V. Evaluation and Treatment of Low HDL-C

objective

Reduce risk of CVD through raising the level of HDL-C.

background

Causes of low HDL-C include genetic factors, elevated serum TGs, overweight and obesity, physical inactivity, cigarette smoking, very high carbohydrate intake, diabetes, and certain drugs (NCEP ATP-III, 2002).

Large epidemiologic trials have shown that a low HDL-C is associated with an increased risk for CHD, and thus, it is classified as a major risk factor for CHD.  Despite these observations, the independent contribution of low HDL-C to CHD risk is complex, as it is usually associated with other metabolic factors such as diabetes, metabolic syndrome, and other atherogenic dyslipidemias that also increase CHD risk.  In addition, clinical trials targeting low HDL-C also affect other lipid parameters that influence CHD risk.  Nonetheless, patients with low HDL-C should have non-pharmacologic as well as pharmacologic interventions aimed at increasing its level, depending on underlying risk for CHD events.

recommendations

1. Patients with CVD who have low HDL-C (<40 mg/dL), TG >200 mg/dL and normal levels of LDL-C may benefit from gemfibrozil therapy.  [A]
2. Lifestyle modifications, including weight loss, exercise, and smoking cessation should be given high priority in the therapeutic plan for patients with low HDL-C.  [B]
3. CVD patients with low HDL-C (<40 mg/dL), may be considered for treatment with niacin.  [B]

Table 10.  Drug Treatment for Isolated Low HDL-C

LDL-C <130 and Low HDL-C
Drug	Efficacy (Expected % Reduction in TG)
Gemfibrozil	LDL-C +10 to –35	HDL-C +2 to 34

 

discussion

Multiple epidemiologic studies, including the Framingham Study, have observed an inverse relationship between HDL-C levels and risk for CVD, where a difference of one mg/dL is associated with a 2-3 percent change in risk (Gordon et al., 1989).  In the Framingham Study, for instance, men with an HDL lower than 25 mg/dL had an incidence of CHD of 176.5/1000, compared to an incidence of 100/1000 in men with an HDL-C of 25 to 34 mg/dL.  Likewise, women with an HDL-C of 25 to 34 mg/dL had an incidence of CHD of 164.2/1000, compared to 54.5/1000 in women with an HDL of 35 to 44 mg/dL.  The importance of low HDL as a risk factor for developing CHD was borne out in the AFCAPS/TexCAPS trial, in which the most significant benefit was seen in patients treated with an entry HDL lower than 35 mg/dL (Downs et al., 1998).  Just as a low HDL level is inversely linked to an increased risk for developing CHD, a high HDL level is inversely linked to a decreased risk for developing CHD (Wilson et al., 1998). It has been established that the protective effect of a high HDL is present even in the setting of a high LDL (Kannel, 1995).

There are relatively few trials targeting low HDL-C.  Most important is VA-HIT (Robins et al., 1999), which randomized patients with established CVD, and HDL-C <40 mg/dL, and LDL-C <140 mg/dL to either gamfibrozil, or placebo.  Mean entry HDL-C was 32 mg/dL, and LDL-C was 111 mg/dL.  After a mean follow-up of five years, the gemfibrozil treatment arm had a 22 percent relative risk reduction in the combined end-point of nonfatal MI or death due to CVD, and a 25 percent reduction in stroke.  The study was not statistically powered to detect overall mortality benefit.  Subgroup analysis of VA-HIT strongly suggests that CHD patients with low HDL-C, TGs >200 mg/dL, HTN, or impaired glucose tolerance were particularly likely to benefit from gemfibrozil therapy.

More recently, a small study of U.S. military retirees with known CHD assessed a strategy aimed at increasing HDL-C (Whitney et al., 2005).  The intervention of a 3-drug regimen of gemfibrozil, niacin, and cholestyramine was associated with a 26 percent decrease in a composite endpoint of all CV endpoints.  However, in addition to a 36 percent increase in HDL-C, there was a 26 percent decrease in LDL-C level, thus confounding the interpretation of the benefit associated with increasing the levels of HDL-C.

Niacin reduces LDL-C by up to 25 percent in a dose-dependent manner.  To reduce the risk of hepatotoxicity, the dose of extended- and sustained-release forms of niacin is limited to 2g/d, which reduces LDL-C by 15-20 percent.  Immediate-release niacin can be titrated to 3 g/d (or more) and can reduce LDL-C in the 20-25 percent range.  While niacin’s LDL-C lowering is linear, its effect on TGs and HDL-C is curvilinear.  Modest doses of niacin can significantly alter these two lipid levels.  For example, one g/d of immediate-release niacin can increase HDL-C by 25-30% and reduce TGs by a similar margin.  Niacin is the most effective drug available for raising HDL-C.  It also lowers lipoprotein (a) by about 30 percent.

The effect of various agents on HDL-C was evaluated in other randomized, placebo-controlled trials involving patients with isolated low HDL-C.  In an 8-month study of 22 normolipidemic men with reduced HDL-C levels, Vega and Grundy (1989) reported a 9 percent increase in HDL-C (from 0.78 to 0.85 mmol/L) with gemfibrozil therapy, which was significantly different from placebo.  In a 3-month study of 14 men with low levels of HDL-C but desirable TC, Miller et al. (1993) reported a 9 percent increase in HDL-C with gemfibrozil versus placebo.  In a report by Lavie and colleagues (1992), 3 months of treatment with sustained-release niacin resulted in a 27 percent increase in HDL-C compared with placebo in 19 men with coronary artery disease (CAD) and very low levels of HDL-C (<35 mg/dL).  Unmodified (crystalline) niacin given for 12 weeks achieved a 31 percent increase in HDL-C compared with controls (no treatment) in 15 men with low HDL-C. (King et al., 1994).  Three months of treatment with phenytoin in 37 male and 2 female nonepileptic subjects with low HDL-C levels resulted in a 12 percent increase in HDL-C versus dietary baseline (Miller et al., 1995).

Lifestyle Modification to Raise HDL-C

Nonpharmacologic interventions should be attempted in all patients with low HDL-C.  HDL-C levels are affected by lifestyle modifications, including weight reduction, smoking cessation, and exercise.  Weight loss, exercise, and smoking cessation should be given high priority in the therapeutic plan for all these patients.

Aerobic exercise, such as running, increases HDL-C levels in a dose-dependent manner.  Studies have shown that regular exercise is associated with increased levels of HDL-C (Haskell et al., 1988; Kokkinos et al., 1995; Superko & Haskell, 1987).  A clear dose-response relationship was observed between aerobic exercises (running) and HDL-C concentrations (Wood et al., 1991).  Comparing six groups of runners based on the mean number of miles run per week (0, 5, 9, 12, 17, and 31) the mean HDL-C level was found to increase by 0.308 mg/dL with each 1-mile increase in running distance.  Furthermore, mean HDL-C levels were significantly higher in those who ran 12 or 17 miles per week versus nonrunners and those who ran 5 miles per week, and were significantly higher in those who ran 31 miles per week versus all of the other groups.

HDL-C levels in smokers are 7 to 20 percent lower than those in nonsmokers (Cullen et al., 1998).  In one small RCT (Moffatt, 1988) subjects who stopped smoking for 60 days raised HDL-C levels by 5.7 mg/dL by day 30 and by an additional 6.8 mg/dL by day 60, reaching 63.9 mg/dL.  In contrast, HDL-C levels in re-smokers (stopped smoking for 30 days and resumed smoking thereafter) returned to pre-cessation values (50.7 mg/dL) by day 60.  Before smoking cessation, all smoker had HDL-C levels that were 15 to 20 percent lower than those of the nonsmokers.  Other studies, however, have shown less of an effect of smoking on HDL-C levels, e.g., the Münster Heart Study [PROCAM; 1998], in which mean HDL-C levels were reduced by 6.4 percent in male smokers and by 6.7 percent in female smokers versus nonsmokers.

Dattilo and colleagues meta-analysis of 70 studies (published between 1966 and 1989) found a consistent linear association between weight loss and HDL-C concentrations in both men and women.  For every 3 kg (7 lb) of weight loss, HDL-C levels increased 1 mg/dL when weight reduction was maintained (Dattilo & Kris-Etherton, 1992).  Wood and colleagues (1988) demonstrated in a 1-year randomized controlled study that losing fat weight through dieting, or through exercise (primarily running) significantly increases plasma concentrations of HDL-C and decreases levels of LDL-C but not significantly so.

Dietary modifications also affect HDL-C levels.  Low-fat diets, in addition to reducing LDL-C levels, lower HDL-C levels in all patients.  Alcohol use increases HDL-C in a dose-dependent manner, whereas caloric restriction acutely lowers HDL-C concentrations.  Although there continues to be debate about the optimal dietary and lifestyle modifications necessary to reduce coronary heart disease, there is a consensus that smoking cessation, exercise, weight reduction, and a reduction in saturated fat intake will benefit most individuals.