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    Treatment dm dyslipidemia Treatment dm dyslipidemia Document Transcript

    • review article Diabetes, Obesity and Metabolism 13: 313–325, 2011. © 2011 Blackwell Publishing Ltd article reviewTherapies for diabetic dyslipidaemiaD. S. H. Bell1 , F. Al Badarin2 & J. H. O’Keefe, Jr21 Department of Endocrinology, University of Alabama, Birmingham, AL, USA2 Saint Luke’s Cardiovascular Consultants/Mid America Heart and Vascular Institute, University of Missouri-Kansas City, Kansas City, MO, USACorrection 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 diabetesDate submitted 6 July 2010; date of first decision 16 August 2010; date of final acceptance 17 November 2010Modifiable Cardiac Risk Factors in the Diabetic DyslipidaemiaDiabetic Patient Data from the Framingham study indicate that a low HDLDiabetes mellitus (DM) is a major risk factor for cardiovascular level accompanied by an elevated triglyceride level is twicedisease (CVD). According to the National cholesterol education as common among patients with type 2 diabetes (T2D)program (NCEP) and adult treatment panel III (ATPIII) compared to non-diabetic patients, while concentrations ofrecommendations, patients with diabetes are in a high- calculated LDL and total cholesterol do not differ [10]. Therisk category for cardiovascular (CV) events [1,2] and lowering of total HDL levels in patients with T2D is mainlydiabetes is now considered a coronary heart disease (CHD) because of a decrease in the concentration of the larger moreequivalent [3]. cardioprotective HDL particles, with the smaller more dense Diabetic patients have high prevalence of concomitant and less cardioprotective HDL particles predominating [11].CV risk factors (hypertension, smoking and truncal obe- The low HDL, high triglyceride pattern is also characteristicsity) [4]. In addition, the biochemical and metabolic derange- of individuals with prediabetes or the metabolic syndromements that accompany DM lead to abnormal oxidative (MetSyn), regardless of race, ethnicity and gender. It shouldstress, impaired endothelial function, increased fibrinogen be noted that in the Framingham study, the diabetic Africanand platelet activation and chronic low-grade inflamma- Americans’ lipid pattern was more commonly that of a lowtion, all of which are known to promote plaque for- HDL accompanied by a high calculated LDL level with onlymation and atherogenesis [5–7]. Furthermore, DM predis- 19% (compared with 50% of those of European origin) havingposes to atherogenic lipid abnormalities including elevated hypertriglyceridaemia [12].low-density lipoprotein-cholesterol (LDL-C), greater num- Because of resistance to the action of insulin on the adipocyteber of smaller LDL particles, low high-density lipoprotein- (particularly the peritoneal adipocyte), free fatty acid (FFA)cholesterol (HDL-C) and high triglycerides [8,9]. There- levels are elevated [13]. Increased delivery of FFAs to thefore, an aggressive approach to controlling CVD risk fac- liver promotes hepatic production of triglycerides which aretors, especially dyslipidaemia, is essential in all diabetic packaged in ApoB-containing very low-density lipoproteinssubjects. (VLDLs). The presence of increased VLDL increases the available substrate for cholesterol ester transfer protein (CETP) which enhances the exchange of triglycerides for cholesterolCorrespondence to: Dr. David S. H. Bell, University of Alabama and SouthsideEndocrinology, 1020 26th Street South, Room 204, Birmingham, AL 35205, USA. from the HDL to the LDL particles increasing the triglycerideE-mail: dshbell@yahoo.com; davidshbellmd@charter.net content of both particles.
    • review article DIABETES, OBESITY AND METABOLISM The increased triglyceride content of both the LDL and addition, non-HDL-C is also more convenient for the patientHDL particles causes increased activity of the enzyme hepatic because it can be measured in the non-fasting state. The goalslipase which results in an increased production of both small for non-HDL-C are 30 mg/dl higher than those of the calcu-dense LDL and small dense HDL particles. Small dense LDL lated LDL, so that if the goal for LDL is 100 mg/dl then theparticles are more atherogenic because these particles, especially goal for non-HDL-C is 130 mg/dl and if the goal for LDL iswhen glycated, are more easily oxidized and ‘picked up’ 70 mg/dl then the goal for non-HDL-C is 100 mg/dl [1].by the scavenger receptor on the macrophage which has a Recently, it has been proposed that in the general populationmuch greater affinity for oxidized LDL than for non-oxidized lipid screening should be performed in the non-fasting stateLDL [14]. Macrophages therefore facilitate the transportation with only a total cholesterol and HDL being measured. Thisof these particles through the intima to the subintimal space opinion is based on a study of a European population whereand media of the artery where the process of atherogenesis is it was shown that independent of the calculated LDL levels,initiated and accelerated by these highly atherogenic particles. patients with higher non-HDL-C levels were at an increasedThe concentration of small dense LDL particles is increased risk of CHD [20]. In addition, two large trials of statinnot only with diabetes and the MetSyn but also with cigarette therapy, treating to new targets (TNT) [21] and incrementalsmoking, hypertension and the presence of a low HDL-C level. decreases in endpoints through aggressive lipid-loweringIn addition to facilitating the passage of monocytes through (IDEAL) trial [22], have also shown that levels of non-HDL-Cthe arterial wall, oxidized LDL is also cytotoxic and damages and ApoB are more closely associated with CV outcomesthe endothelium [15]. than calculated LDL levels. However, data documenting that Small dense HDL particles are more easily cleared by the targeting non-HDL-C leads to better outcomes than targetingkidney with more apo-A being filtered and metabolized renally, LDL-C levels is still lacking.which results in a shorter life span of this particle, andaccounts for the lower HDL levels typically seen in patients Therapy of Diabetic Dyslipidaemiawith insulin resistance and/or diabetes [16]. Small dense HDL Based on the UK prospective diabetes study (UKPDS), theparticles are also twofold to threefold less effective than the most powerful risk factor for cardiac events in the diabeticlarger HDL particle in reverse cholesterol transport. This patient is an elevated LDL, closely followed by a decreasedis mainly attributed to the lower concentrations of ApoE HDL level. These lipid risk factors are followed in order by theand lecithin-cholesterol acyltransferase (LCAT) in small dense other independent risk factors including HbA1c, systolic bloodHDL particles. Furthermore, these particles have decreased pressure and cigarette smoking [23].anti-inflammatory and antioxidant properties [17]. Therefore, Thus, while the therapy of diabetic dyslipidaemia is extremelysmall dense HDL particles are potentially less cardioprotective important, it should not be performed in isolation and shouldthan larger HDL particles which are inferred almost entirely be accompanied by aggressive therapy of both hyperglycaemiafrom epidemiological and clinical associations. and hypertension, using evidence-based therapies such as drugs and therapeutic lifestyle changes (diet, weight loss, exercise, smoking cessation, etc).Goals of the Lipid-lowering Therapyin the Diabetic Patient Glycaemic Control and Diabetic DyslipidaemiaCalculated LDL Glycaemic control is the first and most important step inThe Friedewald calculation for serum LDL-C levels is almost controlling dyslipidaemia, which can result in a significantuniversally utilized. However, in the insulin-resistant or improvement in lipid levels particularly in patients withdiabetic patient this calculation may be inaccurate because hypertriglycaeridemia, where lowering of the triglyceride levelit underestimates the number of LDL particles as well as the is usually accompanied by an increase in the HDL level. Inatherogenic potential of these particles. addition, with correction of hyperglycaemia the LDL particle The most logical solution to the problem of an underes- size may be increased, and if pioglitazone or insulin is utilized,timated LDL level, utilizing the Friedewald calculation, is to a decrease in the number of LDL particles may occur as well.directly measure the ApoB levels (one per LDL particle) or Of more importance than overall glycaemic control is theto directly measure the number of LDL particles. However, control of postprandial hyperglycaemia. Varying degrees ofmeasurement of ApoB is preferable because ApoB is also a postprandial hyperglycaemia are invariably present in diabeticcomponent of the other important atherogenic particles (inter- patients, especially when treated with drugs with minimalmediate density lipoproteins, remnant lipoproteins and small effect on postprandial hyperglycaemia, such as basal insulindense VLDL particles). and metformin. The use of non-HDL-C, a surrogate for the number of Triglyceride-rich lipoproteins (TRLs) derived from theApoB-containing atherogenic particles, was shown to be a bet- intestine have been shown to be increased with insulinter predictor of cardiac events than LDL-C [18], particularly resistance not only in the preprandial state but importantlyin patients with DM, insulin resistance and/or hypertriglyceri- also in the postprandial state. Elevated TRLs are also associateddaemia [19]. The non-HDL-C level is recommended by ATPIII with increased cardiac events. In particular, the productionto be utilized as a secondary target in the hypertriglyceridaemia rate of ApoB 48 containing particles is increased with bothsubject where the calculated LDL is invariably falsely low [1]. In insulin resistance and T2D. Enterocytes, which are similar314 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- Figure 2. Postprandial glucose and athero progression—patients withdial dysmetabolism increases the risk of a cardiac event and normal glucose tolerance who had a postprandial glucose level of <87 mg/dlit has been shown that postprandial glucose fluctuations are had coronary regression. The remaining patients had coronary progression in proportion to the increase in postprandial glucose. Adapted withmore likely to trigger oxidative stress than chronic sustained permission from Ref. [28].hyperglycaemia (figure 1) [27,28]. In multiple population studies, postprandial glucose levelshave been associated with CHD and mortality. In the increased cardiac events and mortality [31]. In the HonoluluHOORN [29], DECODE [30], Whitehall, Helsinki policemen study of over 6000 men, the 1-h postprandial glucose level wasand Paris protective studies, which in aggregate included over associated with cardiac events and mortality [32].45 000 subjects, an elevated 2-h glucose was associated with In a study of non-diabetic females with normal glucose tolerance and coronary artery disease, coronary angiography was performed at baseline after 3 years [33]. The lower the 2-h glucose level on a baseline glucose tolerance test, the less the progression of coronary atherosclerotic burden over the course of the 3-year study. Indeed, if the 2-h glucose was lesser than 86 mg/dl there was regression in the coronary atheroma volume (figure 2) [33]. Therefore, even in this study of individuals with postmeal glucose excursions within the normal range, the higher the postprandial glucose rose, the greater was the rate of atheroma formation. Similarly, in a study of individuals with normal fasting and 2-h glucose levels, higher CV mortality was seen among those with higher 2-h glucose levels (closer to 140 mg/dl) [34]. The DECODE study showed that mortality could not be predicted from the fasting glucose level but could be predicted from the postprandial glucose level, which was also shown to be an independent risk factor for mortality [30]. The STOP- NIDDM study, a blinded placebo-controlled study of 1429 individuals with impaired glucose tolerance, assessed whether the α-glucosidase inhibitor, acarbose, could slowdown the progression to T2D [35]. While conversion to diabetes was significantly decreased by 25%, the relative risk of a CV event decreased by 49%. Subsequently, the phase 3 studies of acarbose were re-examined for CV events and it was found that compared to placebo and other diabetic medications the risk of having a myocardial infarction (MI) was decreased by 64% and the risk of any CV event decreased by 35% with acarbose [36]. Additionally, acarbose decreased carotid intima- medial thickening (CIMT) by 50%—a benefit that dissipatedFigure 1. Postprandial—the immediate deleterious effects of a meal when acarbose was discontinued [37]. Acarbose, though itscontaining 75 g of glucose and 700 kcal/m2 of whipping cream in 20 effects on α-glucosidase and lipase, reduces both postprandialdiabetic subjects. Within 2–4 h glucose and triglyceride levels double,causing immediate oxidant stress (nitrotyrosine), inflammation C-reactive glucose and lipid levels. Thiazolidinediones (TZDs), byprotein (CRP), resulting in deterioration in endothelial function (FMD limiting intestinal lipid absorption, which is increased in% = percent flow-mediated dilatation). Adapted with permission from the MetSyn, also reduce both postprandial hyperglycaemiaRef. [28]. and hyperlipidemia. While postprandial glucose is notVolume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01342.x 315
    • review article DIABETES, OBESITY AND METABOLISMlowered 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]. Figure 3. Proactive trial—PROactive: significant difference in principal secondary endpoint (death, MI or stroke; pioglitazone vs. placebo: HR 0.84; 95% CI 0.72–0.98). HR, heart rate; MI, myocardial infarction. AdaptedTZDs and Diabetic Dyslipidaemia with permission from Ref. [124].A head-to-head randomized clinical trial comparing maximaldoses of pioglitazone and rosiglitazone showed that while towards less CV events could have become significant withboth of these drugs were equally effective at lowering the a longer duration of the study because the termination ofHbA1c, pioglitazone was superior to rosiglitazone in increasing the study was based on the number of events which wasboth the HDL and the LDL particle sizes [41]. Paradoxically, surprisingly high and resulted in the study lasting for onlywhile pioglitazone decreased triglycerides by 12%, rosiglitazone 3.4 years. In addition, a retrospective subanalysis of the studyincreased triglycerides by 14.9%. However, a finding of much showed that there was no significant improvement in CV eventsgreater importance was that pioglitazone reduced the number when statins or β-blockers were being utilized. However, forof LDL particles by 51% while rosiglitazone increased this any study to show an additional improvement in cardiacnumber by 111%, resulting in lesser increases in calculated events in the diabetic patient who was utilizing maximalLDL and ApoB levels with pioglitazone. Rosiglitazone has risk-reducing therapies would entail the inclusion of verybeen shown to be ineffective at lowering atherosclerotic plaque large numbers of subjects and would therefore be impracticalburden in the carotid and coronary arteries and has been and cost-prohibitive. The major side effect of pioglitazone ineffectively removed from the US and European markets due to PROACTIVE, especially when used with insulin, was fluidconcerns about its CV safety [42]. retention and non-fatal heart failure [49]. These differences in lipid levels, especially the differencein LDL particle numbers, could explain the differences inaccumulation of coronary artery atheroma and cardiac events Lifestyle Changes and Diabetic Dyslipidaemiaseen with these drugs. However, other factors may be involved Lifestyle factors including dietary changes, increased physicalbecause a total of 23 genes have been shown to be expressed activity, weight loss and smoking cessation may help diabeticwith either rosiglitazone or pioglitazone; of these, 5 genes are patients reach their therapeutic goals. Cessation of smoking,exclusively expressed by rosiglitazone and 12 genes exclusively exercise and weight loss is particularly beneficial in elevatingby pioglitazone [43]. HDL levels. In contrast, in the pioglitazone effect on regression of The benefits of regular exercise, in addition to an improvedintravascular sonographic coronary obstruction retrospective lipid profile, include weight loss, decreased abdominal fat,evaluation (PERISCOPE) study, pioglitazone when compared reduced inflammation, increased insulin sensitivity, decreasedwith glimepiride significantly reduced the percentage of blood pressure levels and improved endothelial function. Theatheroma volume (the primary endpoint) as well as atheroma ADA recommends 150 min of aerobic physical activity perthickness [44]. Of note, the reduction in the atheroma volume week accompanied by resistance training up to three times perachieved with pioglitazone in PERISCOPE compared favorably week [50]. Exercise duration correlates strongly with reductionswith that achieved by the strongest of the statin cholesterol- in triglycerides and weight and increases in HDL levels.lowering drugs [45]. Significant improvements in HDL require at least 20 min of In the PROACTIVE study, the addition of pioglitazone to daily exercise; 40–60 min of exercise daily will produce betterexisting diabetic therapies resulted in significant decreases in results. Aerobic exercise appears to raise HDL better thanthe principle secondary combined endpoint of MI, stroke and strength training or stretching exercises [51,52].death (figure 3). Furthermore, decreases in the recurrenceof MI and stroke were also shown [46,47]. The primarycomposite endpoint which included criteria for peripheral Dietvascular disease was not significantly decreased, probably The ADA recommends weight loss in overweight patients, abecause of the inclusion of subjects with peripheral vascular saturated fat intake of less than 7% of total calories, minimaldisease who showed no improvement in cardiac events with trans-fat intake, reduced cholesterol intake, a carbohydratepioglitazone [47,48]. However, even in this group, the trend intake limited to 130 g/day and fiber intake of at least 14 g316 Bell et al. Volume 13 No. 4 April 2011
    • DIABETES, OBESITY AND METABOLISM review articleper thousand calories [50]. ATPIII also focuses on weight loss, • Low-to-moderate amounts of non-fat or low-fat dairyreduced fat intake, reduced carbohydrate intake in addition • Light-to-moderate daily consumption of wine, typically withto an increase in calories derived from monounsaturated or mealspolyunsaturated fats [1]. • Preference for local, seasonal, produce Investigators from the Framingham Heart study found that • Physically active lifestyle, usually incorporated into activitiesa diet consistent with the fundamentals of the Mediterranean- of daily lifestyle diet appears to prevent development of the T2D andMetSyn. Specifically, a diet high in vegetables, fruits, nuts, Testosterone Replacement Therapy and Diabeticomega-3 fatty acids, olive oil and whole grains but low Dyslipidaemiain refined carbohydrates, saturated fats and trans fats wasassociated with reduced risks for T2D, including lower It has been estimated that as many as 50% of type 2levels of insulin resistance, abdominal obesity, fasting glucose diabetic males have hypogonadotropic hypogonadism [57].and triglycerides, and improvements in HDL-C levels and This is because the excess peritoneal fat associated with theendothelial function [53]. MetSyn and T2D is associated with increased activity of the A more recent epidemiological study of 23 500 Greek adults enzyme aromatase which results in an increased conversion ofreported that the intake of vegetables, fruits, nuts, legumes, and testosterone to estrogen (mainly estradiol). Increased estrogenolive oil, and drinking light-to-moderate amounts of alcohol, levels at the level of the hypothalamus suppress the release ofwhile minimizing the consumption of fatty meats and avoiding gonadotropin-releasing hormone which in turn decreases theexcessive alcohol intake was linked to improved longevity. The release of gonadotropins (particularly luteinizing hormone)proportion of the overall improvement in longevity attributable from the anterior pituitary gland resulting in a decreasedto each of the specific components of the Mediterranean production of testosterone from the Leydig cells of the testicles.diet was as follows: moderate ethanol consumption 24%, low Low testosterone levels have been associated with insulinconsumption of meat 17%, high vegetable consumption 16%, resistance, higher PAI1 and fibrinogen levels, increased FFAhigh fruit and nut consumption 11%, high monounsaturated and triglyceride levels and lower HDL levels [58]. Increasedto saturated lipid ratio 11% and high legume consumption oxidative stress, endothelial dysfunction, increased CIMT and10% [54]. Overall, those individuals who adhered to the increased CV events and mortality have also been associatedMediterranean dietary principles most closely were 25% less with low testosterone levels.likely to die during the course of the study [54]. Testosterone replacement therapy in testosterone-deficient A trial of patients with newly diagnosed T2D randomized subjects lowers insulin resistance and results in lowering ofthem to either a Mediterranean diet or a low-fat American triglyceride and elevation of HDL levels and improved oxidativeHeart Association (AHA) diet. After 4 years, only 44% of newly stress and endothelial function [59]. It has been estimated thatdiagnosed diabetic patients randomized to the Mediterranean for each 5.3 nmol/l elevation in serum testosterone levels thediet vs. 70% of those randomized to the low-fat AHA diet risk of an MI may decrease by 57% [60]. However, the safetyrequired glucose-lowering drug therapy for control of their and clinical benefit of routine testosterone replacement indiabetes. Individuals following the Mediterranean diet also hypogonadal men with MetSyn are currently unknown. Indeed,showed greater improvement in several CV risk factors [55]. a recent randomized study of testosterone dermal gel to assess An epidemiological study of over 13 000 people found that leg strength which improved with testosterone was abandonedthose who followed a Mediterranean-style diet were less likely because of a greater number of cardiac adverse events in theto develop new-onset diabetes. The benefits were especially testosterone group [61,62]. Routine testosterone replacementpronounced in those who were at higher risk of developing in hypogonadal men with MetSyn cannot be recommendedT2D because of issues such as MetSyn, excess weight, family and further prospective studies evaluating the safety and clinicalhistory and blood pressure. Study participants with the best benefit of testosterone replacement are needed.adherence to the Mediterranean dietary principles had >50%decrease in the risk of developing diabetes during 4.4 years Therapies that may Worsen Diabetic Dyslipidaemiafollow-up [56]. Drugs commonly utilized for hormone replacement therapy In summary, following the traditional Mediterranean-style and hypertension may worsen hyperlipidemia. Hypertrigly-diet results in a lower risk of developing T2D, better control caeridemia, often at levels that may cause pancreatitis andof blood glucose in individuals with T2D and a substantially enough pancreatic damage to cause diabetes, is associated withlower need to resort to glucose-lowering drug therapy. The the utilization of oral postmenopausal estrogen replacementMediterranean-style diet has also been shown to improve therapy in vulnerable individuals [63]. Drugs that increasemultiple CV risk factors. insulin resistance not only result in an increase in triglycerides but also a lowering of HDL levels and the development ofPrinciples of the Mediterranean Diet smaller more dense and more atherogenic LDL particles. Use of• A high intake of fruits, vegetables, beans, nuts, seeds and thiazide diuretics, first and second generation β-blockers (but cereal grains not vasodilating β-blockers such as carvedilol and nebivolol)• Olive oil preferred for cooking and dressings increases insulin resistance and adversely affect the lipid profile• Moderate amounts of fish and seafood but modest intake of of the insulin-resistant or diabetic patient. However, ethanol meat and drugs such as blockers of the renin-angiotensin systemVolume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01342.x 317
    • review article DIABETES, OBESITY AND METABOLISM(RAS), both of which reduce insulin resistance, have been daily achieved a 25% reduction in CV events. In PROVE-IT,shown to increase total HDL (mainly smaller HDL particles) only 38% of diabetic patients achieved the combined goal ofand increase the LDL particle size [64]. The use of bile acid an LDL lesser than 70 mg/dl and an hsCRP level of lesser thansequestrants (BASs) may induce hypertriglyceridaemia [65]. 2 mg/l, but if both these goals were achieved there was a furtherHowever, with colesevelam it does not appear to cause signifi- reduction in CV events of 34% [74].cant hypertriglyceridaemia [66]. In the JUPITER trial, where patients with diabetes were excluded, 41% of the subjects had the clinical features of MetSyn. With rosuvastatin 20 mg daily, a similar reduction inStatin (HMG-CoA-Reductase Inhibitor) Therapy CV events was achieved in MetSyn subjects as was achieved inin the Diabetic Patient non-MetSyn subjects [67]. In addition, subjects with impairedStatins are recommended by the ADA as an addition to lifestyle fasting glucose had similar reductions in CV events withtherapy for all diabetic patients with CVD and for those without rosuvastatin as those with normal fasting glucose levels.known CVD who are over the age of 40 and have an additional Importantly, the development of new T2D did not negateCV risk factor (family history of heart disease, cigarette smoking the statin-conferred reduction in adverse CV events noted inor hypertension) [50]. Even without risk factors, statins should those patients randomized to rosuvastatin in the JUPITERbe considered for those diabetic patients without known CVD trial [67].who are under the age of 40 and who have a calculated LDL of There have been three large-blinded and placebo-controlledover 100 mg/dl [50]. Statins mainly lower LDL levels but also studies with atorvastatin 10 mg daily, which have beenraise HDL levels and may increase LDL particle size. In addition, restricted to diabetic subjects. Neither the die deutsche diabetesstatins lower highly sensitive C-reactive protein (hsCRP) (a dialyse studies (4D) of hemodialysis patients with diabetes [75]marker of inflammation which is strongly associated with the nor the atorvastatin for prevention of CHD endpoints inMetSyn, diabetes and CV disease). non-insulin-dependent DM (ASPEN) [76] showed significant In the diabetic patient, statins may worsen glycaemic control reductions in CV events because of the advance stages ofand in the prediabetic patient increase the risk of development atherosclerosis in these subjects. In contrast, the collaborativeof T2D. Rosuvastatin has, in the JUPITER trial [67], been shown atorvastatin diabetes study (CARDS) showed not only ato increase both the HbA1c and the incidence of reported decrease in LDL and an increase in HDL, but also an increasenew-onset diabetes. Alternatively, in the West of Scotland in LDL particle size and a 37% reduction in CV events [77]study [68] the incidence of diabetes was decreased by 30% with (figure 4).pravastatin. A meta-analysis of mega trials suggested that, with Prior to the availability of statins, the POSCH studythe exception of pravastatin, the statins appear to modestly of subjects with familial hypercholesterolemia showed thatincrease the risk of new diabetes (approximately by 9%), with the LDL level was significantly lowered by small bowelsimvastatin showing the highest risk [69]. A more recent meta- bypass surgery [78]. In spite of significant LDL lowering,analysis showed that treating 255 patients with a statin for an improvement in CV events did not occur over the first4 years would result in one extra case of diabetes [70]. Because 5 postsurgical years, but after 5 years positive differences inin the JUPITER trial the HbA1c but not the fasting glucose was cardiac events began to appear and by 12 years these differencesincreased [67], it is likely that statins (with the exception of became statistically significant with a 35% reduction. Becausepravastatin) increase postprandial glucose. Indeed, atorvastatin the protective effect of statins on cardiac events in mosthas been shown to both increase insulin levels and HbA1c [69]. clinical trials begins to appear within 3–6 months, this earlierOverall, 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]. Figure 4. The CARDS Trial, significant reduction in the primary endpoint Subgroup analyses of major statin trials have also shown that (acute CHD events, coronary revascularization or stroke). Atorvastatin alsoachieving lower LDL levels in diabetic subjects was associated resulted in a 48% relative risk reduction for stroke, p = 0.016, and a 47%with a greater lowering of CV events. In the pravastatin or relative risk reduction for non-fatal MI, p = 0.0178. CHD, coronaryatorvastatin evaluation and infection therapy (PROVE-IT) and heart disease; MI, myocardial infarction. Adapted with permission fromthe TNT trials, diabetic subjects treated with atorvastatin 80 mg Ref. [77].318 Bell et al. Volume 13 No. 4 April 2011
    • DIABETES, OBESITY AND METABOLISM review articleimprovement cannot be related to LDL lowering and is Niacinprobably because of the pleiotropic effects of statins. The key components of diabetic dyslipidaemia are improved The pleiotropic effects of statins include lowering of with niacin therapy with both LDL and triglyceride levels beingplasma viscosity, decreased generation of thrombin and lowered and both total HDL levels and HDL and LDL particledecreased platelet aggregation [79]. Most importantly, statins sizes being increased. In addition, niacin (2 g/day) can loweralso decrease inflammation, both systemically and within the lipoprotein (a) levels by 25% [89–91]. In practice, the use ofatheromatous plaque [80]. The decrease in systemic inflamma- niacin is limited by its side effects, particularly that of cutaneoustion lowers oxidative stress and improves endothelial function. flushing. This side effect is mediated through the interaction ofWithin the atheromatous plaque a decrease in inflammation prostaglandin D2 with the DP1 receptor in the skin [92].promotes a more stable fibrous plaque by reducing the elabo- The use of extended-release preparations and/or patientration of collagenases and metalloproteinase’s by white blood education may improve compliance. Taking an extended-cells, thereby lowering the likelihood of plaque rupture. Statins release preparation with apple sauce or psyllium (metamucil)also increase angiogenesis and the formation of collateral ves- and an aspirin can decrease the frequency and severitysels and thus reduce ischaemia severity in the setting of acute of flushing. Combining niacin with laropiprant, a potentand chronic coronary artery occlusions [81]. prostaglandin receptor antagonist, is a safe and promising Subjects with diabetes and/or the MetSyn almost invari- option to improve patients’ tolerability of niacin [93] and isably have elevated hsCRP levels because excess macrophage- being tested in a large outcome-based clinical trial [94].infiltrated peritoneal fat produces Interleukin 6 which stim- Another side effect of niacin is an increase in insulinulates hepatic production of CRP. In the setting of bacterial resistance, which is usually short-lived, so that over the longinfections, CRP is protective by adhering to the wall of the term the effect on glycaemic control is minimal. For example,pneumococcus bacteria where it combined with complement in the arterial disease multiple intervention trial (ADMIT) [95]to damage the bacterial cell membrane and activate the immune and the assessment of diabetes control and evaluation of thesystem [82]. While CRP is beneficial during an acute infection, efficacy of niaspan trial (ADVENT) [96], niacin was utilizedchronically elevated CRP levels are detrimental, mainly because without significant long-term increases in glucose levels.CRP binds to oxidized LDL particles. Therefore, when oxidized Niacin was utilized in the double-blind coronary drugLDL levels are high, as occurs in both the diabetic and insulin- project (CDP) which was a study of men who had had anresistant patients, CRP not only accelerates the growth of the MI and of whom 40% had impaired fasting glucose and/oratheromatous plaque but also increases inflammation within impaired glucose tolerance [97]. In this study, while the primarythe atheroma and increases the risk of plaque rupture and CV endpoint of all-cause mortality was not significantly reducedevents. with niacin, after 6.2 years non-fatal MI was decreased by Lowering of inflammation, with drugs other than statins, has 26% and transient ischemic attacks or strokes by 24%, inbeen shown to decrease CV events, and decreasing inflamma- spite of a poor adherence due to troublesome side effects.tion as a result of statin therapy has been associated with reduced However, 9 years after the termination of the study there was arisks for some non-cardiac diseases. For example, the use of residual 10.2% decrease (58.2 vs. 52.0%) in all-cause mortalitymethotrexate in patients with rheumatoid arthritis has been which was largely because of a decrease in death from CVD,shown to decrease cardiac events by as much as 40–60% and suggesting that niacin therapy may have residual long-lastingveterans admitted to hospital with septicemia have a higher sur- benefits [98].vival rate if they have been taking a statin [83]. In the PROVE-IT While the use of niacin in the CDP study resulted in modeststudy, lowering of LDL and hsCRP to goal were equally effective increases in both fasting and 1-h postprandial glucose levels,in lowering cardiac events, and when both goals were achieved the need for initiation of insulin or the addition of an oralthe reduction in CV events was maximized [84]. In the PROVE- antidiabetic agent was no greater in the niacin group than itIT, subjects with the higher CRP levels had all the characteristics was in the placebo group [97]. In addition, in those who didof the MetSyn, i.e. higher levels of glucose, triglyceride and develop a fasting glucose of more than 126 mg/dl, there was ablood pressures with a higher BMI and a lower HDL [85]. significant 57% reduction in MI after 6 years, which was similarTherefore, in the type 2 diabetic patient where hsCRP is almost to those whose fasting glucose remained in ranges lesser thaninvariably elevated, statins and doses of statins that maximally 126 mg/dl, suggesting that niacin may be even more effectivelower both LDL and hsCRP should be utilized. In the JUPITER in the insulin-resistant or diabetic subject, probably becausetrial, those subjects on rosuvastatin who achieved LDL levels of niacin’s ability to elevate HDL levels. Therefore, in spite<70 mg/dl and CRP levels <1.0 experienced a 79% reduction of poor compliance and short-term worsening of glycaemicin adverse CV events during the randomized trial [67]. control, niacin significantly reduces cardiac events in both the However, it may be that rather than being a treatment target, diabetic and insulin-resistant patients and thus should be usedCRP may simply be another risk factor that strengthens the more frequently utilized in these cohorts [99].case 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 high Fibrateslevels of inflammation and CV risk in diabetic patients, maximal Fibrates, through stimulating the activity of lipoprotein lipase,statin therapy as utilized in the REVERSAL [86], TNT [87], reduce both triglyceride levels and the levels of the TRLsPROVE-IT [88] and JUPITER [67] trials should be utilized. through decreased hepatic production of VLDL [100]. As aVolume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01342.x 319
    • review article DIABETES, OBESITY AND METABOLISMresult, 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/dl Figure 5. In the ACCORD lipid trial, fenofibrate did not significantlyand a calculated LDL lesser than 140 mg/dl. In a subgroup improve the primary outcome. Adapted with permission from Ref. [108].analysis of the VA-HIT of those subjects with diabetes,gemfibrozil reduced cardiac events by 32% and in those with 2.2 and 2.4 events per year, respectively, in the two treatmentinsulin resistance (defined as non-diabetic subjects with an arms (p-value 0.32). Also, there was no statistically significantelevated fasting hyperinsulinemia) by 35% [105]. difference between the two treatments among the secondary In prospective placebo-controlled studies of diabetic endpoints.subjects, fibrates have been shown to be inconsistent in theirability to decrease the progression of coronary atherosclerosisand/or decrease cardiac events. With fenofibrate being Omega-3 Fatty Acidsadministered in a dose of 200 mg daily, in the diabetes Omega-3 fatty acids at high doses, 3–5 g of eicosapentanoicatherosclerosis intervention study (DIAS) [106] there was, acid (EPA) + docasahexanoic acid (DHA) per day, effectivelyafter 3 years, significantly less progression of coronary artery lower triglyceride levels [109], while concurrently increasingdisease as measured by the minimal coronary artery lumen calculated LDL levels which is probably because of an increase indiameter. In the DIAS study, however, the primary endpoint of particle size rather than an increase in particle numbers [110].a decrease in mean segment diameter did not reach statistical The decrease in mortality that has been shown with omega-significance. Similarly, in the fenofibrate intervention and event 3 fats appears to be in part because of an antiarrhythmiclowering in diabetes (FIELD) study [107], daily administration effect. Recently, omega-3 fats have also been shown toof 200 mg fenofibrate did not significantly change the primary decelerate telomere shortening which is a marker of biologicalendpoint of non-fatal MI or death related to CHD. However, aging [111].in the FIELD study, there was a significant 24% reduction In diabetic subjects, daily administration of 3.6 g ofin non-fatal MI and a significant 11% decrease in CV EPA + DHA has been shown to decrease triglyceride levelsevents as well as improvements in albuminuria and diabetic by 28%, increase HDL levels by 7% and not to have anretinopathy as was later documented with fenofibrate in the effect on ApoB or LDL-concentrations in spite of decreases inACCORD study of type 2 diabetic subjects. Fenofibrate also the ApoB component of VLDL and an increased conversionnon-significantly increased total mortality, mortality related to of VLDL to LDL [112]. In the COMBOS trial, the use ofcoronary artery disease and the incidence of acute pancreatitis omega-3 fats (3.6 g of EPA + DHA) was tested in subjectsand pulmonary embolism. The FIELD study was confounded with hypertriglyceridaemia. In this randomized trial, theby a greater use of statins in the placebo group which may non-HDL-C was decreased by an additional 9% when omega-3account for the less than expected improvement in CV events. fats were added to simvastatin 40 mg compared with 2.2%Again, the greatest CV benefit of fenofibrate was seen in patients when placebo was added to 40 mg of simvastatin daily [113].who had the characteristic lipid profile (high triglyceride and In addition, triglycerides were lowered by 30% with thelow HDL) of the MetSyn. combination compared to 6% with simvastatin alone and In the action to control cardiovascular risk in diabetes HDL-C was increased by 3.4% with the combination.(ACCORD) trial [108], the investigators examined the effects A subgroup analysis of the Gruppo Italiano per lo Studioof combination lipid therapy in 5518 patients with T2D. The della Infarto Miocardico (GISSI-Prevenzione) showed thataddition of fenofibrate to simvastatin vs. simvastatin plus total mortality was decreased by 28% with 1 g of omega-3placebo did not reduce the risk CV events (fatal CV events, fats in diabetic subjects which compared favorably with non-non-fatal MI or non-fatal stroke) (figure 5). There was a trend diabetic subjects where omega-3 fats decreased mortality bytowards the benefit of fenofibrate in the cohort of patients with 18% [114]. In another subgroup analysis from the Japanhigh triglyceride and low HDL levels. After a mean follow-up EPA lipid intervention study (JELIS), subjects who had theof 4.7 years, the annualized rates of the primary endpoint were characteristics of the MetSyn (defined as a high triglyceride320 Bell et al. Volume 13 No. 4 April 2011
    • DIABETES, OBESITY AND METABOLISM review article LDL levels, BASs, at least in one trial, may be equally effective at lowering cardiac events. This is because for every 1% the LDL is lowered by a statin there is a 1% lowering of car- diac events, whereas for every 1% the LDL is lowered with a BAS there is a 2% decrease in cardiac events [119]. Addi- tional advantages of BASs are their beneficial effects on glucose metabolism (improvement in fasting, postprandial glucose as well as HbA1c) and reductions in systemic inflammation (BASs lower CRP by about 20–25%). Because many statins may modestly increase the risk of new T2D, the combina- tion of a well-tolerated BAS such as colesevelam and a statin could potentially prevent the development of diabetes in those who are at the highest risk (subjects with the MetSyn or prediabetes) and improve glycaemic control in subjects withFigure 6. In the JELIS trial, supplementation with omega-3 fatty acids established diabetes [69]. In the setting of T2D, colesevelam atreduced the primary endpoint of major coronary events particularly well a daily dose of 3.75 g has been shown to lower the HbA1c byin those patients with impaired glucose metabolism (IGM) as comparedto those with normal glucose (NG) levels. Adapted with permission from 0.5% and the postprandial glucose by 32 mg/day [120], mak-Ref. [116]. ing colesevelam a logical add-on to statin therapy in diabetic patients [69].to HDL ratio) had a 71% increased risk of a CV eventwhich was decreased by 53% with the daily combination of EzetimibeEPA (1800 mg) and a statin [115,116] (figure 6). In addition, Another lipid-lowering agent, ezetimibe, acts at the brusheven with the lower daily intake of 250 mg of omega-3 fats border of the small intestine by blocking the absorption of bothdaily, diabetic subjects showed a 17% reduction in mortality dietary and biliary cholesterol and plant sterols. Consequently,and a 36% reduction in mortality related to coronary artery this leads to the depletion of intracellular cholesterol anddisease [116]. increased clearance of circulating LDL by the liver, resulting in In addition, to their beneficial effects on lipid levels, omega- the reduction of both LDL and total cholesterol levels [121].3 fats have other non-LDL-dependent benefits, including However, no data currently exist to document that ezetimibereduced heart rate and blood pressure and antithrombotic (despite its beneficial effects on LDL levels) reduces CV eventseffects which protect against ischemic stroke and non-fatal MI. or atherosclerosis progression in the overall population or inHowever, the most important cardioprotective effect of omega- diabetic or insulin-resistant subjects.3 fats may be their antiarrhythmic properties, protecting fromboth atrial and ventricular fibrillation, the incidences of whichare increased in the diabetic patient [117]. Combination Therapies Often, to achieve goals in the diabetic patient, combinations ofBile Acid Sequestrants different lipid-lowering agents with different modes of actionHistorically, BASs have been used where statins are not need to be utilized. Better results can usually be obtained bytolerated or untested and/or associated with safety concerns adding a BASs, omega-3 fats or niacin to a statin rather than(fertile women and children). These agents have a non- by increasing the dose of the statin, because doubling of thesystemic action; BASs are not absorbed out of the lumen dose of statin only results in a further 6% reduction in theof the intestine. They work to lower cholesterol, by decreasing LDL. The combination of a statin with omega-3 or niacin willthe reabsorption of bile acids resulting in a compensatory also result in a greater increase in HDL-C levels and moreincrease in the hepatic production of bile acids, decreasing robust decreases in triglycerides and non-HDL-C levels. Theintracellular cholesterol and increasing the utilization of potential for adverse events is increased when gemfibrozil andcholesterol and depletion of the LDL pool. However, BASs to a lesser extent other fibrates are utilized with a statin becausecan also increase triglyceride levels, cause gastrointestinal the combination of a statin and a fibrate increases the risk ofsymptoms (particularly constipation) and are associated with myalgias, myositis and rhabdomyolysis.an increased prevalence of cholelithiasis. A more modern A secondary analysis of diabetic subjects in the SANDS trial,BAS, colesevelam, has been chemically altered to improve the where the goals for LDL were less than 100 mg/dl or 70 mg/dlrelative affinity of binding of bile acids and thus has a much and goals for non-HDL-C lesser than 100 or 130 mg/dl, showedlower incidence of these side effects [66,118]. While it carries that irrespective of whether these goals were reached with aa warning of induction of severe hypertriglyceridaemia, this is high statin dose or the combination of a statin with ezetimibegenerally only an issue for patients with elevated triglycerides or fenofibrate, those subjects with the lower goals had aat baseline [66,118]. statistically significantly greater decrease in the CIMT [122]. BASs are considered as second-line therapy for lowering As detailed above, in the ACCORD study, the effect of aLDL levels and are most commonly utilized in combination combination of a statin and fenofibrate did not improve CVtherapy. While not as potent as statins in the lowering of outcome [123].Volume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01342.x 321
    • review article DIABETES, OBESITY AND METABOLISMConclusions treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001; 285: 2486–2497.In this article, we emphasize that the correction of diabetic dys- 11. Syvanne M, Ahola M, Lahdenpera S et al. High density lipoproteinlipidaemia is the most important factor in reducing cardiac risk, subfractions in non-insulin-dependent diabetes mellitus and coronarywith the most important goal being to lower the non-HDL-C artery disease. J Lipid Res 1995; 36: 573–582.level. Lowering glucose levels in general and postprandial levels 12. Cook CB, Erdman DM, Ryan GJ et al. The pattern of dyslipidemia amongin particular is helpful as is the use of hypoglycaemic agents urban African-Americans with type 2 diabetes. Diabet Care 2000; 23:that may also have a beneficial effect on dyslipidaemia. Lifestyle 319–324.change is essential and utilization of statins is recommended in 13. Coppack SW, Jensen MD, Miles JM. In vivo regulation of lipolysis inmost type 2 diabetics to lower the LDL-C level to that recom- humans. J Lipid Res 1994; 35: 177–193.mended for patients with existing CV disease. Many patients 14. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;will also need to utilize therapies to lower triglycerides and/or 365: 1415–1428.increase HDL levels, meaning that most patients with dia- 15. Chapman MJ, Guerin M, Bruckert E. Atherogenic, dense low-densitybetic dyslipidaemia will need combination therapies which will lipoproteins. Pathophysiology and new therapeutic approaches. Eur Heartinclude two or more of the following: a statin, niacin, omega-3 J 1998; 19(Suppl. A): A24–A30.fats and BASs. The addition of a fibrate may be needed particu- 16. Horowitz BS, Goldberg IJ, Merab J, Vanni TM, Ramakrishnan R, Gins-larly in the patient with elevated triglycerides and/or depressed berg HN. Increased plasma and renal clearance of an exchangeableHDL-C levels. The role of ezetimibe and fibrates in reducing pool of apolipoprotein A-I in subjects with low levels of high densitycardiac events is questionable. lipoprotein cholesterol. J Clin Invest 1993; 91: 1743–1752. 17. Kontush A, Chapman MJ. Antiatherogenic function of HDL particle subpopulations: focus on antioxidative activities. Curr Opin Lipidol 2010;Conflict of Interest 21: 312–318.All authors contributed to the entire writing of the manuscript, 18. Cui Y, Blumenthal RS, Flaws JA et al. Non-high-density lipoproteincorrections and updates. cholesterol level as a predictor of cardiovascular disease mortality. J. H. O. is the speaker for AstraZeneca, GlaxoSmithKline, Arch Intern Med 2001; 161: 1413–1419.Takeda and Merck. F. A. B. has nothing to declare and D. S. 19. Lu W, Resnick HE, Jablonski KA et al. Non-HDL cholesterol as a predictorH. B. is the consultant and speaker for Bristol Myers-Squibb, of cardiovascular disease in type 2 diabetes: the strong heart study.AstraZeneca, Novo Nordisk and Takeda. Diabet Care 2003; 26: 16–23. 20. Di Angelantonio E, Sarwar N, Perry P et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302: 1993–2000.References 21. Shepherd J, Barter P, Carmena R et al. Effect of lowering LDL cholesterol 1. Grundy SM. Approach to lipoprotein management in 2001 National substantially below currently recommended levels in patients with Cholesterol Guidelines. Am J Cardiol 2002; 90: 11i–21i. coronary heart disease and diabetes: the treating to new targets (TNT) study. Diabet Care 2006; 29: 1220–1226. 2. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III 22. Pedersen TR, Faergeman O, Kastelein JJ et al. High-dose atorvastatin guidelines. 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