Besides abetalipoproteinemia, a rare autosomal recessive disorder and an extreme example of an MTP defect, there is a condition called hypobetalipoproteinemia in which the heterozygotes have half normal levels of apoB-containing lipoprotein. They do not have the symptoms associated with abetalipoproteinemia, but they have an increased longevity. Combining this information with the preceding information on MTP makes one wonder if an inhibitor of MTP could be developed which would lower LDL and triglyceride into desirable ranges without producing adverse side effects. The following three abstracts speak to this issue.

Abstract 1341: Bay 13-9952, an Inhibitor of the Microsomal Triglyceride Transfer Protein (MTP), Inhibits Atherosclerotic Plaque Formation in Cholesterol-Fed Rabbits in Spite of a Concomitant Reduction of Vitamin E.

Cholesterol fed rabbits develop marked hypercholesterolemia and fatty infiltration of the thoracic aorta. In this study, New Zealand White rabbits were fed a cholesterol rich diet with amounts of MTP inhibitor equivalent to 0, 4 and 12 mg/kg. At baseline, the cholesterol levels averaged 56 mg/dl. When tested after the experimental period, the control rabbits with no MTP inhibitor had cholesterol levels of 1817 mg/dl whereas those taking 4 mg/kg of inhibitor had cholesterol levels of 139 mg/dl and those taking 12 mg/kg had cholesterol levels of 7.5 mg/dl. The thoracic aortas were stained with Sudan stain to show fat content. Fatty streaks covered 27% of the thoracic aorta in the controls whereas no fatty streaks were detectable in either of the treated groups. These changes occurred despite the fact that plasma Vitamin E concentrations were 47.5 mmol/ml in the control rabbits compared to 0.1 and 0 mmol/ml in the two treated groups.

Abstract 1342: Effect of Bay 13-9952, a Microsomal Triglyceride Transfer Protein Inhibitor on Lipids and Lipoproteins in Dyslipoproteinemic Patients.

This is the first study in patients with an MTP inhibitor, a phenylglycinolamide derivative. A 10 day, double blind, placebo (Plc) controlled trial was carried out in 61 patients, 28 men, 33 women, ages 18-65 years, with LDL > or =130 mg/dl or TG > or = 200 mg/dl or Lp(a) > or = 30 mg/dl. Twenty received placebo, 8 received 20mg of inhibitor, 17 received 40mg, 8 received 80mg and 8 received 160mg. The incidence of adverse events was similar in drug Rx and Plc, although nausea and diarrhea tended to be more frequent with 80 and 160mg. Transaminase elevations were similar in drug and Plc, 22% vs 30%, and no elevations exceeded 2x the upper limit of normal. On the eleventh day, 160mg of inhibitor resulted in significant decreases of CHOL -48%, LDL -43% and ApoB -50% (p<0.001 in each case). Lesser decreases were seen in TG and HDL.

Abstract 1343: Bay 13-9952, an Inhibitor of the Microsomal Triglyceride Transfer Protein (MTP), Dose - Dependently Blocks the Formation of Atherosclerotic Plaques and Renders Them More Stable in Apo E Knockout Mice.

Apo E knockout mice, whose Apo E has been altered by genetic manipulation, develop advanced atherosclerotic lesions and provide a model for research on atherosclerosis. In such mice, MTP inhibitor produced a dose dependent reduction in VLDL and TG along with a reduction of the aortic root plaque area and lipid content.

These reports, in the context of previous information on MTP, offer the exciting possibility of a new class of drugs in the future, acting to lower LDL and TG through an entirely different pathway than those currently used.

References
2. J.Biol Chem 259:10863, 1984
3. Biochem et Biophys Aeta 1345:136, 1997
4. Current Opinion in Lipidology 8:131, 1997
5. Science 282:751, 1998

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During follow-up in the 5 year study, the lipids in the Pravastatin treated patients, compared to control, were: CHOL 20% lower, LDL 28% lower, HDL 5% higher and TG 14% lower (p<0.001 for all comparisons). Pravastatin reduced CHD deaths and non-fatal MIs by 24% (p=0.003), CABG by 26% (p=0.005), angioplasty by 23% (p=0.01) and stroke by 31% (p=0.03). A similar decrease in risk occurred across the spectrum of HDL values. All of the reduction in the events was seen in those patients with a baseline LDL of 125 mg/dl or greater, leading these investigators to postulate a threshold below which response does not occur, in contrast to those who believe the response is curvilinear, if not linear (2).

Subset analyses, published during the past year, have analyzed the effect of lipid lowering treatment on cardiovascular events in elderly (3) and diabetic patients (4).

Elderly Patients: One thousand two hundred eighty three patients were 65 to 75 years of age at randomization in the study. The mean age of these "older" patients was 69 years at randomization and 74 years of age at the end of the trial. Baseline characteristics differed for these older patients in contrast to the "younger" patients (<65 years). The older patients were more frequently women (18% vs 12%), hypertensive (48% vs 40%), diabetic (19% vs 12%), and had a second previous MI (21% vs 15%). They more frequently had angina (23% vs 20%), CHF (11% vs 5%), and CABG (31% vs 25%), but less frequently angiography (75% vs 80%), angioplasty (29% vs 35%) or thrombolytic therapy (36% vs 45%). They less frequently had a family history of CHD (33% vs 44%) and less frequently smoked currently (12% vs 24%) or in the past (70% vs 81%). Fewer received beta blockers (37% vs 41%), but more received calcium channel blockers (42% vs 38%), ACE inhibitors (16% vs 14%), digitalis (13% vs 6%) and diuretics (19% vs 9%) (p<0.05 for all of the preceding differences).

The baseline lipids were the same in both the younger and older patients with the exception of the TG being lower (158 vs 150 mg/dl). Pravastatin (Prav) changed all lipids similarly, averaging a 19.5% decrease in CHOL, 28% decrease in LDL, 4.5% increase in HDL and 13% decrease in TG (p<0.001, compared to placebo [Plc] in each case).

In older patients, major coronary events (death from CHD, non-fatal MI, CABG or PTCA) occurred in 19.7% (Prav) vs 28.1% (Plc), representing a 32% relative risk reduction and a 9% absolute reduction (p=0.001). CHD deaths occurred in 5.8% (Prav) vs 10.3% (Plc) for a 45% relative risk reduction and 4.6% absolute reduction (p=0.004). Stroke occurred in 4.5% (Prav) vs 7.3% (Plc) for a relative risk reduction of 40% and a 2.9% absolute reduction (p=0.03). The rate of reduction of major coronary events was similar in older women and men. Younger patients, treated with Pravastatin, experienced a lower rate of coronary events than those treated with placebo, but the number that needed to be treated to prevent a coronary event was less for the older patients. Four older patients and 8 younger patients needed to be treated to prevent a hospitalization for cardiovascular events during the 5 years of this study. The author�s conclude, "In older patients with myocardial infarction and cholesterol levels in the average range, Pravastatin is associated with a clinically important reduction in risk for major coronary events and stroke." It is postulated that these results apply to patients over 75 years of age. That hypothesis is being tested in 2 large trials, "Anti-Hypertensive and Lipid Lowering Treatment to Prevent Heart Attack" (ALLHAT) and a "Prospective Study of Pravastatin in The Elderly at Risk" (PROSPER).

Diabetic Patients: The CARE Trial included 586 patients (14.1% of the total) identified by history of having been diagnosed as diabetic or received medication to treat diabetes mellitus. Of these patients, 45.4% were receiving Sulfonylurea drugs and 18.6% insulin. The demographic and clinical characteristics of this population revealed that the diabetic patients, compared to non-diabetics, were older (61 vs 58 years), more likely to be female (19.6% vs 12.9%) and a member of a minority group (15% vs 6.2%). The diabetics were more frequently obese (BMI=29.4 vs 27.3), smoked less (16.3% vs 21.4%), drank no alcohol (75.4% vs 54.7%). They more frequently had a history of hypertension (51.5% vs 41.2%), intermittent claudication (13.7% vs 6.8%), stroke (6% vs 2.4%) and CHF (12.5% vs 6.2%).

In comparing diabetics vs non-diabetics, baseline fasting glucose was 149 +/- 52 vs 97 +/- 14 mg/dl (p<0.001). The LDL was lower (136 vs 139, p<0.001) as was the HDL (37 vs 39, p<0.001) and total CHOL (206 vs 209, p<0.001). The TG was higher (164 vs 154, p<0.001). Pravastatin produced similar changes in both the diabetic and non-diabetic groups, averaging 19.5% reduction of cholesterol compared with placebo, 27.5% reduction of LDL, 4% increase in HDL and 13% decrease in TG. With the exception of angioplasty, cardiovascular events occurred with greater frequency in the diabetic group (D) than in the non-diabetic group (ND) (p<0.05 or <0.01 depending on the event). CHD death or non-fatal MI (primary endpoint) occurred in 20% of D and 12% of ND (p<0.001) while stroke occurred in 8% D vs 3% ND (p<0.001). The risk of a coronary event in D was reduced 25% by pravastatin, similar to the ND group. The authors conclude that "Diabetic patients and nondiabetic patients with impaired fasting glucose are at high risk of recurrent coronary events that can be substantially reduced by pravastatin treatment."

The CARE Study excluded patients with a fasting glucose of >220 mg/dl and TG > 350 mg/dl. None the less, it was more inclusive for diabetes than the 4S Study which had only 4.6% diabetic patients (5). In both studies, statin therapy reduced the risk of CHD in diabetic patients.

References
1. NEJ. Med 335: 1001, 1996
2. Circulation 97:1436, 1998
3. Ann Int Med 129:681, 1998
4. Circulation 98:2513, 1998
5. Diabetes Care 20: 614, 1997