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Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #93: Lipid and Lipoprotein Metabolism, Hypolipidemic Agents, and Therapeutic Goals Part 5

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #93: Lipid and Lipoprotein Metabolism, Hypolipidemic Agents, and Therapeutic Goals Part 5

Treatment options

Diet and lifestyle modification

Appropriate lifestyle interventions involving diet and exercise can lead to weight loss, and since obesity is a major contributor to the IR and T2DM, weight loss should provide significant benefits to individuals with these problems. The Diabetes Prevention Program [74] demonstrated that a 6% weight loss and the addition of two hours of exercise per week was associated with a 58% reduction in the incidence of new T2DM in a group with IGT. Similar results were obtained in the Finnish Diabetes Prevention Study using similar interventions [75].

The 1-year results of Look AHEAD (Action for Health in Diabetes), a study of weight loss and diet in overweight and obese individuals, reported that intensive lifestyle intervention resulted in clinically significant weight loss in people with T2DM [76]. Participants in the intensive lifestyle intervention group achieved an average loss of 8.6% of initial body weight and a 21% improvement in CV fitness. These participants had a significantly greater decrease in the number of medicines used to treat their DM and blood pressure as well as a greater improvement in glycemic control when compared with participants receiving only diabetes support and education. These results, for the most part, withstood the demands of a 10-year follow-up, although the primary endpoint, decreased mortality in the intensive intervention group, was not reached [77]. In addition to simply reducing caloric intake, interventions that alter the nutrient composition of the diet may have benefits on risk factors for CVD and T2DM. There has been much debate, however, both in the popular press and in the medical community, regarding which diet strategy is most effective for both weight loss and reductions in CV risk. Conclusions that may be drawn from these diet interventions must be considered with the following caveat: We do not know if the changes that we see in plasma TG levels and, in particular, in HDL-C concentrations, are indicative of changes in risk for CVD.We are, in fact, extrapolating from large epidemiologic databases that show that increased TG and reduced HDL-C levels are associated with increased CV risk; this extrapolation remains to be proven in a clinical trial with dietary intervention.

Pharmacologic therapy

Before discussing in detail specific pharmacologic therapies, it is important to note that improving glycemic control in T2DM can result in mild to modest improvement in the dyslipidemia of diabetes.This is particularly true for hypertriglyceridemia in the setting of poor glycemic control; furthermore, the degree of TG-lowering may be related to the magnitude of improvement in glycemia. Concomitant with optimization of glucose control, therapeutic lifestyle changes (TLC), including dietary modification, weight reduction, and regular physical activity, should be initiated prior to, or simultaneously with, pharmacologic therapy. Pharmacologic therapy for dyslipidemia should be considered in the context of these changes [61,63,78]. Additionally, it must be noted that the new AHA/ACC guidelines for the treatment of cholesterol support the use of statins in several high-risk groups but do not support additional medications in combination with statins [56]. The new guidelines do allow non-statin drugs for patients intolerant to statins and for individuals with initial LDL-C levels greater than 190mg dL−1 (usually with familial hypercholesterolemia). It is noteworthy that the ADA/ACC guidelines for the management of lipoproteins in patients with cardiometabolic risk (which includes people with diabetes), while supporting the addition of non-statin drugs for people not at LDL-C goal on statin monotherapy, provided little support for non-statin drugs for the treatment of TG and HDL-C abnormalities [63].

3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors

The HMG CoA reductase inhibitors, or “statins,” are the most effective pharmacologic agents for reducing LDL-C concentrations and should be considered first-line therapy for this purpose, both in individuals with and without T2DM [48,63]. Several agents are available for clinical use, including lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, and pitavastatin. As a class, they produce LDL-C reductions of 18–55%, with more modest changes in HDL-C and TG levels (5–15% elevations and 7–30% reductions, respectively) [79]. The new AHA/ACC guidelines suggest high-intensity statin therapy for most individuals with diabetes.

ITDM-Table17.2The effectiveness of statin therapy in primary and secondary CV risk reduction in both the general population with hypercholesterolemia and in people with diabetes is extremely strong (Table 17.2) [48,62]. Included in the meta-analyses were data from the following trials: The CARDS, a primary prevention study of 2838 participants with T2DM, demonstrated a statistically significant 37% reduction in major CV events among participants on low-dose atorvastatin treatment [54]. The Medical Research Council/British Heart Foundation Heart Protection Study (MRC/BHF HPS) included a large cohort of participants with T2DM, approximately half of whom had no evidence of existing coronary or other occlusive arterial disease [80]. Simvastatin therapy produced substantial reductions in the risk of coronary events, stroke and revascularizations in participants with DM, irrespective of pre-existing occlusive arterial disease or lipid concentrations. Further support was added by a subgroup analysis of the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, which demonstrated a reduction in CV events, including stroke, in participants with IFG or T2DM and established CHD [81]. Moreover, the absolute risk reductions seen in those with IFG or T2DM were greater than those seen in the overall study population.These findings were supported and extended by the results of post hoc analyses of participants with IFG or DM in the Scandinavian Simvastatin Survival Study (4S) [82]. Another post hoc analysis demonstrated an increased risk of CHD events and greater benefit with simvastatin therapy among 4S participants with low HDL-C and elevated TG accompanying elevated LDL-C levels at baseline, compared with participants with isolated elevations in pretreatment LDL-C [71]. The Cholesterol and Recurrent Events (CARE) trial demonstrated a beneficial effect of pravastatin treatment on coronary outcomes in the overall study population as well as in the subgroups with DM or IFG, the latter being defined in that study by fasting glucose levels between 110 to 125 mg dL−1 [83]. Finally, a post hoc analysis of the TNT study that examined those participants who met the ATP III criteria for the MetS, but excluded individuals with T2DM, suggested an incremental benefit of high-dose atorvastatin therapy in this group [84].

The ASPEN trial, which included primary and secondary prevention participants, did not, however, demonstrate a significant reduction in the primary composite endpoint with atorvastatin [55]. The negative finding was attributed to certain features of the study design, as well as to changes in lipid treatment guidelines during the course of the study that necessitated protocol changes. Similarly, statin therapy did not impart a benefit with regard to coronary events in the subgroup of participants with T2DM in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA) [85]. The lack of benefit was ascribed to a low coronary event rate, a result stemming in part from the early cessation of the trial because of a marked benefit of statin therapy in the general study population. In the nonblinded Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT), the lack of effect with pravastatin therapy in participants with T2DM is believed to be due to the high usage of lipid-lowering therapy in the “usual care” control group, resulting in a smaller differential in LDL-C levels between the statin and control groups compared with that seen in other large statin trials [86].

A recent issue that must be addressed is how to balance aggressive statin treatment with recent data indicating an increase in risk for new diabetes in individuals receiving statins in large clinical trials. Although an early report from the WOSCOPS suggested that statins may prevent incident diabetes, JUPITER found the opposite, with a rate of incident diabetes of 30% in the rosuvastatin group versus 2% in the placebo group [87]. Several meta-analyses since then have indicated that statin treatment is associated with about a 9% increase in new diabetes [88] and that this risk is greater in people receiving higher doses of statins [89] as well as in people with more criteria for the MetS [90]. The meta-analyses presented to date do not suggest heterogeneity in the effects of different statins on incident diabetes, although some small, short-term studies indicate that certain statins may be less likely to raise blood glucose or HbA1c levels. In any event, it is clear that the benefit of statins in lowering CVD events far outweighs the risk of new onset T2DM in high risk and secondary prevention patients. Obviously, a risk for new onset diabetes is not relevant in people with diabetes, but health professionals should consider these new data because they indicate that control of existing diabetes is likely to worsen modestly due to long-term statin therapy.

Many “lipid/diabetes experts” believe that the greatest potential value of statin therapy in the treatment of the dyslipidemia of T2DM would be in combination with other lipid-modifying agents. This would clearly be the case when LDL-C-lowering to levels below 70mg dL−1 is considered an appropriate goal, for example, in patients with T2DM who have CVD or multiple poorly controlled risk factors [50].This view is now dependent on whether one accepts the newest AHA/ACC guidelines [56] or the ADA/ACC guidelines [63]. For those following the ADA recommendations, LDL-C below 79mg dL−1 may be attained through up-titration of statin doses or through combination with other agents, such as plant stanol and sterol esters, bile acid-binding resins and inhibitors of enteral cholesterol absorption. However, neither guideline give much support for the addition of niacin or peroxisome proliferator-activated receptor α (PPARα) agonists to statins.

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