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Congres Report
 

Symposium 3

 
Current Progress in the Management of Dyslipidemia
 
Impact of the LDL-Receptor-Related Molecules on the Achievement of Optimal LDL Cholesterol Level: Evidence from Newly Identified Gene Mutations.
Masa-aki Kawashiri
Kanazawa University, Kanazawa, Japan
Effects of Baseline LDL Level and Statin on Atherosclerotic Events in Patients with Type 2 Diabetes: Insights from JPAD Trial
Takeshi Morimoto
Kyoto University Graduate School of Medicine, Kyoto, Japan
 
Impact of the LDL-Receptor-Related Molecules on the Achievement of Optimal LDL Cholesterol Level: Evidence from Newly Identified Gene Mutations.
Masa-aki Kawashiri
Kanazawa University, Kanazawa, Japan
 

Dr. Masa-aki Kawashiri, Kanazawa University, discussed gene mutations found in patients with familial hypercholesterolemia (FH) and explored their relationship to LDL-C levels. FH is related to abnormalities of the LDL receptor, apolipoprotein B, and to proprotein convertase subtilisin/kexin type 9 (PCSK9) in the dominant form and LDL receptor adopter protein 1 (LDLRAP1) in the recessive form.

Autosomal recessive hypercholesterolemia (ARH) is a phenocopy of homozygous FH caused by a defect in LDLRAP1). Statins are highly effective for controlling cholesterol levels in patients with ARH. Statins are known to inhibit cholesterol synthesis in hepatocytes but little is known about the mechanism of responsiveness to statins in ARH patients. Dr. Kawashiri et al conducted a kinetic study using a labeled amino acid to trace apolipoproteins in an ARH patient. In the ARH patient, the VLDL production rate (PR) was higher than in normal controls but the VLDL fractional catabolic rate (FCR) was similar to controls. The LDL PR was slightly higher than in controls; the FCR was markedly less than controls but was normalized by statin therapy. Direct removal of VLDL was 330% higher than in controls and was increased to 496% higher by statin therapy. The effect of the statin may be related to the activation of LDLRAP1.

An FH patient with a PCSK9 (E32K) gain-of-function mutation responded well to statin therapy. Kinetic studies revealed a high VLDL PR with a very slow FCR and a normal LDL PR with very slow FCR compared to controls. There were considerable differences in VLDL metabolism and remnant fractions between the PCSK9 mutation patient and controls. Conversion from VLDL1 to VLDL remnant was 20 times higher than in controls, while VLDL1 conversion to VLDL2 was 35% lower. Direct removal of VLDL was 330% higher versus controls.

Serum LDL-C levels have been reduced by inhibition of PCSK9 using small interfering RNA, antisense, or anti-PCSK9 antibody in animal studies. SREBP induces PCSK9, which attenuates LDL-C lowering by LDLR induction. Thus, PCSK9 inhibition may act synergistically with statins to reduce serum LDL-C.

Dr. Kawashiri concluded that a lack of LDLRAP1 activates an alternate pathway to directly remove VLDL. An LDLRAP1-independent LDL catabolic pathway may exist and contribute to increased responsiveness to statins. The gain-of-function mutation in PCSK9 (E32K) causes delayed VLDL and LDL catabolism. In vivo experiments showed that inhibition of PCSK9 decreases serum LDL-C. Theoretically, activation of LDLRAP1 or inhibition of PCSK9 could be novel approaches for further reduction of LDL-C over statin therapy alone.

 

 
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Effects of Baseline LDL Level and Statin on Atherosclerotic Events in Patients with Type 2 Diabetes: Insights from JPAD Trial
Takeshi Morimoto
Kyoto University Graduate School of Medicine, Kyoto, Japan
 

Dyslipidemia coexists with type 2 diabetes in 34% of Japanese patients. Statins and low-dose aspirin are commonly used to reduce the risk of atherosclerosis in diabetic patients. Dr. Takeshi Morimoto presented results of a trial that explored the burden of dyslipidemia, prevalence and effects of statin use, and the rationale for treatment strategies in Japanese patients with type 2 diabetes.

The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was a randomized, controlled, open-label, blinded-endpoint study to examine the efficacy of low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes mellitus. A total of 2,539 patients with no history of cardiovascular disease were randomized to aspirin (N=1,262) or no aspirin (N=1,277). Statins were prescribed by physicians based on clinical judgment. The primary endpoint was the composite of all atherosclerotic events. The median follow-up was 4.4 years.

Dyslipidemia was present in 53% of patients at baseline. Aspirin reduced the risk of atherosclerotic events by 20% (HR=0.8, 95% CI 0.6-1.1, p=0.16). A total of 154 events occurred, most consisting of nonfatal ischemic strokes. There were 59 hemorrhages, 40 in the aspirin group and 19 in the non-aspirin group.

Key findings in relation to LDL levels were:

 Baseline LDL was ≥120 mg/dL in 50% of patients and ≥100 mg/dL in 75% of patients.
 Statins were received by 25% of patients.
 Patients with baseline LDL ≥120 mg/dL had a higher risk of atherosclerotic events versus those with LDL <120 mg/dL (HR=1.5, 95% CI 1.1-2.1, p=0.02). Patients with LDL ≥100 mg/dL in the aspirin group had significantly less atherosclerotic events versus the non-aspirin group (HR=0.68, p=0.05).
 Aspirin use made no difference in atherosclerotic events in patients with LDL <100 mg/dL.

Statin use at baseline made no difference in risk of atherosclerotic events. Among patients who did not receive statins, those in the aspirin group had significantly fewer atherosclerotic events versus those in the non-aspirin group (HR=0.7, p=0.0047). Aspirin use made no difference in the number of atherosclerotic events in patients receiving statins. Among patients with LDL ≥100 mg/dL, those who did not receive aspirin or statins had a significantly higher risk of atherosclerotic events (p=0.02).

The JPAD trial confirmed that in Japanese patients with type 2 diabetes, baseline LDL is a risk factor for atherosclerotic events. Both aspirin and statins reduced the risk of atherosclerotic events in patients with increased LDL. Cumulative risk factors justify the use of aspirin and statins for primary prevention. Consideration of individual risks is important. Limitations of the trial were that it was a post-hoc analysis with a relatively shorter follow-up, low power, alpha errors due to multiple comparisons, and statins were not randomized.

 

 
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