acipimox and Hypertriglyceridemia

Topics: Animals; Biological Transport; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Insulin; Insulin Resistance; Lipolysis; Models, Biological; Niacin; Obesity; Pyrazines

Metabolic abnormalities such as hypertriglyceridemia remain a challenge for optimizing long-term health in HIV-infected patients.. Elevation of free fatty acids (FFAs) may contribute to hyperlipidemia and insulin resistance in HIV. We evaluated the efficacy and safety of chronic inhibition of lipolysis in HIV-infected men and women with hypertrigyceridemia. We hypothesized that acipimox would lead to significant reductions in triglycerides and improved insulin sensitivity, compared with placebo.. A 3-month, randomized, double-blind, controlled trial of acipimox (250 mg thrice daily) vs. placebo was conducted in 23 HIV-infected men and women with hypertriglyceridemia (>150 mg/dl), abnormal fat distribution, and no current lipid-lowering therapy. The primary outcome variable was triglyceride concentration, and insulin sensitivity measured by hyperinsulinemic euglycemic clamp was a secondary outcome.. The study was conducted at an academic medical center.. Acipimox resulted in significant reductions in FFAs [mean change -0.38 (0.06) vs. 0.08 (0.06) mEq/liter with placebo, -68 vs. +17% change from mean baseline, P < 0.0001], decreased rates of lipolysis (P < 0.0001), and a median triglyceride decrease from 238 mg/dl at baseline to 190 mg/dl, compared with an increase from 290 to 348 mg/dl in the placebo group (P = 0.01). Acipimox improved insulin sensitivity [acipimox +2.31 (0.74) vs. placebo -0.21 (0.90) mg glucose per kilogram lean body mass per minute, or +31 vs. -2% change from mean baseline values, P = 0.04]. Improvements in insulin sensitivity were significantly correlated with reductions in FFAs (r = -0.62, P = 0.003) and lipolysis (r = -0.59, P = 0.005).. Acipimox resulted in significant sustained reductions in lipolysis, improved glucose homeostasis, and significant but modest reductions in triglycerides in HIV-infected individuals with abnormal fat distribution and hypertriglyceridemia. Improvement in overall metabolic profile with acipimox suggests a potential clinical utility for this agent that requires further investigation.

Topics: Adult; Body Composition; Double-Blind Method; Fatty Acids, Nonesterified; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Insulin; Insulin Resistance; Male; Middle Aged; Placebos; Pyrazines; Triglycerides

32 patients with hypertriglyceridemia, excessive hypertriglyceridemia, and combined hyperlipidemia, were treated with the nicotinic acid derivative acipimox (Olbetam). First line treatment with bezafibrate, or statins in some with combined hyperlipidemia, had failed. In 10 acipimox was discontinued due to side effects or absence of clinical response. The other 22 completed 6 months of treatment with no side effects. Acipimox caused a significant 54% decrease in triglyceride levels, a 23% decrease in total cholesterol, and a 12% increase in HDL-cholesterol. LDL-cholesterol was difficult to calculate because of the high triglyceride levels, so no results are presented. Although acipimox was much better tolerated than nicotinic acid, it also had side effects, but fewer. Acipimox can therefore be used as a second-line drug, mainly in those with combined hyperlipidemia and hypertriglyceridemia.

Topics: Adult; Aged; Cholesterol; Cholesterol, HDL; Drug Therapy, Combination; Female; Humans; Hyperlipidemias; Hypertriglyceridemia; Hypolipidemic Agents; Male; Middle Aged; Pyrazines; Triglycerides

Hyperlipidemia, hypertriglyceridemia in particular, is a common feature in patients with noninsulin dependent diabetes mellitus (NIDDM) and may associate with insulin insensitivity. Acipimox, being widely prescribed for treating hypertriglyceridemia, is also used in NIDDM patients for their dyslipidemia. In the present study, we evaluated the effect of acipimox in Chinese NIDDM patients with hypertriglyceridemia. A total of 16 patients enrolled in a double-blind, randomized, placebo-controlled and two-period crossover study. After an 8 week run-in period, patients were randomly assigned into two groups receiving either acipimox (250 mg, twice daily) or placebo treatment. A total of 12 weeks later, these two groups switched their treatment for an additional 12 weeks. Blood samples were collected at the end of the run-in period and then at 4-week intervals in the whole study for lipid profile. A modified insulin suppression test was performed at the ends of the run-in period, 12-week and 24-week treatment to assess changes in insulin sensitivity. Our results showed that acipimox significantly lowered serum total triglyceride while compared to those by placebo. However, no difference was observed in serum non-esterified fatty acid, low-density lipoprotein cholesterol, total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C) and HDL-C/ TC ratio between the two groups. Furthermore, glycemic indices and insulin sensitivity were similar during the base-line, placebo or acipimox periods. Taken together, our data suggest that acipimox significantly lowered TG without perturbation of insulin sensitivity in hypertriglyceridemic NIDDM patients.

Topics: Adult; Aged; Apolipoprotein A-I; Apolipoproteins B; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypertriglyceridemia; Hypolipidemic Agents; Insulin; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Pyrazines; Triglycerides

Hypertriglyceridaemia is associated with insulin resistance of both lipid and glucose metabolism. It is not known whether the insulin resistance affects both glucose oxidation and glycogen formation. To study the oxidative and non-oxidative pathways of non-esterified fatty acids (NEFA) and glucose metabolism, eight male hypertriglyceridaemic subjects were studied during insulin infusion (75 and 340 pmol/m2.min) in combination with indirect calorimetry and infusions of [3-3H]glucose and [1-14C]palmitate before and after 4 weeks of treatment with the antilipolytic agent acipimox (250 mg three times daily). Compared with eight healthy subjects the hypertriglyceridaemic subjects were resistant to the antilipolytic effect of insulin, both in the basal state (P < 0.05) and during insulin infusion (P < 0.05). This was associated with impaired insulin-stimulated glucose uptake (P < 0.05), predominantly in the non-oxidative pathway (P < 0.05). Acipimox decreased basal NEFA concentrations (P < 0.01) and reduced lipid oxidation during low-dose insulin infusion (P < 0.05). Glucose uptake, predominantly glycogen formation, was stimulated by acipimox (P < 0.05). In conclusion, the insulin resistance of glucose metabolism associated with hypertriglyceridaemia is largely due to a defect in non-oxidative glucose metabolism. Acipimox improves glucose metabolism both by affecting glucose oxidation (low-dose insulin) and non-oxidative glucose metabolism (high-dose insulin).

Topics: Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Lipolysis; Male; Middle Aged; Oxidation-Reduction; Palmitates; Pyrazines

We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol >2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60-120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60-120 in the 50% having the lowest levels of hemoglobin A(1c) (379 +/- 34 vs. 326 +/- 30 pmol x kg(-1) x min(-1) without Acipimox, P < 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Dietary Proteins; Energy Intake; Exercise; Fasting; Fatty Acids; Female; Glucagon; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertriglyceridemia; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Proinsulin; Pyrazines

We report the case of a 34-year-old man with extreme hypertriglyceridaemia (276.6 mmol/l) that was corrected by diet and triple-drug therapy. No primary defect could be found despite an intensive biochemical and genetic evaluation. Early in the time course of triglyceride-lowering therapy, the composition and concentration of different lipoprotein species changed markedly. His lipoprotein profile mimicked type III hyperlipidaemia, then familial hypercholesterolaemia, and finally hyperalphalipoproteinaemia. The increase in LDL cholesterol and apolipoprotein B was paralleled by a sixfold increase in lipoprotein(a). We conclude that these different forms of hypercholesterolaemia disappear solely with a continuation of the triglyceride-lowering therapy.

Topics: Adult; Cholesterol, LDL; Combined Modality Therapy; Docosahexaenoic Acids; Eicosapentaenoic Acid; Gemfibrozil; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Male; Pyrazines; Triglycerides

Thirty patients were investigated with hyperlipoproteinaemia, 15 patients with non-insulin dependent diabetes mellitus (NIDDM) and 15 with primary hyperlipoproteinaemia. The patients took 250 mg acipimox (5-metyl-pyrazine-carboxylic acid 4-oxide) 3 times per day for 2 months. Serum examinations were performed before and after 1 and 2 months of acipimox administration. After treatment the cholesterol and triglyceride levels decreased in both groups. Patients with NIDDM had 11% increase of high density lipoprotein-cholesterol (HDL-C) level at the end of the first, and 18% increase at the end of the second month, while patients with primary hyperlipoproteinaemia did not change significantly. The low density lipoprotein (LDL) level did not change significantly in either groups of patients. The apolipoprotein A 1 (apo A 1) levels increased significantly during the second month of acipimox administration. Uric acid levels decreased in both groups, but significant change could be detected mainly in the NIDDM group. Serum glucose level did not change in the non-diabetic patients, while it decreased significantly in the NIDDM group.

Topics: Apolipoprotein A-I; Blood Glucose; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Female; Humans; Hypercholesterolemia; Hyperlipoproteinemias; Hypertriglyceridemia; Hypolipidemic Agents; Lipoproteins, LDL; Male; Middle Aged; Pyrazines; Time Factors; Triglycerides; Uric Acid

Hypertriglyceridaemia associated with low HDL-concentrations is considered an independent risk factor of ischaemic heart disease. The drug of choice in this disorder is nicotinic acid. The aim of the presented work was to compare the hypolipidaemic effect of fish oils rich in omega-3 fatty acids (Activepa 30-TGR, Hydromartens, Norway) with a nicotinic acid derivative, acipimox (Olbetam, Farmitalia Carlo Erba, Italy).. The preparations were administered for a three-week period to two groups of patients with hypertriglyceridaemia and low HDL cholesterol levels. The groups had comparable body weights and baseline parameters of lipid metabolism. In the group treated with Olbetam (750 mg/day), 17x hyperlipoproteinaemia type IV and 6x IIB) after treatment significant changes of the following parameters were recorded: triglycerides (-18%; P < 0.001), HDL cholesterol (+19%; P < 0.01), HDL2 and HDL3 cholesterol (+33%; +14%; P < 0.001, P < 0.01), apo B (+25%; P < 0.01), apo A-I (+7%; P < 0.01), ratio of apoB/A-I (+17%; P < 0.01). Furthermore, there was s drop of the atherogenic index (total cholesterol/HDL cholesterol) by 22% (P < 0.001). In the group of subjects (17x type IV and 8x type IIB) whose diet was enriched with omega-3 fatty acids (3.5 g/day), the following parameters changed significantly: triglycerides (-44%; P < 0.001), the atherogenic index (-23%; P < 0.001), HDL cholesterol (+11%, P < 0.01), HDL2 and HDL3 cholesterol (+13%, +17%; P < 0.01, P < 0.05). Changes of apo B, apo A-I concentrations and their ratios were not significant. Comparison of the effect of the two preparations on the investigated parameters revealed a more marked rise of the HDL cholesterol (P < 0.05), apo B (P < 0.01) concentrations and the apo B/-A-I ratio (P < 0.05) during Olbetam treatment. As to the action of the two preparations on further investigated parameters (total and LDL-cholesterol), no significant differences found.. The assembled results indicate that enrichment of the diet with fish oil rich in omega-3 fatty acids has a hypolipidaemic effect comparable to acipimox. It is thus feasible to use fish oils as a drug of first choice in the treatment of hypertriglyceridaemia associated with a reduction of HDL cholesterol concentration.

Topics: Fatty Acids, Omega-3; Female; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Male; Middle Aged; Pyrazines

The regulation of cellular LDL metabolism by hypertriglyceridemic LDL was tested before and after treatment with acipimox, a nicotinic acid derivative, in 11 type IV hyperlipidemic patients. Large, less dense LDL particles were found in plasma after acipimox treatment. HDL subfractions were only slightly modified, with an increase of dense, cholesteryl ester-enriched and triglyceride-poor HDL3 particles. The LDL (B, E) receptor activity in human skin fibroblasts of LDL isolated before and after treatment was also evaluated. Hypertriglyceridemic LDL proved rather inefficient in regulating receptor activity, with a close to 30% lower capacity than normal LDL to inhibit receptor-mediated uptake and degradation of 125I-LDL. This abnormality was fully corrected after acipimox. The reported findings indicate that acipimox treatment in type IV patients can normalize the defective interaction of hypertriglyceridemic LDL with the LDL (B, E) receptor.

Topics: Adult; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Lipoproteins, LDL; Male; Middle Aged; Pyrazines; Receptors, LDL

Modifications in plasma low and high density lipoprotein (LDL and HDL) subfraction distribution, as well as the regulation of cellular LDL metabolism by hypertriglyceridemic LDL were tested before and after treatment with acipimox, a nicotinic acid derivative, in 11 type IV hyperlipidemic patients. Large, less dense LDL particles were found in plasma after acipimox treatment, reflecting compositional changes, characterized by a 25.4% increase in cholesteryl ester content and by a 46.2% reduction of triglycerides in LDL. HDL subfractions were only slightly modified, with an increase of dense, cholesteryl ester-enriched and triglyceride poor HDL3 particles. The LDL (B,E) receptor activity in humans skin fibroblasts of LDL isolated before and after treatment was also evaluated. Hypertriglyceridemic LDL proved rather inefficient in regulating receptor activity with a close to 30% reduction vs. normal LDL in the capacity to inhibit receptor-mediated uptake and degradation of 125I-LDL. Such abnormality was fully corrected after acipimox. The reported findings indicate that acipimox treatment in type IV patients, in spite of a relatively modest plasma triglyceride reduction, can markedly modify LDL distribution and composition, normalizing the defective interaction of hypertriglyceridemic LDL with the LDL (B,E) receptor.

Topics: Humans; Hypertriglyceridemia; Hypolipidemic Agents; Lipoproteins, LDL; Male; Pyrazines; Receptors, LDL

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Pyrazines

Acipimox, a nicotinic acid analog, is known to reduce the plasma lipid concentration in hyperlipidemic patients. In a study to check whether the drug improved hemo-rheological parameters, 21 patients (17 M, 4 F) with asymptomatic hypertriglyceridemia were treated with acipimox (250 b.i.d.) for 30 days. Plasma lipid concentrations were measured before and after therapy, together with blood and plasma viscosity. Mean plasma cholesterol and triglyceride levels decreased from 234 +/- 51 (SD) mg/dl to 202 +/- 53 mg/dl (p less than 0.01) and from 515 +/- 231 mg/dl to 298 +/- 130 mg/dl (p less than 0.01) respectively. Blood viscosity decreased (p less than 0.05 and less than 0.01) (range of reduction 6-20%) at all shear rates examined (from 2.25 s-1 to 450 s-1); plasma viscosity was significantly reduced only at lower shear rates (2.25 and 4.50 s-1). Changes in blood and plasma viscosity after acipimox treatment were not related to changes in plasma triglycerides. Acipimox seems to act beneficially on hemo-rheological parameters, independently of its hypolipidemic effect and could be usefully prescribed to patients with clinical signs of arteriosclerosis.

Topics: Adolescent; Adult; Blood Viscosity; Cholesterol; Female; Humans; Hypertriglyceridemia; Lipids; Male; Middle Aged; Pyrazines; Triglycerides