Dyslipidemia

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

G.B. John Mancini MD, FRCPC, FACP, FACC Robert A. Hegele MD, FRCPC, FACP Lawrence A. Leiter MD, FRCPC, FACP, FAHA

  • Key Messages
  • Recommendations
  • Figures
  • Full Text
  • References

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.

Dyslipidemia in Diabetes

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 (1–3). Aggressive management of all CVD risk factors, including dyslipidemia, is, therefore, generally necessary in individuals with diabetes (4). 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 (5,6). Many of these abnormalities also are seen in patients with metabolic syndrome (7,8).

Risk Assessment of Individuals with Diabetes

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 (9), and efforts were made to ensure consistency between the guidelines.

Screening

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 (10). 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 Modification

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 (11–22). 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).

LDL-C

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 (23–34). 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 (23–25). 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 (26,28). 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.

Table 1
Dyslipidemia components associated with type 2 diabetes and metabolic syndrome (5)
Apo, apolipoprotein; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; TG, triglyceride.
  • 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 lipids

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 (27). 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) (26). 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 (28). 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 (28,35). 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 (28). 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” (28,37). Indeed, the investigators questioned whether any individual with type 2 diabetes can be considered at sufficiently low risk for statin therapy to be withheld (28). 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 (36).

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 (38). 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) (30). 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 (39). The proportional reductions were very similar in all subgroups, including those with diabetes without pre-existing vascular disease (39). 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 (40). 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 (41).

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 (42,43). 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 constituted 23% of the study population of the recently reported Study of Heart and Renal Protection (SHARP) trial. The study showed that LDL-C reductions with simvastatin plus ezetimibe were associated with reductions in the incidence of major atherosclerotic events vs. placebo. Subgroup and heterogeneity analysis revealed no difference in risk reduction between patients with or without diabetes using the statin/ezetimibe combination (44).

Tables 2A and 2B summarize considerations that should guide the choice of pharmacological agent(s) for the treatment of dyslipidemia. Colesevelam, a bile acid sequestrant now approved in Canada, appears to have an ancillary effect on lowering A1C (45,46). People with impaired glucose tolerance (IGT) (particularly in the context of metabolic syndrome) are at significant risk for the development of CVD. Indeed, some studies suggest that their vascular risk is almost as high as individuals with existing type 2 diabetes (47,48). No clinical trials of lipid-lowering agents have been conducted exclusively in people with IGT; however, given their increased CVD risk, it is reasonable to consider treating this population to the same targets as people with diabetes (49). To reduce the CVD morbidity and mortality associated with prediabetes and metabolic syndrome, an aggressive approach aimed at associated CVD risk factors, including dyslipidemia, is warranted. Lifestyle interventions aimed at reducing the risk of developing both type 2 diabetes and CAD are essential.

Additional lipid markers of CVD risk

The TC/HDL-C ratio is a sensitive and specific index of CVD risk (53) and is considered to be an important determinant of the need for lipid-lowering therapy. An elevated TC/HDL-C ratio is usually associated with a low HDL-C and/or elevated TG, both of which are commonly seen in individuals with diabetes and often in individuals without diabetes, even in the face of an optimal LDL-C of ≤2.0 mmol/L. The elevated TC/HDL-C ratio is considered to represent a source of lipid-derived, residual risk in treated patients. This form of dyslipidemia is considered more responsive to lifestyle modification (e.g. an increase in physical activity and weight reduction) and improvements in glycemic control than is an isolated LDL-C elevation. Accordingly, initial treatment should consist of intensifying lifestyle modification strategies and improving glycemic control through the use of glucose-lowering therapies as needed.

Table 2A
First-line therapy to achieve a primary lipid target of LDL-C ≤2.0 mmol/L
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.
Note: Physicians should refer to the most current edition of the Compendium of Pharmaceuticals and Specialties (Ottawa, ON: Canadian Pharmacists Association) for product monographs and complete prescribing information.
Prevention of statin-induced myopathy requires attention to factors that increase risk, such as age >80 years (especially women); small body frame and frailty; higher dose of statin; multisystem diseases (e.g. chronic renal insufficiency due to diabetes); multiple medications; hypothyroidism; perioperative periods; alcohol abuse; excessive grapefruit juice consumption; and specific concomitant medications, such as fibrates (especially gemfibrozil) (refer to specific statin package inserts for others) (50).
† Listed in alphabetical order.
Statins
Generic name Trade name Considerations
Atorvastatin Lipitor and generics Statins are drugs of choice to lower LDL-C
and have modest TG-lowering and HDL-C raising
effects at higher doses
Fluvastatin Lescol
Lovastatin Mevacor and generics
Pravastatin Pravachol and generics
Rosuvastatin Crestor and generics
Simvastatin Zocor and generics  

To reduce the residual CVD risk despite statin therapy, the potential benefit of additional lipid-lowering efforts with adjuvant pharmacotherapy has garnered tremendous interest. However, 2 recent studies, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (cohort consisted exclusively of patients with diabetes) and the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial (34% of this study cohort had diabetes), highlight the importance of maintaining LDL-C lowering as the primary focus of treatment, particularly with statins (54,55). The goal of both trials was to optimize the residual dyslipidemic profile of statin-treated patients with LDL-C at or near target levels through the use of agents known to lower TG and raise HDL. Fenofibrate was used in ACCORD and niacin was used in AIM-HIGH. Both of these second-line adjunctive therapies failed to show any added clinical benefit compared to statin therapy alone. Therefore, neither niacin nor fibrates can be recommended as routine adjunctive therapy in patients already meeting LDL-C targets with statins since these agents appear to have no additional impact on macrovascular disease endpoints. In some patients, however, these agents may be required to help achieve LDL-C targets. The results of 4 recent meta-analyses examining the effects of fibrate therapy on CV outcomes found that fibrates may be particularly beneficial in patients with atherogenic dyslipidemia, which is characterized by elevated TG, small LDL particles and reduced HDL-C (56–59).

Also, recent evidence suggests that fibrate therapy may help reduce the microvascular complications associated with diabetes (i.e. retinopathy and nephropathy), and it appears as if these beneficial effects are not solely due to the lipid changes induced by this drug class (51,60,61). For example, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study found that long-term treatment with fenofibrate reduced albuminuria and slowed estimated glomerular filtration rate loss over 5 years, despite initially and reversibly increasing plasma creatinine (51). Furthermore, if residual hyper-TG is high enough to impart a risk of pancreatitis, fibrates or niacin may be warranted. If HDL-C is low and LDL-C is not at target, niacin in either the immediate-release or extended-release formulation may be effective and is generally safe (62–65). Although niacin can cause deterioration of glycemic control (62), there is now evidence that this particular adverse effect may have been overemphasized (63,66).

Specific TG targets are not provided in these guidelines because there are very few clinical trial data to support recommendations based on any specific plasma TG level. Nonetheless, a TG level <1.5 mmol/L is considered optimal since, below this level, there are fewer associated metabolic abnormalities, such as low HDL-C, small dense LDL particles and postprandial lipemia (32,67–70).

Table 2B
Other lipid-modifying medications
A1C, glycated hemoglobin; GI, gastrointestinal; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.
Note: Physicians should refer to the most current edition of the Compendium of Pharmaceuticals and Specialties (Ottawa, ON: Canadian Pharmacists Association) for product monographs and complete prescribing information.
Listed in alphabetical order.
See Table 2A footnote for prevention of myopathy.
Drug class
Generic name (trade name)
Principal effects Other considerations
Bile acid sequestrants
  • Cholestyramine resin (Questran)
  • Colesevelam (Lodalis)
  • Colestipol HCl (Colestid)
  • Lowers LDL-C
  • GI intolerability, which worsens with increasing doses
  • May elevate TG
  • Colesevelam has A1C-lowering effect
 
Cholesterol absorption inhibitor
  • Ezetimibe (Ezetrol)
  • Lowers LDL-C
  • Less effective than statins as monotherapy
  • Effective when used in combination with a statin to further lower LDL-C (34)
 
Fibrates
  • Bezafibrate (Bezalip SR and generic 200 mg)
  • Fenofibrate (micronized/microcoated/nano crystals) (Lipidil Supra, Lipidil EZ, and generics)
  • Gemfibrozil (Lopid)
  • Lowers TG
  • Variable effect on LDL-C
  • Highly variable effect on HDL-C (more effective at raising HDL-C when baseline TG is high)
  • May increase creatinine and homocysteine levels; however, favourable effects on renal function have been noted with long-term fenofibrate treatment (51)
  • Do not use gemfibrozil in combination with a statin due to increased risk of myopathy and rhabdomyolysis
 
Nicotinic acid
  • Extended-release niacin (Niaspan, Niaspan FCT)
  • Immediate-release niacin (generic, nonprescription)
  • Long-acting (e.g. “no-flush”) niacin (generic, nonprescription) not recommended
  • Raises HDL-C
  • >Lowers TG
  • Lowers LDL-C
  • Can cause dose-related deterioration of glycemic control
  • Extended-release niacin has similar efficacy and better tolerability than immediate-release niacin
  • Long-acting niacin should not be used due to increased hepatotoxicity and decreased efficacy (52)

While several studies have shown that fibrate therapy is associated with CVD prevention, there is much less evidence for CVD risk reduction with fibrates relative to statins, specifically in people with diabetes (71–75). In some studies, no statistically significant reduction in the primary endpoint was demonstrated with fibrate therapy (76,77). Combination therapy with fenofibrate (78,79) or bezafibrate plus a statin appears to be relatively safe if appropriate precautions are taken ( Tables 2A and 2B). but, as discussed above, the efficacy of these approaches in improving patient outcomes has not been established (54). Although combination treatment with fenofibrate appears to be safe (54,76), statins should not be used in combination with gemfibrozil due to an increased risk of myopathy and rhabdomyolysis (80).

To reduce the risk of pancreatitis and to do so rapidly, a fibrate is recommended for individuals with fasting TG levels >10.0 mmol/L who do not respond to other measures, such as intensified glycemic control, weight loss and restriction of refined carbohydrates and alcohol. When there is no overriding concern for acute pancreatitis and when there is evidence of hyper-TG in association with an elevated apo B or high non-HDL-C, it would be reasonable to consider a statin as first-line therapy with the subsequent addition of a fibrate or niacin as needed.

As discussed above, evidence has emerged to support the use of apo B in the management of patients with dyslipidemia (9,37). Mechanistically, it is important to consider that there is one apo B molecule per LDL, lipoprotein (a) [Lp(a)], very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) particle, all of which are atherogenic. Apo B has repeatedly been shown to be a better risk marker for CVD events than LDL-C. Consequently, the measurement of apo B and its monitoring in response to lipid-lowering therapy have been advocated by some authors (9,37,81). The measurement of apo B is most clinically useful in the individual with hyper-TG since it provides an indication of the total number of atherogenic lipoprotein particles in the circulation. Because hyper-TG is commonly seen in people with diabetes, knowledge of the apo B level may guide the aggressiveness with which lipid-lowering therapy is pursued (i.e. more aggressive therapy in individuals with an elevated apo B level). Based on available evidence, an optimal level of apo B can be considered to be at least ∼<0.9 g/L (82) or, as supported by the CARDS study in subjects with diabetes, ≤0.8 g/L (37).

Further important information has emerged from CARDS with respect to alternative targets and therapeutic goals (28). In an extensive analysis of both spontaneous and statin-induced changes in LDL-C, apo B concentrations and non-HDL-C, apo B was found to be a more consistent goal for statin treatment than LDL-C or non-HDL-C (37). In statin-treated patients, the average apo B concentration in the subgroup with concomitant LDL-C ≤2 mmol/L was 0.708 g/L with an upper 95% confidence limit of 0.720 g/L.

The calculated non-HDL cholesterol (TC minus HDL-C) has features similar to apo B: the calculation is valid in the nonfasting state, and it relates mainly to cholesterol contained in atherogenic particles, each of which has an apo B [atherogenic triglyceride-rich elements, such as VLDL and IDL, LDL-C, and Lp(a)]. A linear relationship between apo B and non-HDL exists over a broad range (83). A non-HDL-C level of 2.6 mmol/L is approximately equal to an apo B of 0.8 g/L and may be considered alternate goals of therapy. Although there is general agreement that non-HDL and apo B are more predictive of CV risk than LDL-C, controversy exists regarding the superiority of either apo B or non-HDL, presumably because they are so closely correlated. Since non-HDL is available without further cost or separate assay, it is attractive to consider it as supported by several analyses (84–86).

Apo AI is a surrogate marker of the number of HDL particles in the circulation. The relationship between apo AI and HDL is more complicated than the 1:1 relationship of the number of apo B molecules and atherogenic particles because there may be 2 to 4 apo AI molecules per HDL particle. The apo B/apo AI ratio has been proposed to be the best single predictor of CVD risk, accounting for 50% of population-attributable events in an ethnically diverse population without diabetes (although its comparison to the TC/HDL-C ratio as a risk predictor was not reported in this study) (87). Currently, in Canada, however, the measurement of apo AI is even less widely available than apo B, thus limiting the practical value of both this measurement and the apo B/apo AI ratio for clinical decision making.

In summary, in order to reduce CVD risk among individuals with diabetes, it is important to understand the atherogenicity of small, dense LDL particles, remnant lipoproteins, TG-rich particles and the antiatherogenic role of HDL particles. It is also important to improve these metabolic parameters through lifestyle modifications, improvements in glycemic control and, perhaps, pharmacotherapy, when indicated. Despite academic interest in various lipid parameters, it is of paramount importance to realize that the current best outcome evidence for minimizing the atherogenic impact of lipid abnormalities in patients with diabetes is to remain focused on achieving very low plasma concentrations of LDL-C, typically with statin-centred therapy, as this conclusion is based on the most extensive clinical trial evidence. For patients who are not at goal, despite maximally tolerated stain therapy or in the case of statin intolerance, the use of second-line LDL-C–lowering therapies ( Table 2A ) can be considered, including ezetimibe, bile acid sequestrants or niacin.

Statin Therapy and Incident Diabetes

Although statins are the cornerstone of lipid-altering therapy for CVD risk reduction in people with or without diabetes, recent evidence has suggested that chronic statin use is associated with an increased risk of incident diabetes. The interplay between statin therapy and incident diabetes was highlighted in a prespecified analysis of the West of Scotland Coronary Prevention Study (WOSCOPS), which actually showed a decrease in the incidence of new-onset diabetes with statin therapy (88). In contrast, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) showed an increase in incident diabetes (89). Several meta-analyses suggest that there is indeed a small overall increase in diabetes with chronic statin use (90,91) and that this risk may be related to the statin dose (92).

Although this finding is of little relevance to patients with established diabetes, it may be of relevance to patients who are at risk for developing diabetes irrespective of statin treatment, such as those who are obese and/or who manifest metabolic syndrome. However, as discussed earlier, even these patients with risk factors for the development of diabetes enjoy a marked benefit in CVD risk reduction through the LDL-C–lowering effects of statins, which appears to far outweigh any small risk of new-onset diabetes (47,48). Accordingly, these recent analyses do not affect the recommendation that statins are the preferred agents for lowering LDL-C in most instances, including in patients with established diabetes or in those with risk factors for developing the disease.

Recommendations

  1. 1.A fasting (8-hour fast) lipid profile (TC, HDL-C, TG, and calculated LDL-C) or nonfasting lipid profile (apo B, non-HDL-C calculation) should be measured at the time of diagnosis of diabetes. If lipid-lowering treatment is not initiated, (see Vascular Protection chapter. p. S100. for indications) repeat testing is recommended yearly. More frequent testing (every 3–6 months) should be performed after treatment for dyslipidemia is initiated [Grade D, Consensus].
  2. 2.For patients with indications for lipid-lowering therapy (see Vascular Protection chapter, p. S100), treatment should be initiated with a statin [Grade A, Level 1 (26,28), to achieve LDL-C ≤2.0 mmol/L [Grade C, Level 3 (40)].
  3. 3.In patients achieving goal LDL-C with statin therapy, the routine addition of fibrates or niacin for the sole purpose of further reducing CV risk should not be used [Grade A, Level 1 (54,55) ].
  4. 4.For individuals not at LDL-C target despite statin therapy as described above, a combination of statin therapy with second-line agents may be used to achieve the LDL-C goal [Grade D, Consensus].
  5. 5.For those who have serum TG >10.0 mmol/L, a fibrate should be used to reduce the risk of pancreatitis (Grade D, Consensus) while also optimizing glycemic control and implementing lifestyle interventions (e.g. weight loss, optimal dietary strategies, reduction of alcohol).

Abbreviations:
apo B, apolipoprotein B; CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC,  total cholesterol; TG, triglyceride.

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