Therapeutic approaches to the dyslipidemia of insulin resistance and type 2 diabetes mellitus
Key points: The rationale for treating the diabetic dyslipidemia is clear, it is associated with significantly increased risk of cardiovascular events.Weight loss, exercise, and diet modifications are key to successful treatment of all of the lipid abnormalities in patients with T2DM. Statins are the mainstay of therapy—they lower LDL cholesterol up to 50%, lower triglycerides about 15–25%, and have minimal effects of HDL cholesterol levels.
Statins significantly lower cardiovascular events in people with diabetes. Benefits of treatment of high triglycerides and low levels of HDL cholesterol after reaching optimal treatment status with statins is unclear. Rationale for treating LDL Over the past 50 years, results from epidemiologic studies, animal models, and clinical trials have clearly demonstrated that elevated LDL-C is a major risk factor for CV morbidity and mortality . In addition, it has been demonstrated that aggressively lowering LDL-C levels can decrease CV risk . As a result, a system of guidelines for LDL goals for therapy developed over the past 25 years; a quick review of the progression of these guidelines was published recently . Beginning in 2004, there had been a push to drive LDL-C goals lower and lower with the hope that this would lead to an improvement in CV outcomes. In fact the NCEP issued a “white paper” suggesting an even lower LDL-C goal of <70mg dL−1 for patients at very high CV risk , and this was reiterated in the 2006 AHA/ACC guideline paper .
These reports were based in part on data from the Treating to New Targets (TNT) study, which demonstrated that intensive therapy with atorvastatin 80 mg compared with atorvastatin 10mg significantly reduced the rate of major CV events by 22%. In TNT, the end-of-treatment mean LDL-C levels were 98.6mg dL−1 and 77 mg dL−1 with atorvastatin 10mg and 80mg, respectively . The results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE-IT–TIMI 22) study , in which patients with acute coronary syndrome who had their LDL-C levels reduced to 62mg dL−1 fared better than those patients whose LDL-C was 95mg dL−1, support the TNT results.
Statin trials have also been conducted specifically in patients with T2DM. In the Collaborative Atorvastatin Diabetes Study (CARDS) trial, treatment with atorvastatin resulted in a significant reduction in major CV events irrespective of pretreatment cholesterol levels . On the other hand, the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN), which randomized patients with T2DM to receive 10mg of atorvastatin or placebo in a 4-year study, did not demonstrate a significant reduction in the primary composite endpoint of CV death with atorvastatin treatment . Several post hoc, subgroup analyses of large trials not specifically targeted to diabetics did show similar benefit in the latter groups; they will be reviewed further in this chapter.
The very recent AHA/ACC guidelines  suggested, however, major changes in the way healthcare professionals should lower blood cholesterol levels to reduce cardiovascular disease. A strong point was the change in the use of initial LDL-C levels as the approach to initiation of treatment to identification of four groups of individuals whose risk was high enough to be considered for statin therapy: those with LDL-C >190mg dL−1; those with prior CVD; those with diabetes and LDL-C ≥70≤190mg dL−1; those without CVD or diabetes but an LDL-C ≥70≤190mg dL−1 who have a 10-year risk for CVD ≥7.5%. The new guidelines do not use MetS as a criteria for statin therapy. Clearly, the presence of diabetes is a major factor in these new guidelines. The new guidelines then declared that there were no data from randomized clinical trials (RCTs) to support the use of LDL-C goals to determine the intensity of treatment. The guidelines panel concluded that use of statins was supported strongly by RCT results and that high-intensity treatment was appropriate in most cases, particularly in patients with diabetes. However, the panel found no evidence for the use of non-statin drugs as “add-on” treatment to statins . The new guidelines have, as may be expected, generated significant controversy. In particular, the conclusion that there is no evidence that “lower is better” is thought by some to fly in the face of the trials noted above in this section as well as the meta-analyses of the statin trials , epidemiologic data, animal-based studies, and natural genetic examples.
Rationale for treating HDL and TG
While LDL-C remains a primary target of cholesterol-modifying therapy for the primary and secondary prevention of CVD in the general population and among people with DM,HDL-C and TG have been given high importance, especially in higher risk individuals [25,47].The characteristically elevated TG levels and decreased HDL-C with IR, in the presence or absence of T2DM [2,3,5] led to the recommendation that non-HDL-C (total cholesterol – HDL-C) be considered a surrogate marker for the apo B100-containing lipoproteins [57,58]. The new AHA/ACC guidelines  concluded, however, that there is no evidence to target either LDL-C or non-HDL-C. The new guidelines also stated that other targets, such as TG or HDL-C have no support based on RCT; in fact, data from two trials where niacin was added to statins, Aim High  and HPS2-THRIVE (not yet published), and one in which fenofibrate was added to statin therapy, ACCORD , indicate no overall benefit compared to patients treated with statins alone.The ADA on the other hand, emphasizes the prime importance of attaining target LDL-C levels, but employs a different approach to the management of TGs and HDL-C (Table 17.1). The ADA guidelines recommend lowering TG levels to <150mg dL−1 and include gender-specific HDL-C goals; namely, >40 mg dL−1 in men and >50mg dL−1 in women [61–63].
With the AHA/ACC and ADA guidelines at odds, it is valuable to review the rationale for treatment to improve HDL-C levels in people with IR or T2DM. First, there is evidence from numerous epidemiologic studies in which low HDL-C is an independent predictor of CHD morbidity and mortality, including studies involving large numbers of people with IR or T2DM . Second, evidence from prospective intervention trials and secondary analyses has suggested a benefit of raising HDL-C levels on the risk of CHD events, independent of changes in other lipid and nonlipid risk factors . Of note, a post hoc analysis of the Bezafibrate Infarction Prevention (BIP) Study focusing on the subgroup of participants with the MetS revealed a reduced incidence in MI associated with significant improvements in HDL-C and TG levels . Furthermore, in that analysis a cardiac mortality benefit was demonstrated among subjects having “augmented” (i.e., four or five) features of The MetS, as defined by the ATP III. In VA-HIT, where increases in HDL-C were predictive of reductions in CV endpoints in the group treated with gemfibrozil , the greatest overall benefit of treatment was observed in subgroups with IR, with or without T2DM. On the other hand, the recent negative niacin trials, Aim High  and HPS2-THRIVE, do not support the use of adding niacin to statin therapy. A subgroup, post hoc analysis of Aim High did suggest, nonsignificantly, that participants with high TG and low HDL-C at baseline did benefit .
Data regarding the independent effects of plasma TG levels on CHD risk are even more controversial, partly due to the close interrelationships between levels of TGs and the atherogenic apo B-containing lipoproteins. TG levels have nevertheless been shown to predict CHD risk in observational studies . However, in the largest cohort study to date, Danesh and colleagues found that while TG was a strong predictor of CVD outcomes in more than 300,000 people, it lost all predictive power after adjustments for both HDL and non-HDL cholesterol .
One could argue, however, that adjustment for non-HDL, which contains cholesterol carried in TG-rich lipoprotein, is not a valid approach. In several clinical trials, stratification of individuals by TG and HDL-C levels has revealed higher risk subgroups with dyslipidemia that have benefited most from LDL-C-lowering interventions with respect to CHD risk reduction . The FIELD Trial, in which 10,000 diabetics were randomized to placebo or fenofibrate, did not show an overall CVD benefit for the fenofibrate-treated group. However, a subgroup with baseline TG over 200 mgdL−1 and HDL-C less than 40mg dL−1 showed a 30% reduction in the combined primary endpoint of CAD death and nonfatal myocardial infarction . Similarly, in the ACCORD Lipid Trial, which was negative overall, 17% of the subjects with baseline TG in the upper tertile (>200mg dL−1) and HDL-C in the lower tertile (<34mg dL−1) had a 28% reduction in the primary endpoint of nonfatal myocardial infarction, nonfatal stroke, and CVD death . On the other hand, no clinical trials thus far have demonstrated an independent relationship between TG-lowering and CHD risk reduction, including VA-HIT, where TG levels fell 31%.
As mentioned earlier, it is worth noting that postprandial lipemia has been associated with CAD in individuals without DM, whereas the evidence is less convincing or absent in individuals with IR or DM.Data from two cross-sectional studies do not support an association between postprandial lipemia and the presence of CAD among people with T2DM .
Another small study suggests that postprandial numbers of small remnant particles may contribute to the severity of angiographic CAD in T2DM . Larger prospective studies are needed before recommendations can be made regarding the potential utility of postprandial hyperlipidemia as a predictor of CV risk in IR or DM. This, along with the lack of simple, clinically useful uniform measures of postprandial lipemia, explains the lack of guidelines for therapy of postprandial hyperlipidemia.