1. Major classes of drugs to reduce lipids
Content Points:
There are five major types of lipid-lowering drugs discussed in the current NCEP guidelines.
They are bile acid sequestrants (resins); nicotinic acid (niacin); HMG-CoA reductase inhibitors (statins); fibric acid derivatives (fibrates); and estrogen replacement therapy.

2. Cholesterol biosynthetic pathway
Content Points:
The newest class of lipid-lowering agents contains the HMG-CoA reductase inhibitors. This slide helps to explain their mechanism of action.
The rate-limiting step in the cholesterol biosynthetic pathway involves the conversion of HMG-CoA to mevalonic acid, which is a precursor of cholesterol.
The HMG-CoA reductase inhibitors, or statins, are competitive inhibitors of HMG-CoA reductase in the liver. The statins inhibit the formation of mevalonate, thus reducing the amount of cholesterol produced in the body.
The efficacy of the statins in reducing LDL-C occurs as follows: The resulting decrease in endogenously produced cholesterol leads to an increase in the number of hepatic LDL-C receptors, leading to increased clearance of LDL-C from the blood.

3. Atorvastatin effect on lipids in patients with hypertriglyceridemia
Content Points:
This slide shows the impact of lipid-lowering therapy in patients with hypertriglyceridemia.26 The study was a randomized, double-blind, placebo-controlled, parallel-group trial conducted over four weeks. It assessed the lipid-lowering effects of atorvastatin in 56 patients with primary hypertriglyceridemia.
The mean baseline lipid concentrations were: triglycerides, 603 mg/dL; LDL-C, 119 mg/dL; and HDL-C, 32 mg/dL.
The protocol called for each subject to receive the NCEP Step l diet regimen and either placebo or atorvastatin at doses of 5, 20, or 80 mg per day.
After four weeks, mean reductions in triglycerides were 26% at the 5 mg atorvastatin dose, 32% at the 20 mg dose, and 46% at the 80 mg dose. The changes achieved with the 20 and 80 mg doses were statistically significant.
All the reductions seen in LDL-C were statistically significant compared to placebo.
Increases in HDL-C were also seen... with the 13% improvement at the 20 mg dose being statistically significant.

4. Achieving NCEP goals for LDL-C
Content Points:
Studies have also provided insights into the comparative efficacy of agents in achieving desired NCEP target goals for LDL-C.
This slide depicts results of a double-blind, placebo-controlled, 52-week study comparing effects of atorvastatin (10 mg per day) and lovastatin (20 mg per day) in 1,049 hypercholesterolemic patients.27
After 16 weeks, there was a 36% reduction in LDL-C with atorvastatin compared with 27% for lovastatin.
The chart at the right shows comparisons of the two agents in helping patients reach target goals for LDL-C. Seventy-four percent of patients on atorvastatin (vs 55% on lovastatin) reached target LDL-C goals.

5. Achieving NCEP goals for LDL-C
Content Points:
Another study compared atorvastatin (10 mg/day) with pravastatin (20 mg/day) in 305 patients with hypercholesterolemia.28
Subjects had baseline LDL-C levels of greater than 160 mg/dL. If their LDL-C targets were not achieved by 16 weeks, the drug doses were doubled.
The chart at the left shows results at 16 weeks. Note the 35% reduction in LDL-C associated with atorvastatin therapy compared with 24% with pravastatin. In addition, 65% of patients treated with atorvastatin had achieved the LDL-C target of 130 mg/dL.

6. Safety summary: HMG-CoA reductase inhibitors
Content Points:
In that hypercholesterolemia is a chronic condition for which long-term therapy is likely, the issue of tolerability and safety, in addition to efficacy, become key concerns.
Statins have demonstrated excellent patient acceptance, and have few drug-drug interactions and side effects. The most common side effects are of the gastrointestinal type, and they are usually mild to moderate in severity, and usually resolve spontaneously.
At high doses, elevated hepatic transaminases (ALT/AST) occur in approximately 1% to 2% of cases (and even less frequently at low doses).
In a mere 0.1% of cases, myopathy (creatine kinase value greater than 10 x ULN) has been reported. Mild elevations do not require discontinuation of statin therapy.

7. CURVES Trial design
Content Points:
The CURVES study is the first to compare the lipid-lowering efficacy of all available HMG-CoA reductase inhibitors across their dose ranges.29
It was a multicenter, open-label, randomized, parallel group study conducted over eight weeks. It compared the dose efficacy and safety of once-daily atorvastatin with simvastatin, pravastatin, lovastatin, and fluvastatin.
The study consisted of 534 patients with elevated baseline lipids as follows: LDL-C greater than 160 mg/dL and triglycerides less than 400 mg/dL.

8. CURVES Trial methodology
Content Points:
This slide provides the CURVES Trial methodology. There was a 6-week dietary baseline, followed by an 8-week active treatment period.
Patients who qualified were randomized to one of 15 treatment groups at the doses shown here.

9. CURVES Trial results: Patient inclusion criteria and demographics
Content Points:
The study included men and women greater than 18 and less than 80 years of age. Eligibility for inclusion included two consecutive visits where there was an LDL-C greater than 160 mg/dL, and triglycerides less than 400 mg/dL. Inclusions also pertained to those with a body mass index less than 32 kg/m2.
Mean age of the patients was 55.2 years, and 59% were males and 41% were females. Thirty-seven percent had a family history of coronary heart disease. Thirteen percent were smokers, and the average body mass index was 26.7 kg/m2.

10. Comparative LDL-C reductions across dose ranges
Content Points:
This slide shows the lipid-lowering effects from the available dosing strengths of fluvastatin, pravastatin, simvastatin, lovastatin, and atorvastatin.
Over the 10- to 40-mg dose range, atorvastatin demonstrated significantly greater LDL-C reductions than milligram-equivalent doses of comparative agents.

11. CURVES Trial results: LDL-C reductions at usual starting doses
Content Points:
Also from the CURVES Trial, this slide compares the LDL-C reductions observed at the usual starting doses of the available statins.

12. CURVES Trial results: LDL-C reductions at usual first titrations
Content Points:
Effects of the statins varied in their ability to achieve LDL-C reductions at the usual first titrations. For atorvastatin the mean percent LDL-C reduction at the 20 mg dose was 46%.

13. Future clinical challenge
Content Points:
Over the years, great strides have been made in progressively decreasing risk of coronary heart disease risk through reductions in LDL-C.
The key point and the clinical challenge for health care delivery: How much more can be accomplished? Expectations are high as newer trials and newer therapeutic modalities answer whether or not the achievement of even lower LDL-C levels can lead to further risk reduction in coronary heart disease.