Novel HDL-Targeted Therapies -- The Search Continues

The Atherogenic Dyslipidemia Study

A total of 309 patients (70% men; mean age, 54 years) participated in the atherogenic dyslipidemia study, all fulfilling the entry criteria, which included:

HDL cholesterol < 45 mg/dL (men) or < 50 mg/dL (women);
Triglycerides 150-600 mg/dL;
LDL cholesterol ≤ 160 mg/dL; and
No poorly controlled diabetes (glycosylated hemoglobin levels ≥ 8%).

At enrollment, mean triglycerides were elevated (average, 250 mg/dL) and HDL was reduced (average, < 40 mg/dL); 40% of patients were taking statins. After a 4-week placebo lead-in period on the National Cholesterol Education Program Therapeutic Lifestyle Changes diet,^[3] patients were randomized to 12 weeks of active treatment with LY518674 10 micrograms (mcg), 25 mcg, 50 mcg, or 100 mcg; fenofibrate 200 mg; or placebo.

Summarized below, the 2 primary endpoints of the study were the percentage change in HDL cholesterol and the percentage change in triglycerides ( Table 1 ):

Triglycerides: Both fenofibrate and LY518674 markedly decreased triglyceride levels (32.8% and 34.9% to 41.7%, respectively).
The reduction with LY518674 was not statistically different from the effect produced by fenofibrate.
LDL: Both fenofibrate and LY518674 increased levels of LDL cholesterol, with an increase of 2.3% with fenofibrate and a significantly greater increase for LY518674 at the 50-mcg and 100-mcg doses (18.3% and 19.5%, respectively) (P ≤ .002).
HDL: Fenofibrate increased HDL levels by 14.4%. LY518674 showed an unusual dose-response pattern, with the lowest dose (10 mcg) producing a modest increase (9.6%) in HDL levels, a maximum increase occurring with the 25-mcg dose (15.8%), and lesser increases occurring at higher dosages. The 100-mcg dose of LY518674 produced only a 2.1% increase in HDL, which did not differ significantly from the effect of placebo and was smaller than that with fenofibrate.

Levels of apolipoprotein (Apo)A-I rose in parallel with HDL cholesterol, but levels of apoA-II rose with a dose-response relationship for LY518674.

Cite this: Novel HDL-Targeted Therapies -- The Search Continues - Medscape - Jun 12, 2007.

Atherogenic Dyslipidemia Study: Percent Change in Lipoprotein Levels
	Placebo	Fenofibrate	LY518674
	Placebo	Fenofibrate	10 mcg	25 mcg	50 mcg	100 mcg
Total cholesterol (%)	-1.4	-6.0	-7.3	-4.4	0.8	-2.4
LDL cholesterol (%)	-0.3	2.3	2.1	11.9	18.3	19.5
HDL cholesterol (%)	-1.1	14.4	9.6	15.8	11.1	2.1
Triglycerides (%)	-1.4	-32.8	-36.1	-40.9	-41.7	-34.9
Non-HDL cholesterol (%)	-0.7	-10.6	-10.8	-9.1	-1.9	-3.5
ApoB (%)	-0.1	-8.1	-5.9	-6.5	1.4	2.5
ApoA-I (%)	-2.3	-8.7	4.0	10.3	7.6	-4.2
ApoA-II (%)	-0.3	-17.0	7.8	21.6	27.6	30.0

Apo = apolipoprotein; LDL = low-density lipoprotein; HDL = high-density lipoprotein; mcg = micrograms

Hypercholesterolemia Study: Changes in Lipoproteins and Inflammatory Markers
	Placebo			Atorvastatin 10 mg			Atorvastatin 40 mg
	Placebo	LY 10 mcg	LY 50 mcg	Placebo	LY 10 mcg	LY 50 mcg	Placebo	LY 10 mcg	LY 10 mcg
Total cholesterol (%)	0.12	11.6	-14.6	-29.3	-27.8	-32.3	-33.5	-35.7	-39.7
LDL-C (%)	-1.0	-13.2	-15.8	-40.7	-36.6	-41.1	-45.5	-47.7	-49.7
HDL-C (%)	6.9	15.0	12.5	2.0	12.6	17.6	3.4	11.9	5.9
Triglycerides (%)	-5.3	-36.9	-37.5	-18.5	-39.4	-55.4	-23.4	-44.4	-52.5
ApoA-I (%)	4.9	6.7	12.4	0.3	6.5	8.9	-0.2	4.2	-2.4
ApoA-II (%)	0.29		33.7	-6.3	11.9	35.4	-4.2	14.1	31.9
hsCRP (mg/dL)	1.8	0.03	0.00	0.3	-0.8	0.1	-1.0	0.7	-1.3

LDL-C = LDL cholesterol; HDL-C = HDL cholesterol; hsCRP = high-sensitivity C-reactive protein; Apo = apolipoprotein; mcg = micrograms

Hypercholesterolemia Study: Changes After Atorvastatin Randomization From 4 Weeks Until End of Treatment
	Placebo			Atorvastatin 10 mg			Atorvastatin 40 mg
	Placebo	LY 10 mcg	LY 50 mcg	Placebo	LY 10 mcg	LY 50 mcg	Placebo	LY 10 mcg	LY 10 mcg
Total cholesterol (%)	-3.6	-1.1	-5.7	-3.6	-1.1	-5.7	0.3	-4.5	-9.3
LDL-C (%)	-7.9	-0.6	-7.4	-7.9	-0.6	-7.4	-6.3	-5.8	-11.8
HDL-C (%)	-1.8	9.8	11.9	-1.8	9.8	11.9	0.5	9.2	0.6
Triglycerides (%)	3.1	-20.4	-42.7	3.1	-20.4	-42.7	12.5	-26.9	-36.1
ApoB (%)	-6.4	-3.7	-8.9	6.4	-3.7	-8.9	2.2	-8.4	-10.9
ApoA-I (%)	-3.2	5.1	6.8	-3.2	5.1	6.8	0.4	3.1	-5.5
ApoA-II (%)	-7.8	12.7	33.6	-7.8	12.7	33.6	-2.4	13.0	29.1
hsCRP (mg/dL)	0.9	-0.2	0.6	0.9	-0.2	0.6	-0.3	1.1	-0.3

LDL-C = LDL cholesterol; HDL-C = HDL cholesterol; hsCRP = high-sensitivity C-reactive protein; Apo = apolipoprotein; mcg = micrograms

ANOVA Showing Interaction by Sex
Source	P Value
D-4F dose	< .0001
Sex	.0105
Dose*sex interaction	.0163

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

My Alerts

Add to Email Alerts

Your Name is required.

Subject is required.

Please enter a Recipient Address and/or check the Send me a copy checkbox.

Your email has been sent.

is an Invalid Email Address.

Novel HDL-Targeted Therapies -- The Search Continues

The Atherogenic Dyslipidemia Study

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Comments

Email This

Feedback