Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #94: Lipid and Lipoprotein Metabolism, Hypolipidemic Agents, and Therapeutic Goals Part 6

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #94: Lipid and Lipoprotein Metabolism, Hypolipidemic Agents, and Therapeutic Goals Part 6

Oct 10, 2017

Nicotinic acid

Nicotinic acid (niacin) has been used for more than 50 years to lower LDL-C and TGs, and increase the level of HDL-C. Indeed, niacin is the most potent HDL-C-raising pharmacologic agent available. Of note, we still, at this late time in the life of niacin, do not have definitive evidence regarding its mechanism(s) at the molecular level [91].

Niacin is available in short-acting and extended-release forms and is typically associated with increases in HDL-C of 15–35%, with 20–35% reductions in TG levels [92]. In contrast, it has a more modest effect on LDL-C levels, with reductions in the range of 10–20%. For this reason, it is not recommended as first-line therapy for LDL-C-lowering. It is, however, suggested for use as monotherapy in individuals with the diabetic lipid phenotype but without concomitant elevations of LDL-C. For people who exhibit elevated LDL-C in addition to abnormal HDL-C and TG levels, niacin can be used in combination with statins, or other LDL-C-lowering agents. Niacin can also reduce levels of lipoprotein (a) between 15–25%.

Despite the array of potentially beneficial effects on plasma lipids, the role of niacin has now been significantly diminished as an agent to prevent CVD. As described earlier, two recent completely negative trials where niacin was added to statin, far outweigh the positive outcome in the Coronary Drug Project (CDP) where niacin was given as monotherapy. In addition, niacin is associated with glucose intolerance and hyperglycemia, particularly at higher doses.The basis for these adverse effects on carbohydrate metabolism appears to result from niacin-induced IR [93]. Increased incident diabetes and worsening of existing diabetes was evident in HPS2-THRIVe [94].

At the present time, niacin treatment should be limited to individuals with familial hypercholesterolemia who do not reach goals on statins and other agents and possibly in statin-intolerant patients at low risk for diabetes. Physicians wishing to use niacin in other situations, that is, in patients with very low levels of HDL-C or high levels of Lp (a), must consider the absence of evidence for benefit.

Bile acid sequestrants (BAS)

This is another class of agents that have long been used in the management of lipid disorders. They have also been successful in monotherapy RCTs for preventing cardiovascular events [95]. In the United States, currently available drugs in this category include cholestyramine, colestipol and colesevelam. BAS lower LDL-C by reducing the enterohepatic return of cholesterol to the liver, leading to increased use of hepatic cholesterol for the bile acid synthesis pathway and consequent lowering of hepatic cholesterol content. The latter leads to upregulation of hepatic LDL receptors, which in turn lowers LDL-C levels. Typical improvements seen with BAS therapy include 15–30% reductions in LDL-C and smaller increases in HDL-C, in the order of 3–5%. In some cases, therapy with agents in this class increases hepatic VLDL production, thereby increasing plasma TG levels and worsening hypertriglyceridemia. These drugs should therefore be avoided in individuals with severe hypertriglyceridemia (TG > 400mg dL−1), and caution should be exercised when considering bile acid sequestrants for LDL-C-lowering in patients with moderately elevated TG levels (TG > 200mg dL−1), a group that encompasses a considerable number of people with T2DM. In addition, BAS should be avoided in patients with DM complicated by autonomic neuropathy and constipation, due to the gastrointestinal side effects associated with these drugs, particularly cholestyramine and colestipol. Use of ezetimibe as an adjunct to statin treatment would depend on whether one believes in the AHA/ACC or the ADA/ACC guidelines for lowering LDL-C.

Over the past several years, there has been a renewed interest in BAS, especially as a potential LDL-C-lowering agent in people with diabetes. Preclinical studies of the role of farnesoid X receptor (FXR) in the regulation of carbohydrate metabolism have raised interest in the glucose-lowering effects of BAS [96]. Of note, glucose levels improved and there were reductions in HbA1c levels in the range of 0.4% in a recent study with colesevelam [97]. Indeed, colesevalem received an indication from the FDA for glucose lowering.

Cholesterol absorption inhibitors

Ezetimibe was the first available agent in a new class of molecules that interferes with cholesterol absorption by selectively inhibiting the uptake of cholesterol from the intestinal lumen at the level of the brush border of the enterocyte; for a number of reasons, it remains the only available agent in this class. A multicenter, randomized, double-blind, placebo-controlled trial demonstrated that ezetimibe 10 mg decreased LDL-C by 17–20% compared with placebo [98]. It has small effects on TG and HDL-C levels; these are significant in some, but not all, studies. Studies in individuals without DM have demonstrated that combined therapy with ezetimibe and a statin produces greater reductions in LDL-C and TG levels, and greater increases in HDL-C, than either therapy alone [99,100]. Several studies have specifically examined the effects of ezetimibe when added to statin therapy in individuals with the MetS and/or T2DM; the results were similar to those observed in groups without DM. Ezetimibe has not been demonstrated to reduce atherosclerosis in combination with a statin. More recently, in the Study of Heart and Renal Protection (SHARP) trial, ezetimibe plus simvastatin significantly reduced CVD events in a population with moderate to severe renal failure; treatment did not, however, reduce progression to dialysis [101]. Use of ezetimibe as an adjunct to statin treatment would depend on whether one believed in the AHA/ACC or the ADA/ACC guidelines for lowering LDL-C.

PPARα agonists

The fibrates are a class of drugs that act as ligands for PPARα receptors. The latter are proteins that, as heterodimers with another protein, retinoid X receptor (RXR), bind to specific DNA sequences in the promoters of genes and activate them. The natural ligands for PPARα are likely to be FAs or their derivatives. PPARα are mainly expressed in the liver and activate genes important for hepatic lipid and lipoprotein metabolism [102]. Two fibrates, gemfibrozil and fenofibrate, are available in the United States. Typically, TG levels are reduced by 35–50% and HDL-C levels are increased by 5–20% with PPARα treatment; greater changes are seen with more extreme baseline abnormalities [103,104]. Three major fibrate monotherapy studies with CV events as the major outcome have included some participants with the MetS and/or T2DM. The Helsinki Heart Study (HHS) was a primary prevention study of hypercholesterolemic subjects in which gemfibrozil treatment reduced CV events by 35% in the overall group of participants [105] and had a similar benefit in the very small group of participants with T2DM [106]. In the VA-HIT trial, a secondary prevention study of men with “normal” LDL-C levels (112mg dL−1), moderately elevated TG levels (160 mg dL−1), and very low levels of HDL-C (32mg dL−1), gemfibrozil treatment was associated with a 22% reduction in MI or CHD death in the overall study group [107] and a similar benefit in the 25% of participants with T2DM [108]. Although these studies support the use of gemfibrozil monotherapy therapy, particularly in subjects with T2DM, its use is limited because most of those individuals will already be treated with statins, and gemfibrozil increases the risk of statin-associated myositis when the two are used in combination. Unfortunately, several additional fibrate trials have failed to reach their primary endpoints. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study was a monotherapy study in individuals with T2DM that enrolled both primary and secondary prevention participants [109]. Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events (CHD death and nonfatal MI) compared to placebo; nonfatal MI was reduced, but CHD death was unchanged. A potential confounder of the FIELD study was an imbalanced statin “drop-in;” by the end of the study, nearly 40% of subjects in the placebo group had been exposed to statins, while only 20% of the fenofibrate group were treated with statins at some point in the study. Additional disappointment concerning the role of PPARα agonists derive from the overall results of the ACCORD Lipid Trial where fenofibrate therapy did not significantly reduce the primary CVD outcome when added to simvastatin treatment [60]. Thus, despite a subgroup analysis suggesting a dramatic (28%) benefit in 17% of the patients with baseline TG levels in the upper tertile (>204 mg dL−1) and the lower tertile of HDL-C levels (<34 mg dL−1), which parallels similar subgroup findings in fibrate monotherapy trials, a study specifically targeting such individuals will have to be successful before recommendations for combination therapy with fibrate and statin can be recommended. Very recently, aliglitazar, a dual PPARα/γ agonist, also failed to reduce CVD events in a population with T2DM [110]. At this time, therefore, PPAR agonists do not have evidence-based roles in the prevention of CVD in T2DM. At the time this chapter was being written, the VA Hospital System was planning to perform an RCT based on ACCORD, with all participants having TG >200 and HDL <35 mg dL−1 while on statin monotherapy.

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