmay modestly increase the risk of new T2D, the combina-tion of a well-tolerated BAS such as colesevelam and a statincould potentially prevent the development of diabetes in thosewho are at the highest risk (subjects with the MetSyn orprediabetes) and improve glycaemic control in subjects withestablished diabetes [69]. In the setting of T2D, colesevelam ata daily dose of 3.75 g has been shown to lower the HbA1c by0.5% and the postprandial glucose by 32 mg/day [120], mak-ing colesevelam a logical add-on to statin therapy in diabeticpatients [69].

Ezetimibe

Another lipid-lowering agent, ezetimibe, acts at the brushborder of the small intestine by blocking the absorption of bothdietary and biliary cholesterol and plant sterols. Consequently,this leads to the depletion of intracellular cholesterol andincreased clearance of circulating LDL by the liver, resulting inthe reduction of both LDL and total cholesterol levels [121].However, no data currently exist to document that ezetimibe(despite its beneficial effects on LDL levels) reduces CV eventsor atherosclerosis progression in the overall population or indiabetic or insulin-resistant subjects.

Combination Therapies

Often, to achieve goals in the diabetic patient, combinations ofdifferent lipid-lowering agents with different modes of actionneed to be utilized. Better results can usually be obtained byadding a BASs, omega-3 fats or niacin to a statin rather thanby increasing the dose of the statin, because doubling of thedose of statin only results in a further 6% reduction in theLDL. The combination of a statin with omega-3 or niacin willalso result in a greater increase in HDL-C levels and morerobust decreases in triglycerides and non-HDL-C levels. Thepotential for adverse events is increased when gemfibrozil andto a lesser extent other fibrates are utilized with a statin becausethe combination of a statin and a fibrate increases the risk ofmyalgias, myositis and rhabdomyolysis.

A secondary analysis of diabetic subjects in the SANDS trial,where the goals for LDL were less than 100 mg/dl or 70 mg/dland goals for non-HDL-C lesser than 100 or 130 mg/dl, showedthat irrespective of whether these goals were reached with ahigh statin dose or the combination of a statin with ezetimibeor fenofibrate, those subjects with the lower goals had astatistically significantly greater decrease in the CIMT [122].As detailed above, in the ACCORD study, the effect of acombination of a statin and fenofibrate did not improve CVoutcome [123].



ConclusionsIn this article, we emphasize that the correction of diabetic dys-lipidaemia is the most important factor in reducing cardiac risk,with the most important goal being to lower the non-HDL-Clevel. Lowering glucose levels in general and postprandial levelsin particular is helpful as is the use of hypoglycaemic agentsthat may also have a beneficial effect on dyslipidaemia. Lifestylechange is essential and utilization of statins is recommended inmost type 2 diabetics to lower the LDL-C level to that recom-mended for patients with existing CV disease. Many patientswill also need to utilize therapies to lower triglycerides and/orincrease HDL levels, meaning that most patients with dia-betic dyslipidaemia will need combination therapies which willinclude two or more of the following: a statin, niacin, omega-3fats and BASs. The addition of a fibrate may be needed particu-larly in the patient with elevated triglycerides and/or depressedHDL-C levels. The role of ezetimibe and fibrates in reducingcardiac events is questionable.

Conflict of InterestAll authors contributed to the entire writing of the manuscript,corrections and updates.

J. H. O. is the speaker for AstraZeneca, GlaxoSmithKline,Takeda and Merck. F. A. B. has nothing to declare and D. S.H. B. is the consultant and speaker for Bristol Myers-Squibb,AstraZeneca, Novo Nordisk and Takeda.

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