Thursday, March 30, 2023
| Risk Factor | Cutpoint |
|---|---|
| Abdominal obesity | |
| Men | Waist circumference ≥ 40 inches |
| Women | Waist circumference ≥ 35 inches |
| Elevated triglycerides | ≥ 150 mg/dL |
| Low HDL cholesterol: | |
| Men | < 40 mg /dL |
| Women | < 50 mg/dL |
| Elevated blood pressure | ≥ 130 / ≥ 85 mm Hg |
| Elevated fasting glucose | ≥ 110 mg/dL |
Table 1. ATP III Diagnostic Criteria for Metabolic Syndrome[37]
| Risk Factor | Cutpoint |
|---|---|
| Abdominal obesity | |
| Men | Waist circumference ≥ 40 inches |
| Women | Waist circumference ≥ 35 inches |
| Elevated triglycerides | ≥ 150 mg/dL |
| Low HDL cholesterol: | |
| Men | < 40 mg /dL |
| Women | < 50 mg/dL |
| Elevated blood pressure | ≥ 130 / ≥ 85 mm Hg |
| Elevated fasting glucose | ≥ 110 mg/dL |
Table 1. ATP III Diagnostic Criteria for Metabolic Syndrome[37]
| Risk Factor Component | Cutpoint for Abnormality |
|---|---|
| Overweight/obesity | BMI ≥ 25 kg/m2 |
| Elevated triglycerides | ≥ 150 mg/dL |
| Low HDL-C | |
| Men | < 40 mg/dL |
| Women | < 50 mg/dL |
| Elevated blood pressure | ≥ 130/85 mm Hg |
| 2-hour postglucose challenge | |
| Other risk factors | Family history of type 2 diabetes, hypertension, or cardiovascular disease |
| Polycystic ovary syndrome | |
| Sedentary lifestyle | |
| Advancing age | |
| Ethnic groups having high risk for type 2 diabetes or cardiovascular disease |
Table 2. AACE Diagnostic Criteria for the Insulin Resistance Syndrome*[37]
AACE = American Association of Clinical Endocrinologists; BMI = body mass index
*Diagnosis depends on clinical judgment, which is based on risk factors.
| Parameter | Mean (SD) | |
|---|---|---|
| Metabolic Syndrome (n = 194) |
No Metabolic Syndrome (n = 382) |
|
| LDL-C, mg/dL | ||
| Baseline | 187 (20) | 186 (18) |
| Week 12 | 99 (31) | 96 (25) |
| % change | -47 (15) | -48 (12) |
| HDL-C, mg/dL | ||
| Baseline | 44 (9) | 54 (13) |
| Week 12 | 49 (11) | 58 (14) |
| % change | +10 (13) | +9 (12) |
| Triglycerides (mg/dL) | ||
| Baseline | 216 (60) | 155 (57) |
| Week 12 | 167 (64) | 122 (50) |
| % change | -23 (20) | -19 (24) |
| Non-HDL-C (mg/dL) | ||
| Baseline | 230 (23) | 217 (21) |
| Week 12 | 132 (35) | 120 (27) |
| % change | -43 (14) | -45 (12) |
| Non-HDL-C/HDL-C ratio | ||
| Baseline | 5.4 (1.2) | 4.2 (1.0) |
| Week 12 | 2.8 (1.1) | 2.2 (0.8) |
| Δ % | -47 (15) | -48 (13) |
| ApoB (mg/dL) | ||
| Baseline | 182 (22) | 173 (20) |
| Week 12 | 115 (26) | 106 (21) |
| % change | -37 (14) | -38 (12) |
| ApoA-I (mg/dL) | ||
| Baseline | 141 (23) | 155 (25) |
| Week 12 | 150 (25) | 164 (27) |
| % change | +7 (13) | +6 (12) |
| ApoB/ApoA-1 ratio | ||
| Baseline | 1.3 (0.3) | 1.1 (0.2) |
| Week 12 | 0.8 (0.2) | 0.7 (0.2) |
| % change | -40 (15) | -41 (13) |
Table 3. Baseline and Week 12 Lipid Levels and Percent Change From Baseline in Patients With Hypercholesterolemia Treated With Rosuvastatin 10 mg
Reproduced with permission from Ballantyne et al.[57] Copyright 2004. Elsevier Science.
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If patients with metabolic syndrome are given an adequate trial of lifestyle change but persist with behaviors that put them at higher risk, consideration can be given to controlling particular risk factors with drugs. Thus, hypertension may require blood pressure-lowering drugs, and the presence of diabetes likely will call for glucose-lowering drugs. If the 10-year risk for CHD, as determined by Framingham risk scoring, is ≥ 10%, low-dose aspirin to prevent acute coronary syndrome will be indicated unless there are complications. Finally, consideration should be given to lipid-lowering drugs in those patients with elevated cholesterol or with atherogenic dyslipidemia (high triglycerides and low HDL-C). The following reviews the current status of lipid-lowering drugs in patients with the metabolic syndrome.
HMG-CoA reductase inhibitors are the most potent LDL-C-lowering medications. They act by inhibiting cholesterol synthesis in the liver. Statin monotherapy and/or adjunctive regimens involving fibrates (preferably fenofibrate) and niacin may also lower CRP levels, fibrinogen, and other proinflammatory and prothrombotic indices.[48-51]
The chief hypotriglyceridemic effects of fibrates are attributed to these agents' ability to enhance catabolism of triglyceride-rich particles and reduce VLDL output.[52] Fibrates raise HDL and lower triglycerides by activating PPAR-alpha, with upregulated expression of apoA genes and reduced expression of genes for apoC-III, PAI-1, and fibrinogen. Fibrates also increase expression of the gene for lipoprotein lipase, which renders sdLDL particles larger and less dense (ie, less atherogenic).
Fibric-acid derivatives also stimulate cellular FFA uptake, conversion of FFAs to cholesteryl esters, and FFA catabolism by beta-oxidation pathways. These effects are mediated by binding of fibrates to PPAR-alpha receptors in the liver. Bezafibrate, which has been termed a "PPAR panagonist,"[53] is evidently a weak ligand for PPAR-gamma receptors on adipocytes to which the more potent insulin sensitizers (eg, thiazolidinediones [TZDs]; glitazones) bind; this receptor activity may partly explain the beneficial effects of bezafibrate on both glycemic regulation and BMI.[53] (Bezafibrate is not currently approved for use in the United States.) On the other hand, fenofibrate therapy does not bind to PPAR-gamma and thus does not improve glucose tolerance or FFA concentrations or turnover.[54] Niacin reduces FFA mobilization from adipocytes and reduces hepatic VLDL output.
Statins. A series of major clinical trials with statin therapy have documented the benefit of LDL-C-lowering therapy in reducing cardiovascular risk in many types of patients at high risk or moderately high risk.[55,56] The most recently approved drug in this class is rosuvastatin. In 5 multicenter open-label trials involving a total of 580 patients, treatment with low-dose rosuvastatin (10 mg) for 12 weeks significantly improved the lipid panel from baseline. Rosuvastatin lowered LDL-C and the non-HDL-C/HDL-C ratio by 47%, non-HDL-C by 43%, and triglycerides by 23% while increasing HDL-C by 10%).[56] Low-dose rosuvastatin also raised apoA and lowered apoB levels. Lipid benefits were of similar magnitude in 194 patients (33%) with the metabolic syndrome,[53] according to modified ATP III definitions, compared with 382 patients without metabolic syndrome ( Table 3 ). A total of 55% of patients with triglyceride level ≥ 200 mg/dL met their non-HDL-C goals following treatment with rosuvastatin 10 mg.
A subanalysis of 212 (26.2%) patients with metabolic syndrome (by modified ATP III definitions)[54] showed that treatment with atorvastatin 80 mg for 36 weeks lowered LDL-C by 50%, non-HDL-C by 47%, triglycerides by 32%, and the total cholesterol/HDL-C ratio by 40%. By comparison, simvastatin 80 mg lowered these parameters by 49%, 45%, 27%, and 42%, respectively. As has been observed in other clinical trials, simvastatin 80 mg raised HDL-C to a greater extent (+9%) than did atorvastatin 80 mg (+3%). Following treatment with either agent, ~48% of patients with metabolic syndrome at baseline no longer met ATP III definitions.
Fibrates. A series of clinical trials have shown that fibrate therapy will reduce the risk of CHD.[57] Of note is the Veterans Affairs HDL Infarction Trial (VA-HIT), which showed that gemfibrozil reduced the risk for major cardiovascular events in high-risk patients, particularly in those with diabetes and insulin resistance.
An intriguing analysis of the placebo-controlled Bezafibrate Infarction Prevention (BIP) study in CHD patients was reported recently by an Israeli group.[53] A total of 303 nondiabetic patients with a history of CHD and impaired fasting glucose (FBG = 110-125 mg/dL) but not type 2 diabetes received bezafibrate 400 mg (n = 156) or placebo (n = 147) daily and were monitored for ~6 years. Ongoing statin use was prohibited. In the overall BIP trial, bezafibrate significantly lowered all-cause and cardiac mortality only in patients with triglyceride level ≥ 200 mg/dL. Among the subgroup with impaired fasting glucose, 42% of bezafibrate patients developed type 2 diabetes compared with 54% of placebo controls (P = .04). Bezafibrate treatment also significantly delayed the onset of type 2 diabetes (P = .004); the mean delay was ~10 months. Treatment with the fibrate increased HDL-C by 16% and lowered triglycerides by 24%.
Notably, patients receiving bezafibrate also had significantly lower FBG and BMI values compared with those receiving placebo.[53] The improvements in glycemic regulation and BMI may be attributable to effects of bezafibrate on adipocyte PPAR-gamma receptors, for which insulin sensitizers (TZDs; glitazones) are also ligands. One potential pitfall with fibrate therapy is an increase in LDL-C in some patients.[58]
Statin-fibrate combinations. In a recent 3-phase, randomized, crossover trial,[59] 20 patients with metabolic syndrome by modified ATP III definitions and combined hyperlipidemia (LDL-C > 160 mg/dL and triglycerides 200-800 mg/dL) were treated daily with placebo, simvastatin 10 mg, or simvastatin 10 mg plus fenofibrate 200 mg. Each of these 3 treatment phases lasted 3 months. In this study, the following results were reported:
|
Niacin. Niacin, alone or in combination with statins, has been utilized in a number of studies involving patients with type 2 diabetes. In general, niacin increases HDL-C to the greatest extent of all available monotherapies: from 15% to 35% at higher daily doses on the order of 3 grams.
High-dose niacin can worsen glucose disposal, so lower doses (≤ 2 grams per day) are considered prudent.[60] (By different mechanisms, both high-dose diuretics and beta-blockers can also adversely affect glycemic regulation in patients with hypertension.) Fixed-dose combinations of extended-release niacin with lovastatin are commercially available.
Because either fibrates (particularly gemfibrozil) or niacin can increase the risk of statin myopathy, prescribers are urged to carefully weigh the benefits of combined treatment against its risks. This warning is a class label for the statins, although the issue of different myopathic risks with different statins or fibrates is an area of considerable debate. Concomitant administration of fenofibrate plus rosuvastatin did not increase the systemic exposure of either agent in a study reported by Garg and Grundy, and the regimen was well tolerated.[61] Regular monitoring of muscle and liver enzymes, particularly during the first months of statin or statin combination therapy, is mandatory.
