diabetes mellitus is associated with a considerably increased risk of premature atherosclerosis , particularly coronary heart disease ( chd ) and peripheral arterial disease [ 1 , 2 ] . although more recent analyses have suggested a less marked effect , most authorities consider diabetes to confer at least a twofold excess risk , independently from other conventional risk factors [ 3 , 4 ] . even in people without diabetes , fasting blood glucose concentration and glycated hemoglobin ( hba1c ) early studies of cardiovascular mortality in type  1 diabetes suggested that risk only significantly increases after the development of nephropathy , which coincides with a marked deterioration of the lipid profile and blood pressure . in patients with type  1 diabetes and proteinuria a 37-fold excess risk has been described , compared with a relative risk of 4.3 in patients without proteinuria . more recent analyses have suggested that improved management of other risk factors can reduce the overall relative risk to 3.0 for women and 2.3 for men . in type  2 diabetes an increased cardiovascular risk often exists for many years before the onset of biochemical hyperglycemia . during this period obesity and insulin resistance are often present , associated with hypertension and dyslipidemia , usually referred to as metabolic syndrome . these risk factors may lead to the early development of chd and may account for the increased incidence of diabetes in the period following a diagnosis of cardiovascular disease . in keeping with this observation , about one in six patients with newly diagnosed type  2 diabetes enrolled in the united kingdom prospective diabetes study ( ukpds ; controlled-trials.com identifier : isrctn75451837 ) had evidence of previous silent myocardial infarction . however , neither the diabetes control and complications trial ( dcct ; clinicaltrials.gov identifier : nct00360815 ) or the ukpds ( apart from 342 patients in the ukpds metformin subgroup ) showed a statistically significant reduction in chd risk with more intensive glycemic control [ 12 , 13 ] . both the action in diabetes and vascular disease ( advance ; clinicaltrials.gov identifier : nct00145925 ) and veterans affairs diabetes ( vadt ; clinicaltrials.gov identifier : nct00032487 ) trials also failed to show the desired beneficial effects on cardiovascular outcomes from intensive glycemic control [ 14 , 15 ] . this apparent lack of effect was confirmed in the outcome reduction with initial glargine intervention ( origin ; clinicaltrials.gov identifier : nct00069784 ) trial with insulin . reassuringly , prior intensive therapy was associated with long - term reductions in chd during the observational follow - up studies of both the dcct and ukpds [ 17 , 18 ] , although the action to control cardiovascular risk in diabetes ( accord ; clinicaltrials.gov identifier : nct00000620 ) study group reported previously unrecognized harm from intensive glucose lowering in patients with type  2 diabetes with established cardiovascular disease or additional cardiovascular risk factors . there is an association between atherosclerotic cardiovascular disease and serum cholesterol and triglyceride levels in both type  1 and type  2 diabetes [ 21 , 22 ] . the risk of chd is greater at any given level of serum cholesterol in patients with diabetes and its association with hypertriglyceridemia is stronger than in the general population . importantly , there is strong and convincing evidence that cholesterol lowering therapy significantly reduces chd in patients both with and without diabetes [ 2426 ] . there also appears to be no threshold below which a further reduction in low - density lipoprotein ( ldl ) cholesterol might be beneficial [ 25 , 26 ] . improved glycemic control generally has favorable effects on lipoprotein levels in diabetes , with a reduction in cholesterol and triglyceride levels through decreased circulating very - low - density lipoprotein ( vldl ) and by increased catabolism of ldl through reduced glycation and upregulation of ldl receptors [ 27 , 28 ] . it is certainly possible that any cardiovascular benefit which might be derived from intensive glucose lowering is related to effects on lipoprotein metabolism rather than directly through altered glycemia . this article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors . the dyslipidemia of type  2 diabetes is characterized by high triglyceride levels and decreased high - density lipoprotein ( hdl ) cholesterol , changes observed many years before the onset of clinically relevant hyperglycemia [ 9 , 30 ] . recent evidence suggests that low hdl cholesterol is an independent factor not only for cardiovascular disease but also for the development of diabetes itself . these changes , and the presence of small dense ldl particles , probably contribute to accelerated atherosclerosis even before diabetes is formally diagnosed [ 9 , 32 ] . in type  1 diabetes , hypertriglyceridemia may occur , but hdl cholesterol levels are often normal or even high unless glycemic control is poor or nephropathy is present . in addition , patients with diabetes show qualitative and kinetic abnormalities for all lipoproteins . a number of factors may contribute to the alterations in lipid metabolism observed in patients with diabetes , including insulin deficiency or resistance , adipocytokines , and hyperglycemia . many aspects of the pathophysiology and consequences of diabetes dyslipidemia remain unclear , but the mechanism by which hypertriglyceridemia arises is fairly well understood . insulin deficiency or resistance activates intracellular hormone - sensitive lipase which increases the release of non - esterified fatty acids ( nefa ) from triglycerides stored in the more metabolically active centrally distributed adipose tissue . . increased hepatic triglyceride synthesis is associated with increased secretion of apolipoprotein  b ( apob )   ( see fig .  1 ) . furthermore , the normal inhibitory effect of insulin on hepatic apob production and triglyceride secretion in vldl is lost , and the vldl secreted is larger and more triglyceride - rich [ 3739 ] . lipoprotein lipase located on vascular endothelium largely determines the rate of removal of triglycerides from the circulation . in contrast to intracellular hormone - sensitive lipase this lipoprotein lipase may be downregulated in states of insulin resistance or deficiency . apoai apolipoprotein  ai , apob apolipoprotein  b , apociii apolipoprotein  ciii , apoe apolipoprotein  e , ce cholesteryl esters , cetp cholesteryl ester transfer protein , hdl high - density lipoprotein , idl intermediate - density lipoprotein , ldl low - density lipoprotein , ldl - r low - density lipoprotein receptor , nefa non - esterified fatty acids , sdldl small dense low - density lipoprotein , tg triglycerides , vldl very - low - density lipoprotein qualitative changes in lipoproteins in diabetes . apoai apolipoprotein  ai , apob apolipoprotein  b , apociii apolipoprotein  ciii , apoe apolipoprotein  e , ce cholesteryl esters , cetp cholesteryl ester transfer protein , hdl high - density lipoprotein , idl intermediate - density lipoprotein , ldl low - density lipoprotein , ldl - r low - density lipoprotein receptor , nefa non - esterified fatty acids , sdldl small dense low - density lipoprotein , tg triglycerides , vldl very - low - density lipoprotein it is essential to rectify the commonly held misconception that triglyceride concentration is a poor indicator of cardiovascular risk . there is a strong relationship between triglycerides and chd in both type  1 and type  2 diabetes . raised serum triglycerides herald the development of type  2 diabetes mellitus , particularly when associated with other features of metabolic syndrome or chd , and once diabetes has developed they continue to predict chd risk , often independently of other risk factors . triglycerides are positively correlated with cholesterol , obesity , glucose intolerance , cigarette smoking , and hyperuricemia , and are negatively correlated with hdl cholesterol . when these factors are included in multivariate analysis , the element of risk attributable to triglycerides themselves appears less significant , but the risk associated with hypertriglyceridemia is still substantial with fasting levels of 2.64.5 mmol / l associated with a twofold excess of chd risk and levels of 4.59.0  mmol / l with up to a ninefold elevation [ 41 , 42 ] . triglyceride - rich lipoproteins ( chylomicrons and vldl ) are not known to participate directly in atherogenesis , but they are central to the mechanism by which small dense ldl cholesterol is generated and hdl cholesterol levels are depressed in diabetes . cholesteryl ester is transferred from other lipoproteins into the enlarged circulating pool of triglyceride - rich lipoproteins by cholesteryl ester transfer protein , and the rate of transfer is increased in both type  1 and type  2 diabetes [ 43 , 44 ] . there is transfer of triglyceride in the opposite direction such that cholesteryl ester - depleted hdl and ldl become triglyceride - rich . the subsequent removal of this triglyceride by hepatic lipase results in smaller , denser hdl and ldl particles . levels of small dense ldl are thus increased , and the apparently relatively undisturbed cholesterol and apob levels observed in many patients with diabetes may thus hide a major atherogenic change [ 4547 ] . circulating ldl is not believed to participate directly in atherogenesis , but must first undergo structural modification to allow its apob to act as a ligand for the scavenger receptors of monocyte macrophages in the arterial wall , triggering foam cell formation . glycated ldl may be more susceptible to oxidation or itself represent an atherogenic modification [ 49 , 50 ] . glycation of ldl also decreases its ldl receptor - mediated catabolism . in patients with type  1 diabetes with good glycemic control , insulin upregulates lipoprotein lipase , increasing the production of small hdl particles [ 52 , 53 ] , frequently to higher than normal hdl cholesterol levels . hdl cholesterol in diabetes has thus not arisen physiologically ; hdl dysfunction is suggested by the observation that high hdl cholesterol levels do not always protect against chd [ 55 , 56 ] . reductions in the antioxidative and anti - inflammatory effects of hdl have been reported in patients with diabetes , alongside an impaired ability of hdl to counteract the inhibition of endothelium - dependent vasorelaxation by oxidized ldl [ 34 , 57 ] . the role of hdl in protecting pancreatic beta cells against apoptosis is an important emerging area of research . glycation has recently been shown to reduce the sphingosine-1-phosphate content of hdl , reducing its ability to activate protective intracellular survival pathways during oxidative stress . with the development of nephropathy , increased catabolism of smaller hdl particles likely combines with increased cholesteryl ester activity to lower hdl cholesterol levels [ 6 , 60 ] . diabetes thus leads to impaired reverse cholesterol transport through both reduced hdl concentrations and hdl dysfunction . low hdl cholesterol appears to be of greater importance in patients at high cardiometabolic risk and is amongst the factors that currently favor a decision to further reduce ldl cholesterol levels . the apparently normal serum cholesterol concentrations observed in both type  1 and type  2 diabetes led to the widespread erroneous belief that glycemia alone might explain the observed high chd rates . however , the relatively normal cholesterol levels hide an atherogenic lipid profile , with increased intermediate - density lipoprotein and small dense ldl , and dysfunctional hdl [ 4951 ] . each ldl particle , regardless of its density or cholesterol content , contains only a single tightly bound molecule of apob . normal  level of ldl cholesterol seen in many patients with diabetes actually disguises an increased particle number ( higher apob ) and that clearance of small dense particles is slower . thus , measurement of the serum concentration of apob provides a more discriminating index of atherogenic risk or therapeutic response than ldl cholesterol . while intensive therapy in the dcct did not significantly affect ldl and hdl cholesterol levels , it was associated with decreased apob ( and lipoprotein(a ) ) and with favorable alterations in lipoprotein subclasses that are not revealed by the standard lipid profile , but have implications for the evolution of both microvascular and macrovascular complications . the use of ldl cholesterol in diabetes also underestimates the atherogenic contribution of triglyceride - rich particles so non - hdl cholesterol is a better measure of atherogenicity in diabetes . the introduction of non - hdl cholesterol appears to have obviated the need to introduce apob measurements more widely in patient management . lifestyle modifications are the first - line intervention in the management of diabetes dyslipidemia , and include weight loss , dietary modification , and aerobic exercise . obesity increases insulin resistance and is associated with increased triglycerides and ldl cholesterol and decreased hdl cholesterol . weight loss is known to be associated with improvements in lipids and other cardiovascular risk factors including the incidence of type  2 diabetes [ 65 , 66 ] and should therefore be encouraged in overweight patients with diabetes . to achieve sustained weight loss , caloric restriction remains the key and even modest degrees of weight loss are associated with an improvement in glycemic control , hba1c , and lipid profile . increased physical activity may provide some small adjunct to the effect of dietary restriction , but is unlikely to be successful on its own . the american diabetes association ( ada ) recommends a diet low in trans fat , saturated fat , and cholesterol . in patients without a marked increase in serum triglycerides but who are not obese , some substitution of saturated fat can be made with unrefined carbohydrate foods and some with oleic , linoleic , or omega-3 fish oils . dietary interventions , while considered first - line treatment for all patients with diabetes , have not been successful in demonstrating a mortality benefit , even with prolonged follow - up . the gastrointestinal lipase inhibitor orlistat causes fat malabsorption and should be taken close to meals . there is often early benefit , but then weight loss levels out , likely as the patient learns to omit it if they plan to consume a fatty meal . orlistat has beneficial effects on serum total and ldl cholesterol levels which are greater than might be explained by weight loss alone . weight loss after bariatric surgery is also associated with beneficial glycemic effects in diabetes , including achievement of near normal glycemia without medication or reduced medications . insulin therapy increases hdl cholesterol and reduces circulating triglyceride levels , particularly in patients with poor glycemic control . metformin decreases serum triglycerides and improves insulin resistance but is often overlooked as a lipid - lowering agent and is generally considered only as a hypoglycemic agent in the management of diabetes . other drugs used in the management of diabetes may also have unintended positive and negative effects on lipoproteins ( see table  1 ) . of particular interest is the small increase in ldl cholesterol observed following treatment with sodium - glucose cotransporter  2 ( sglt2 ) inhibitors , suggesting that the recently reported significant improvement in cardiovascular outcomes with empagliflozin is unrelated to effects on dyslipidemia .table 1effects of hypoglycemic agents on lipoproteinsdrugtotal cholesterolldl cholesterolhdl cholesteroltriglyceridesreferencesmetformingliclazide[115 , 116]glimepiride[115 , 117]pioglitazone[118 , 119]sitagliptin[120 , 121]saxagliptin[116 , 122]vildagliptinlinagliptindapagliflozin[125 , 126]canagliflozin[121 , 127]empagliflozin[78 , 128]exenatide[119 , 129]liraglutide[130 , 131] increased ,  no change ,  decreased , hdl high - density lipoprotein , ldl low - density lipoprotein effects of hypoglycemic agents on lipoproteins  increased ,  no change ,  decreased , hdl high - density lipoprotein , ldl low - density lipoprotein statins inhibit 3-hydroxy-3-methylglutaryl - coenzyme  a reductase , the rate - limiting enzyme in cholesterol biosynthesis . there is a wealth of clinical trial evidence that lowering serum cholesterol with statins decreases the risk of chd [ 24 , 79 ] . these trials have demonstrated that statins decrease the risk of both chd and stroke in people with and without pre - existing cardiovascular disease [ 24 , 80 ] . it would appear from such trials that the relative risk reduction achieved with statin treatment is similar in patients with diabetes to that in other people . however , the number needed to treat to prevent one event ( nnt ) will be lower in patients with diabetes compared to those without diabetes but apparently similar lipid profiles . the case for secondary prevention with statin therapy in diabetes is accepted , but whether all patients with diabetes should be considered for statin treatment has been more contentious . in the heart protection study ( controlled-trials.com identifier : isrctn48489393 ) the 2912 patients with diabetes without pre - existing vascular disease randomized to receive simvastatin showed a significant reduction in cardiovascular end - points compared to those allocated to placebo . similarly , in the collaborative atorvastatin diabetes study ( cards ; clinicaltrials.gov identifier : nct00327418 ) , where the mean pretreatment ldl cholesterol was 3.0  mmol / l ( < 2.5 mmol / l in 25% of patients ) , the effect of active intervention with atorvastatin was so favorable that the study was stopped early . in both studies there did not appear to be any threshold below which statin therapy ceased to be beneficial . a meta - analysis of 18,686 people with diabetes from 14 randomized trials ( 1466 with type  1 and 17,220 with type  2 ) demonstrated a 9% reduction in all - cause mortality for every 1  mmol / l reduction in ldl cholesterol . the effects of statin therapy were similar irrespective of baseline characteristics and prior history of vascular disease . although the majority of participants in these trials had type  2 diabetes , the reduction in major vascular events was also statistically significant in people with type  1 diabetes . the risk factor reduction brought about by statins occurs in a dose - dependent fashion , with higher dose statins associated with a greater lowering of cardiovascular events . it should also be noted that in diabetes , in contrast to patients without diabetes , statins do not stop the progression of carotid intima media thickness or intravascular ultrasound - measured atheroma volume at typical doses , implying that high doses may be necessary to prevent atheroma progression . one in seven patients with diabetes treated with statins still goes on to suffer a cardiovascular event over 5  years . clinical trial evidence therefore provides unequivocal evidence to support prescribing statins for both primary and secondary prevention in diabetes , but the populations studied may not be representative of younger patients or those with advanced renal disease . interestingly , statin treatment is associated with a slight increase in the incidence of type  2 diabetes . a meta - analysis showed 4  years of statin treatment in 255 patients would lead to one extra case of type  2 diabetes . however , this risk is low both in absolute terms and when compared with the expected cardiovascular benefit from reducing ldl cholesterol . in the same period 5.4 vascular events would be avoided in these 255 patients . clinical practice in patients with existing cardiovascular disease or moderate or high cardiovascular risk should not change . ezetimibe blocks the absorption of dietary cholesterol and the reabsorption of cholesterol entering the small intestine in bile , the latter accounting for most of its ldl cholesterol lowering . ezetimibe is concentrated in the cells of the intestinal brush border , where it inhibits cholesterol absorption by a process which involves binding to niemann - pick c1-like  1 . it remains a second - line option for ldl cholesterol lowering in diabetes and has its greatest clinical utility as an adjunct to statin therapy . the bile acid sequestrant colesevelam has been shown to reduce hba1c in addition to reductions in total cholesterol , ldl , and non - hdl cholesterol levels . cholestyramine may be more effective in lowering ldl cholesterol , but both agents may increase triglycerides , and neither is particularly well tolerated . many novel therapies are in development to reduce ldl cholesterol , but none has been studied specifically in patients with diabetes . in particular , proprotein convertase subtilisin / kexin  9 ( pcsk9 ) inhibitors have emerged as medications showing significant reductions in ldl , with recent data suggesting similar effects on lipoproteins in patients with type  2 diabetes to those seen in patients without diabetes . an additional potentially beneficial effect on postprandial hypertriglyceridemia is suggested by novel data on pcsk9 regulation of intestinal lipoprotein assembly and secretion . the accord study showed an increased number of cardiovascular events in patients with diabetes and persistently low hdl cholesterol and high triglyceride levels , despite a mean ldl cholesterol below 2.1  mmol / l . fibrates act as peroxisome proliferator - activated receptor ( ppar)- agonists to reduce triglycerides and modestly increase hdl cholesterol but also affect multiple pathways linked to the retinoid - x receptor . to date no decrease in cardiovascular outcomes has been convincingly demonstrated in clinical trials . in the fenofibrate intervention and event lowering in diabetes ( field ; controlled-trials.com identifier : isrctn64783481 ) study 9795 people with type  2 diabetes were randomized to receive micronized fenofibrate or placebo . by the end of the trial statin treatment became a major confounding factor , but the primary end - point ( fatal chd and non - fatal myocardial infarction ) decreased by 11% on fenofibrate compared to placebo . although pretreatment serum triglyceride levels appeared to have no influence on the relative decrease in cardiovascular events , the overall effect was not significant , and the field study did not establish a firm place for fibrate drugs in the management of diabetes dyslipidemia . more recently the accord - lipid trial reported no cardiovascular benefit from the addition of fenofibrate to simvastatin in patients with type  2 diabetes . however , there did appear to be a beneficial effect on chd outcomes in patients with triglycerides above 2.4 there may therefore be a role for fibrates as adjunctive therapy in patients with diabetes and persistently elevated triglycerides . however , fibrates , particularly fenofibrate , may cause paradoxical reductions in hdl cholesterol levels and it is important that clinicians are aware of this phenomenon . most hypertriglyceridemia in diabetes is mild to moderate and statins remain the drug of first choice even in patients with mixed dyslipidemias , but in patients with genetic susceptibility severe hypertriglyceridemia may develop , with attendant risk of pancreatitis . when triglycerides are above 11  mmol / l a fibrate should be considered first to reduce triglycerides and the risk of pancreatitis . purified omega-3 fatty acids can lower triglycerides as much as fibrates , but they have little effect on hdl or ldl cholesterol . omacor ( abbott healthcare , abbott park , il , usa ) contains 90% omega-3 fatty acid ethyl esters ( mostly eicosopentaenoate or docosahexaenoate ) and in combination with a statin can decrease triglycerides by a further 30% , most probably by inhibition of hepatic triglyceride synthesis . despite evidence that omega-3 fatty acids stabilize atheromatous plaques and reports of beneficial hypotensive and antithrombotic effects , a recent trial of omega-3 fatty acids in patients with metabolic syndrome or type  2 diabetes disappointingly found no effect on chd risk [ 100 , 101 ] . another future therapeutic option may be the dual ppar-/ agonist saroglitazar , which was approved in india in 2013 and has been shown to significantly reduce plasma triglyceride , total cholesterol , non - hdl cholesterol , and vldl cholesterol , and hba1c and fasting glucose levels . the role of diabetes in risk assessment processes is more controversial than the simple statement often applied in guidelines that diabetes is a cardiovascular disease - risk equivalent . risk in type  1 diabetes is strongly related to glycemic control , nephropathy , and hypertension and can be significantly increased compared with normoglycemic subjects . risk in type  2 diabetes is still widely considered to be increased two- to fourfold [ 3 , 104 ] . while features such as the presence of nephropathy or retinopathy identify higher risk groups , the use of other biomarkers of risk and likely need for enhanced treatment are often not appreciated . the presence of microalbuminuria for example is a risk factor for chd even at low levels and its severity is also predictive of future events . most clinical guidelines recommend tight control of dyslipidemia , especially in high risk patients [ 106 , 107 ] . importantly , lipid targets are easier to achieve than blood pressure or glycemia targets and target ldl cholesterol levels as low as 1.8  mmol / l are increasingly recommended in patients with established chd [ 108 , 109 ] . a recent position statement from the ada recommends a screening lipid profile at the time of diagnosis , at age 40  years , and periodically thereafter . treatment recommendations beyond lifestyle modification and optimization of glycemic control are for the use of high - intensity statin therapy ( e.g. , atorvastatin 4080  mg or rosuvastatin 2040  mg ) in patients of all ages with overt chd , and those aged 4075  years with additional risk factors , and moderate intensity statin therapy ( e.g. , atorvastatin 1020  mg or simvastatin 2040  mg ) for patients aged over 40  years without additional risk factors . clinical judgment should guide the use of moderate or high - intensity statin therapy in patients younger than 40  years or older than 75  years with additional risk factors . the most recent american heart association / american college of cardiology guidelines for cholesterol management appear less interventional , recommending statin treatment only for patients with diabetes with clinical atherosclerotic cardiovascular disease or if aged 4075  years . there is also a modest recommendation for additional treatment in persons with statin intolerance or an inadequate response , with an emphasis on clinical judgment . the european society of cardiology suggests that ezetimibe be added after intensification of statin therapy in diabetes . the national institute for health and care excellence also recently updated its guidance and now advises clinicians to offer statin treatment for primary prevention to adults with type  1 diabetes who are over 40  years , have had diabetes for more than 10  years , or have established nephropathy or other cardiovascular risk factors . these guidelines also recommend statin therapy for primary prevention in type  2 diabetes if the 10-year risk of developing cardiovascular disease is estimated to be greater than 10% using the qrisk2 assessment tool . in conclusion , statin treatment should effectively be considered for all people with diabetes aged over 40  years or younger if additional cardiovascular risk factors are present , a position recently supported by the joint british societies .
diabetes mellitus is associated with a considerably increased risk of premature atherosclerotic cardiovascular disease . 
 intensive glycemic control has essentially failed to significantly improve cardiovascular outcomes in clinical trials . 
 dyslipidemia is common in diabetes and there is strong evidence that cholesterol lowering improves cardiovascular outcomes , even in patients with apparently unremarkable lipid profiles . here , 
 the authors review the pathophysiology and implications of the alterations in lipoproteins observed in both type  1 and type  2 diabetes , the effect of medications commonly used in the management of diabetes on the lipid profile , the evidence for lifestyle and pharmaceutical interventions , and national and international recommendations for the management of dyslipidemia in patients with diabetes .