Dyslipidemia

Abstract

Key Messages•The beneficial effects of lowering low-density lipoprotein cholesterol (LDL-C) with statin therapy apply equally well to people with diabetes as to those without the disease.•The primary treatment goal for people with diabetes is LDL-C ≤2.0 mmol/L, which is generally achievable with statin monotherapy.•Achievement of the primary goal may require intensification of lifestyle changes and/or statin therapy and, on occasion, the addition of other lipid-lowering medications. •The beneficial effects of lowering low-density lipoprotein cholesterol (LDL-C) with statin therapy apply equally well to people with diabetes as to those without the disease.•The primary treatment goal for people with diabetes is LDL-C ≤2.0 mmol/L, which is generally achievable with statin monotherapy.•Achievement of the primary goal may require intensification of lifestyle changes and/or statin therapy and, on occasion, the addition of other lipid-lowering medications. Diabetes is associated with a high risk of vascular disease (i.e. 2- to 4-fold greater risk than that of individuals without diabetes). In fact, cardiovascular disease (CVD) is the primary cause of death among people with type 1 and type 2 diabetes (1Roglic G. Unwin N. Bennett P.H. et al.The burden of mortality attributable to diabetes: realistic estimates for the year 2000.Diabetes Care. 2005; 28: 2130-2135Crossref PubMed Scopus (663) Google Scholar, 2Morrish N.J. Wang S.L. Stevens L.K. et al.Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes.Diabetologia. 2001; 44: S14-S21Crossref PubMed Scopus (877) Google Scholar, 3Booth G.L. Rothwell D. Fung K. et al.Diabetes and cardiac disease.in: Hux J.E. Booth G. Laupacis A. An ICES Practice Atlas: Institute for Clinical Evaluative Sciences, Diabetes in Ontario2002: 5.95-5.127Google Scholar). Aggressive management of all CVD risk factors, including dyslipidemia, is, therefore, generally necessary in individuals with diabetes (4Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3813) Google Scholar). The most common lipid pattern in people with type 2 diabetes consists of hypertriglyceridemia (hyper-TG), low high-density lipoprotein cholesterol (HDL-C), and relatively normal plasma concentrations of low-density lipoprotein cholesterol (LDL-C). However, in the presence of even mild hyper-TG, LDL-C particles are typically small and dense and may be more susceptible to oxidation. In addition, chronic hyperglycemia promotes the glycation of LDL-C, and both glycation and oxidation are believed to increase the atherogenicity of LDL-C. Both of these processes may impair function and/or enhance atherogenicity even in those with type 1 diabetes with a normal lipid profile. Table 1 lists the components of dyslipidemia associated with diabetes (5Fruchart J.-C. Sacks F.M. Hermans M.P. et al.The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidemic patients.Diabetes Vasc Dis Res. 2008; 5: 319-332Crossref PubMed Scopus (256) Google Scholar, 6Parhofer K.G. Pathophysiology of diabetic dyslipidemia: implications for atherogenesis and treatment.Clin Lipidol. 2011; 6: 401-411Crossref Scopus (31) Google Scholar). Many of these abnormalities also are seen in patients with metabolic syndrome (7Leiter L.A. Fitchett D.H. Gilbert R.E. et al.Cardiometabolic risk in Canada: a detailed analysis and position paper by the Cardiometabolic Risk Working Group.Can J Cardiol. 2011; 27: e1-e33Abstract Full Text Full Text PDF Scopus (113) Google Scholar, 8Ginsberg H.N. MacCallum P.R. The obesity, metabolic syndrome, and type 2 diabetes mellitus pandemic: part I. increased cardiovascular disease risk and the importance of atherogenic dyslipidemia in persons with the metabolic syndrome and type 2 diabetes mellitus.J Cardiometab Syndr. 2009; 4: 113-119Crossref PubMed Scopus (196) Google Scholar).Table 1Dyslipidemia components associated with type 2 diabetes and metabolic syndrome 5Fruchart J.-C. Sacks F.M. Hermans M.P. et al.The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidemic patients.Diabetes Vasc Dis Res. 2008; 5: 319-332Crossref PubMed Scopus (256) Google Scholar•Increased TG and TG-rich lipoproteins•Increased postprandial TG•Low HDL-C•Low apo AI•Small HDL, prebeta-1 HDL, alpha-3 HDL•Increased apo B•Increased LDL particle number•Small, dense LDL•Increased apo C-III•Increased non-HDL-C•Increased oxidized and glycated lipidsApo, apolipoprotein; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; TG, triglyceride. Open table in a new tab Apo, apolipoprotein; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; TG, triglyceride. A detailed overview of risk assessment deciding in whom to use statin therapy is provided in the Vascular Protection chapter (p. S100). Principles of risk assessment also are discussed in the 2012 Canadian Cardiovascular Society (CCS) Guidelines for the Management of Dyslipidemia (9Anderson T.J. Grégoire J. Hegele R.A. et al.2012 update of the Canadian Cardiovascular Society Guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.Can J Cardiol. 2013; 29: 151-167Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar), and efforts were made to ensure consistency between the guidelines. The burden of dyslipidemia is high in people with diabetes. A national cross-sectional chart audit study of 2473 Canadians with type 2 diabetes revealed that 55% of individuals with a diabetes diagnosis of ≤2 years’ duration also had dyslipidemia. This proportion rose to 66% in those with diabetes for ≥15 years (10Harris S.B. Ekoé J.M. Zdanowicz Y. et al.Glycemic control and morbidity in the Canadian primary care setting (results of the diabetes in Canada evaluation study).Diabetes Res Clin Pract. 2005; 70: 90-97Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). Therefore, a fasting lipid profile (total cholesterol [TC], HDL-C, TG and calculated LDL-C) should be conducted at the time of diagnosis of diabetes, and, if the results are initially normal, the assessment should be repeated annually or as clinically indicated. If treatment for dyslipidemia is initiated, more frequent testing is warranted. A fast of >8 hours may be inappropriate for individuals with diabetes, especially if long-acting basal insulin is part of their treatment regimen. Under these circumstances, non-HDL cholesterol (TC minus HDL-C) or apolipoprotein B (apo B) measurements (see below), which are valid, even in the nonfasting state, may be used. For screening in children and adolescents, please refer to the chapters dedicated to diabetes in children and adolescents, p. S153 and S163. Lifestyle interventions remain a key component of CVD prevention strategies and of diabetes management in general. Achievement of ideal weight and aerobic activity level, adoption of an energy-restricted, compositionally well-balanced diet that is low in cholesterol, saturated and trans fatty acids and refined carbohydrates, inclusion of viscous fibres, plant sterols, nuts and soy proteins, use of alcohol in moderation and smoking cessation all are fundamental considerations to improve glycemic control, the overall lipid profile and, most importantly, to reduce CVD risk (11Alberti K.G.M.M. Eckel R. Grundy S. et al.Harmonizing the metabolic syndrome.Circulation. 2009; 120: 1640-1645Crossref PubMed Scopus (9984) Google Scholar, 12Dattilo A.M. Kris-Etherton P.M. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis.Am J Clin Nutr. 1992; 56: 320-328PubMed Google Scholar, 13Wing R.R. Lang W. Wadden T.A. et al.AHEAD Research GroupBenefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes.Diabetes Care. 2011; 34: 1481-1486Crossref PubMed Scopus (1062) Google Scholar, 14Kendall C.W. Jenkins D.J. A dietary portfolio: maximal reduction of low-density lipoprotein cholesterol with diet.Curr Atheroscler Rep. 2004; 6: 492-498Crossref PubMed Scopus (68) Google Scholar, 15Jenkins D.J. Kendall C.W. Faulkner D.A. et al.Assessment of the longer-term effects of a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia.Am J Clin Nutr. 2006; 83: 582-591PubMed Google Scholar, 16Wing R.R. Weight loss in the management of type 2 diabetes.in: Gerstein H.C. Haynes R.B. Evidence-based Diabetes Care. 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Health benefits of physical activity: the evidence.CMAJ. 2006; 174: 801-809Crossref PubMed Scopus (4658) Google Scholar, 22Church T.S. Cheng Y.J. Earnest C.P. et al.Exercise capacity and body composition as predictors of mortality among men with diabetes.Diabetes Care. 2004; 27: 83-88Crossref PubMed Scopus (367) Google Scholar). Each of these is discussed in more detail in accompanying chapters (Physical Activity and Diabetes. p. S40; Nutrition Therapy, p. S45; Weight Management in Diabetes, p. S82). A number of studies and meta-analyses have shown that the degree of LDL-C lowering with statins and the beneficial effects of lowering LDL-C apply equally well to people with and without diabetes (23Pyörälä K. Pedersen T.R. Kjekshus J. et al.Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S).Diabetes Care. 1997; 20: 614-620Crossref PubMed Scopus (1550) Google Scholar, 24Sacks F.M. Pfeffer M.A. Moye L.A. et al.The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.N Engl J Med. 1996; 335: 1001-1009Crossref PubMed Scopus (7191) Google Scholar, 25Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.N Engl J Med. 1998; 339: 1349-1357Crossref PubMed Scopus (5567) Google Scholar, 26Collins R. Armitage J. Parish S. et al.Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.Lancet. 2003; 361: 2005-2016Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 27Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.Lancet. 2002; 360: 7-22Abstract Full Text Full Text PDF PubMed Scopus (7643) Google Scholar, 28Colhoun H.M. Betteridge D.J. Durrington P.N. et al.CARDS Investigators Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.Lancet. 2004; 364: 685-696Abstract Full Text Full Text PDF PubMed Scopus (3259) Google Scholar, 29LaRosa J.C. Grundy S.M. 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Large, published trials have demonstrated the benefits of statin therapy in both the primary and secondary prevention of vascular disease, and subgroup analyses of these studies have shown similar benefits in subsets of participants with diabetes (23Pyörälä K. Pedersen T.R. Kjekshus J. et al.Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S).Diabetes Care. 1997; 20: 614-620Crossref PubMed Scopus (1550) Google Scholar, 24Sacks F.M. Pfeffer M.A. Moye L.A. et al.The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.N Engl J Med. 1996; 335: 1001-1009Crossref PubMed Scopus (7191) Google Scholar, 25Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.N Engl J Med. 1998; 339: 1349-1357Crossref PubMed Scopus (5567) Google Scholar). Across all subgroups, statin therapy provides the same relative risk reduction in terms of outcomes, but the absolute benefit depends on the baseline level of absolute risk, which is typically increased in people with diabetes. Subgroup analyses from statin trials also have shown similar benefits of LDL-C lowering, regardless of baseline LDL-C (26Collins R. Armitage J. Parish S. et al.Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.Lancet. 2003; 361: 2005-2016Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 28Colhoun H.M. Betteridge D.J. Durrington P.N. et al.CARDS Investigators Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.Lancet. 2004; 364: 685-696Abstract Full Text Full Text PDF PubMed Scopus (3259) Google Scholar). Therefore, statin use should be considered for any person with diabetes at risk of a vascular event. In the very small group of lower-risk individuals with type 2 diabetes, the relative reduction in CVD risk with statin therapy is likely to be similar to that seen in those at higher global risk for CVD, but the absolute benefit from statin therapy is predicted to be smaller. However, the global CVD risk of these individuals will increase with age and in the presence of additional CVD risk factors. Therefore, repeated monitoring of the CVD risk status of patients with diabetes (as outlined in the Screening section above) is recommended. The results of the Heart Protection Study (HPS), which compared simvastatin 40 mg daily to placebo, provide considerable insight into the importance of LDL-C lowering in the general population and, in particular, patients with diabetes (27Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.Lancet. 2002; 360: 7-22Abstract Full Text Full Text PDF PubMed Scopus (7643) Google Scholar). In the overall study involving >20 000 subjects, similar risk-ratio reductions were observed in subjects with baseline LDL-C >3.5 mmol/L, 3.0 to 3.5 mmol/L and <3.0 mmol/L. In the subgroup with diabetes (n=5963, including 615 people with type 1 diabetes), treatment with 40 mg simvastatin daily resulted in a 27% reduction in cardiovascular (CV) events and a 25% reduction in stroke relative to treatment with placebo. The risk reduction was similar in the cohorts with and without diabetes, and the treatment benefit was independent of baseline HDL-C and LDL-C levels (LDL-C <3.0 mmol/L or ≥3.0 mmol/L), sex, vascular disease, type of diabetes (type 1 vs. type 2) and glycated hemoglobin (A1C) (26Collins R. Armitage J. Parish S. et al.Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.Lancet. 2003; 361: 2005-2016Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). These results emphasized the benefits of statin treatment irrespective of the pre-existing serum LDL-C level. However, HPS did not demonstrate the effect of treating LDL-C to any particular preset target level. In a post hoc analysis of the entire study sample, the investigators found similar event reductions in individuals with baseline LDL-C values <2.6 mmol/L. However, this analysis was not performed in the subgroup of people with diabetes who had baseline LDL-C values <2.6 mmol/L because of insufficient power. These analyses also have implications for patients with diabetes whose spontaneous LDL-C may already be below treatment goals. In this setting, treatment with a moderate dose of statin, such as simvastatin 40 mg, or equivalent doses of other statins (average LDL-C reduction of approximately 30% to 40%), would be expected to provide comparable relative risk reductions to those seen with statin treatment initiated at higher baseline levels of LDL-C. The Collaborative Atorvastatin Diabetes Study (CARDS) was the first completed statin trial to be conducted exclusively in people with type 2 diabetes without known vascular disease (28Colhoun H.M. Betteridge D.J. Durrington P.N. et al.CARDS Investigators Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.Lancet. 2004; 364: 685-696Abstract Full Text Full Text PDF PubMed Scopus (3259) Google Scholar). The mean baseline LDL-C of the study population was 3.1 mmol/L, and all subjects had at least 1 CVD risk factor in addition to diabetes. CARDS demonstrated that treatment with atorvastatin 10 mg daily was safe and highly efficacious in reducing the risk of a first CV event, including stroke. Treatment resulted in a mean LDL-C of 2.0 mmol/L and was associated with a reduced risk for CV events and stroke of 37% and 48%, respectively. These study findings support the value of treating even so-called “normal” LDL-C levels in people with type 2 diabetes and no known vascular disease. As mentioned previously, all CARDS subjects had at least 1 additional CVD risk factor (i.e. history of hypertension, retinopathy, microalbuminuria or macroalbuminuria, or current smoking), a profile that applies to an estimated 70% to 80% of people with type 2 diabetes (28Colhoun H.M. Betteridge D.J. Durrington P.N. et al.CARDS Investigators Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.Lancet. 2004; 364: 685-696Abstract Full Text Full Text PDF PubMed Scopus (3259) Google Scholar, 35Evans J.M. Wang J. Morris A.D. Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies.BMJ. 2002; 324: 939-942Crossref PubMed Google Scholar). Results from the United States (US) Third National Health and Nutrition Examination Survey (NHANES III) indicate that 82% of people with diabetes and no clinically evident coronary artery disease (CAD) have at least 1 of the CARDS entry criteria risk factors (28Colhoun H.M. Betteridge D.J. Durrington P.N. et al.CARDS Investigators Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.Lancet. 2004; 364: 685-696Abstract Full Text Full Text PDF PubMed Scopus (3259) Google Scholar). The CARDS investigators concluded that the study findings “challenge the use of a particular threshold level of LDL-C as the sole arbiter of which individuals with type 2 diabetes should receive statin therapy…. The absolute risk, determined by other risk factors in addition to LDL-C, should drive the target levels” (28Colhoun H.M. Betteridge D.J. Durrington P.N. et al.CARDS Investigators Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.Lancet. 2004; 364: 685-696Abstract Full Text Full Text PDF PubMed Scopus (3259) Google Scholar, 37Charlton-Menys V. Betteridge D.J. Colhoun H. et al.Targets of statin therapy: LDL cholesterol, non-HDL cholesterol, and apolipoprotein B in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS).Clin Chem. 2009; 55: 473-480Crossref PubMed Scopus (78) Google Scholar). Indeed, the investigators questioned whether any individual with type 2 diabetes can be considered at sufficiently low risk for statin therapy to be withheld (28Colhoun H.M. Betteridge D.J. Durrington P.N. et al.CARDS Investigators Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.Lancet. 2004; 364: 685-696Abstract Full Text Full Text PDF PubMed Scopus (3259) Google Scholar). A subanalysis of the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA) revealed similar benefits of atorvastatin 10 mg vs. placebo in people with type 2 diabetes, hypertension and at least 3 additional risk factors (36Sever P.S. Poulter N.R. Dalhof B. et al.Reduction in cardiovascular events with atorvastatin in 2532 patients with type 2 diabetes. Anglo-Scandinavian Cardiac Outcomes Trial–lipid-lowering arm (ASCOT-LLA).Diabetes Care. 2005; 28: 1151-1157Crossref PubMed Scopus (328) Google Scholar). The Atorvastatin Study for the Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) assessed the effect of atorvastatin 10 mg daily vs. placebo on CVD prevention in 2410 people with type 2 diabetes (38Knopp R.H. D’emden M. Smilde S.J. et al.Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN).Diabetes Care. 2006; 29: 1478-1485Crossref PubMed Scopus (440) Google Scholar). Although originally designed as a secondary prevention trial, the protocol underwent several changes, including the addition of subjects without known CAD and the eventual conversion of all patients with known CAD to open-label, lipid-lowering medication. Over the 4-year study period, mean LDL-C was reduced by 29% in the atorvastatin group compared to placebo (p<0.0001). The composite primary endpoint was reduced by 13.7%; however, this finding was not statistically significant and was generally considered to be related to the methodological limitations of the study design and the protocol changes. In the subgroup with diabetes (n=1051) of the Treating to New Targets (TNT) trial conducted in individuals with stable CAD, those subjects treated with atorvastatin 80 mg daily who achieved a mean LDL-C of 2.0 mmol/L had 25% fewer major CVD events than did those treated with atorvastatin 10 mg daily who achieved a mean LDL-C of 2.5 mmol/L (p=0.026) (30Shepherd J. Barter P. Carmena R. et al.Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study.Diabetes Care. 2006; 29: 1220-1226Crossref PubMed Scopus (455) Google Scholar). Intensive therapy with atorvastatin 80 mg daily also reduced the rate of all CVD and cerebrovascular events compared to atorvastatin 10 mg daily. Notably, an increased event rate for all primary and secondary efficacy outcomes was noted in the diabetes subgroup compared to the overall study population. This finding provides yet further evidence that people with diabetes and CAD are at extremely high risk of subsequent CVD events. The Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis of >170 000 statin-treated subjects found that for every 1.0 mmol/L reduction in LDL-C there was an approximate 20% reduction in CVD events, regardless of baseline LDL-C (39Baigent C. Keech A. Kearney P.M. et al.Cholesterol Treatment Trialists’ (CTT) CollaboratorsEfficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.Lancet. 2010; 366: 1267-1278Google Scholar). The proportional reductions were very similar in all subgroups, including those with diabetes without pre-existing vascular disease (39Baigent C. Keech A. Kearney P.M. et al.Cholesterol Treatment Trialists’ (CTT) CollaboratorsEfficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.Lancet. 2010; 366: 1267-1278Google Scholar). In fact, the CTT meta-analysis of >18 000 subjects with diabetes from 14 randomized statin trials found that the effects of statins on all fatal and nonfatal CV outcomes were similar for participants with or without diabetes (40Kearney P.M. Blackwell L. Collins R. et al.Cholesterol Treatment Trialists' (CTT) CollaboratorsEfficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.Lancet. 2008; 371: 117-125Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar). The updated CTT meta-analysis of 170 000 subjects showed that additional reductions in LDL-C (down to approximately 1.0 to 2.0 mmol/L) with more intensive therapy further reduced the incidence of major vascular events and that these reductions could be achieved safely, even in individuals with lower baseline LDL-C levels (41Baigent C. Blackwell L. Emberson J. et al.Cholesterol Treatment Trialists’ (CTT) CollaborationEfficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681Abstract Full Text Full Text PDF PubMed Scopus (4533) Google Scholar). Although the linear relationship between the proportional CVD risk reduction and LDL-C lowering would suggest that there is no lower limit of LDL-C or specified LDL-C target (as the CTT authors suggest), the clinical trial evidence summarized above would suggest that LDL-C ≤2.0 mmol/L is currently the most appropriate target for high-risk individuals. In the vast majority of people, this target can be achieved with either a statin alone or a statin in combination with another lipid-lowering agent. However, there is presently less support for the latter recommendation. For example, there are currently no completed clinical outcome trials using ezetimibe solely in patients with diabetes; however, a mechanistic trial using carotid intima-medial thickness (CIMT) as a surrogate endpoint has been reported in adult native North American subjects with diabetes (42Fleg J.L. Mete M. Howard B.V. et al.Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes.J Am Coll Cardiol. 2008; 52: 2198-2205Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 43Howard W.J. Russell M. Fleg J.L. et al.Prevention of atherosclerosis with low-density lipoprotein cholesterol lowering-lipoprotein changes and interactions: the SANDS study.J Clin Lipid. 2009; 3: 322-331Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). In this study, reducing LDL-C to aggressive targets resulted in a similar regression of CIMT in patients who attained equivalent LDL-C reductions from a statin alone or a statin plus ezetimibe. Patients with diabetes and renal dysfunction or those requiring dialysis