Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study estimated the cost-effectiveness of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors available in Canada for the primary prevention of coronary heart disease (CHD). A model of the cost-effectiveness of therapy used to modify low-density lipoprotein (LDL) cholesterol and high-density lipoprotein cholesterol levels was developed in the primary prevention of CHD based on risk functions from the Framingham Heart Study and Canadian data on coronary risk factors and the cost of treating the leading manifestations of CHD. Relative to no treatment, discounted gains in life expectancy range from 0.174 year for fluvastatin 40 mg to 0.215 year for simvastatin 10 mg. Costs per year-of-life-saved range from $38,800 for fluvastatin 40 mg to $56,200 for pravastatin 20 mg. In the incremental analysis relative to fluvastatin 40 mg, additional gains in life expectancy range from 0.011 year for pravastatin 20 mg to 0.041 year for simvastatin 10 mg, and incremental cost-effectiveness ratios range from $88,200 for simvastatin, 10 mg to $330,300 for pravastatin 20 mg. Our analysis showed that the cost-effectiveness of cholesterol-lowering therapy is sensitive to pretreatment risk of CHD, as expressed by pretreatment cholesterol levels and the presence of additional risk factors such as hypertension, diabetes, and smoking. The results of the analysis suggest that it is more cost-effective to initiate treatment with fluvastatin than with pravastatin, simvastatin, or lovastatin. Sensitivity analysis showed the results to be stable even if the lipid-lowering effect of fluvastatin is varied by 23% from the original assumption of 25% LDL reduction (ie, from 19.3% to 30.8%). Limitations of the study are recognized and discussed. A head-to-head comparison of these HMG-CoA reductase inhibitors could provide further evidence that therapy initiated with fluvastatin may be the most cost-effective way to treat patients with hypercholesterolemia who are eligible for treatment with HMG-CoA reductase inhibitors.
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PMID:Cost-effectiveness analysis of lipid-modifying therapy in Canada: comparison of HMG-CoA reductase inhibitors in the primary prevention of coronary heart disease. 758 61

Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a greater risk of developing coronary heart disease than would be expected from a similar degree of hyperlipidemia in nondiabetic populations. Accelerated transfer of cholesteryl esters (CET) from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), a process that is associated with atherosclerosis, may be a possible explanation for this. CET, plasma lipoprotein concentration, and mass in the fasting and postprandial state have been examined in 31 hyperlipidemic patients with NIDDM before and after 8 weeks of treatment with the hydroxymethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor pravastatin in a double-blind, placebo-controlled, parallel group study. Body mass index, glycemic control, and blood pressure remained unaltered during the study period. Compared with placebo, pravastatin decreased fasting serum cholesterol (P < 0.001) and LDL cholesterol (P < 0.002) levels. The high basal CET (34.4 +/- 13.1 nmol.ml-1.h-1) was decreased significantly by pravastatin treatment (27.5 +/- 13.7 nmol.ml-1.h-1, P = 0.013). There was a fall in the total cholesterol, free cholesterol, and phospholipid content of the Sf 0-12, 20-60, and 60-400 lipoproteins (all P = 0.001). Lecithin: cholesterol acyl transferase activity was not altered. The postprandial increase in VLDL cholesterol 5 h after a standardized mixed meal was attenuated after pravastatin treatment (P = 0.011). Inhibition of hepatic cholesterol synthesis with an HMG-CoA reductase inhibitor in hyperlipidemic patients with NIDDM decreased serum cholesterol content of triglyceride-rich lipoprotein, thereby decreasing the transfer of cholesteryl ester from HDL to LDL and VLDL.
Diabetes 1995 Apr
PMID:Effect of treatment with a hydroxymethylglutaryl coenzyme A reductase inhibitor on fasting and postprandial plasma lipoproteins and cholesteryl ester transfer activity in patients with NIDDM. 769 16

The question of whether the effects of insulin and glucagon on hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity are mediated largely by changes in the phosphorylation state of the enzyme or by changes in the quantity of enzyme protein was investigated by measuring enzyme protein and mRNA levels. If phosphorylation/dephosphorylation is responsible for the observed changes in HMG-CoA reductase activity, one would not expect to see changes in immunoreactive protein or mRNA levels in response to induction of diabetes, administration of insulin, or administration of insulin and glucagon. It was found that hepatic HMG-CoA reductase mRNA levels were decreased to 12% of control in diabetic rats. Immunoreactive protein was reduced to essentially undetectable levels. Administration of insulin restored both mRNA and immunoreactive protein levels. Glucagon blocked these effects. Enzyme activity changes were fully accounted for by changes in HMG-CoA reductase mRNA and immunoreactive protein. Fasting caused parallel falls in HMG-CoA reductase activity and immunoreactive protein levels with a lesser effect on mRNA levels. The insulin-mediated changes in HMG-CoA reductase gene expression correlated well with changes in blood glucose levels, indicating a physiological effect. Taken together, these results indicate that insulin and glucagon regulate HMG-CoA reductase gene expression largely at the level of enzyme protein through changes in mRNA concentrations.
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PMID:Insulin and glucagon modulate hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity by affecting immunoreactive protein levels. 796 82

The mechanisms by which diabetes leads to various manifestations of tissue damage are not yet fully understood; however, different recent studies suggest that some of them may be mediated by modified lipoproteins, although other lipid abnormalities also have been described in diabetes patients. Principally, the modification consists of an oxidation of the lipoprotein particle [mainly low-density lipoprotein (LDL)]. The oxidized LDL is then rapidly internalized by macrophages, converting them to cholesterol-loaded foam cells. In diabetic patients, oxidation occurs through two pathways: enzymatic (vascular inflammation) and nonenzymatic (polyunsaturated fatty acids) that can be blocked either by acetyl salicylic acid or by antioxidants. Moreover, in diabetes patients, higher glucose levels can also lead to a direct (stimulated by metals) or an indirect (by generation of glycosylated proteins) generation of free radicals, which will also damage proteins and collagen in particular. Clinically, lipid peroxide concentrations are higher in diabetic than in nondiabetic subjects, particularly in patients with vascular complications and with high triglyceride levels. These lipid peroxide levels can be decreased by antioxidants, whose concentrations are lower in diabetic patients. Preliminary data also indicate that HMG CoA reductase inhibitors can decrease lipid peroxide concentrations.
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PMID:Modified lipoproteins in diabetes. 767 61

Patients with non-insulin-dependent diabetes mellitus (NIDDM) are at high risk of cardiovascular disease for many reasons and especially due to the fact that dyslipidemias are more frequent in this group of patients. Fibrate derivatives are the drugs of choice when hypertriglyceridemia is the main lipid anomaly. When hypercholesterolemia is predominant, the use of resins and nicotinic acid has been advocated but these drugs are poorly tolerated on a long-term basis. We assessed the effect of simvastatin, a recent HMG-CoA reductase inhibitor in 12 NIDDM patients with hypercholesterolemia. After 4 weeks of placebo, which did not significantly modify the lipid values, patients were given simvastatin at increasing dosages (from 10 to a maximum of 40 mg daily) during 24 weeks. Compliance and clinical tolerance were excellent. There was no major biological side effect, but a significant deterioration of glucose control was noted at the end of the study. Simvastatin reduced total cholesterol by 28%, LDL-cholesterol by 36% and apo B by 31%. Concomitantly, there was an increase of HDL-cholesterol by 15%. This improvement of lipid profile persisted during the 24 weeks of treatment. Comparing the patients with pure hypercholesterolemia to those presenting combined hyperlipidemia, it was evident that the hypolipidemic effect was more marked in the diabetic subjects with combined hyperlipidemia.
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PMID:Efficacy of simvastatin for lowering cholesterol in non-insulin dependent diabetic patients with hypercholesterolemia. 806 75

Previous studies have shown that both cholesterol synthesis and the activity of hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, are increased in the small intestine of a wide variety of different animal models of diabetes. In the present study, we demonstrate that the mass of HMG CoA reductase protein is increased in the small intestine of both streptozocin-induced diabetic rats (2.5-fold) and streptozocin/alloxan-induced diabetic dogs (2.4-fold). These increases in HMG CoA reductase protein mass are of a magnitude similar to the previously observed increases in either HMG CoA reductase activity and/or cholesterol synthesis in the small intestine of diabetic animals. Furthermore, mRNA levels for HMG CoA reductase in the small intestine of diabetic rats and diabetic dogs are increased 2.1- and 1.7-fold, respectively. These results suggest that the increase in HMG CoA reductase protein levels in the small intestine of diabetic animals is due to an increase in mRNA levels. In contrast, mRNA levels for HMG CoA reductase in the liver of diabetic rats are not increased. Additionally, mRNA levels for the low-density lipoprotein (LDL) receptor are also increased in the small intestine of diabetic animals (rats, 43%; dogs, 59%). The increase in small-intestinal cholesterol synthesis has the potential for adversely affecting lipoprotein metabolism and increasing the risk of atherosclerosis in diabetes.
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PMID:Diabetes increases hepatic hydroxymethyl glutaryl coenzyme A reductase protein and mRNA levels in the small intestine. 815 2

Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (pravastatin sodium) can selectively inhibit cholesterol biosynthesis in the liver and may lower serum cholesterol concentrations even where there are no particular dietary restrictions. A 72-year old housewife with non-insulin-dependent diabetes mellitus complicated by hyperlipaemia type IIb, who did not follow directions for diet therapy or kinesitherapy, was administered HMG-CoA reductase inhibitor. The initial dose of 10 mg/day HMG-CoA reductase inhibitor was increased by 10 mg/day every 4 weeks to 30 mg/day, maintained at 30 mg/day for 8 weeks and then reduced gradually until discontinuation after a further 27 weeks. Test results showed the changes in low-density lipoprotein cholesterol and apoprotein B to be dose-dependent. The findings represent the first clinical evidence that hypercholesterolaemia can be adequately managed by the use of HMG-CoA reductase inhibitor, even when no specific dietary restrictions are imposed, and may contribute to improvements in the quality of daily life for many patients suffering from hyperlipaemia type IIb.
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PMID:Dose-dependent effect of hydroxymethylglutaryl-coenzyme A reductase inhibitor on serum cholesterol with limited dietary restrictions: a case study. 824 90

Atherosclerosis is the principal cause of diabetic morbidity and mortality. Diabetic dyslipidemia, obesity, and hypertension are significant contributing factors in the acceleration of the atherosclerotic process. Regardless of the type of diabetes, increased levels of very-low-density lipoprotein triglyceride, modified levels of low-density lipoprotein cholesterol, and decreased levels of high-density lipoprotein (HDL) cholesterol are the main lipoprotein abnormalities in diabetic patients. These abnormalities can be improved in part by glycemic control, but additional intervention may be needed. Diet and exercise are important elements in the management of dyslipidemia, but lipid-lowering drugs (especially fibrates and HMG-CoA reductase inhibitors) also may be necessary for the control of diabetic dyslipidemia. Based on these findings, the American Diabetes Association Consensus Panel and the revised treatment guidelines of the National Cholesterol Education Program recommend treatment of hypertriglyceridemia/low HDL cholesterol as a risk factor of coronary heart disease in diabetic and nondiabetic individuals alike. Aggressive treatment is recommended, therefore, particularly in diabetic patients and in all patients with existing vascular disease.
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PMID:Prevention of atherosclerosis in diabetes: emphasis on treatment for the abnormal lipoprotein metabolism of diabetes. 826 43

Optimum care of diabetic patients should include screening for lipid abnormalities. The combination of high triglyceride and low high-density lipoprotein cholesterol levels, which is common in non-insulin-dependent (type II) diabetes, should be considered a separate risk factor for coronary artery disease. Pharmacologic therapy for dyslipidemias should be considered early in diabetic patients with atherosclerotic disease that has not responded to hygienic measures, including diet, exercise, and smoking cessation. Use of HMG-CoA reductase inhibitors and gemfibrozil (Lopid) may be more appropriate for treatment of diabetic dyslipidemias than niacin or bile acid-binding resins.
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PMID:Dyslipidemias in diabetic patients. Is standard cholesterol treatment appropriate? 830 64

Hyperlipidemia associated with non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance is characterized by high triglyceride levels; raised levels of total low-density lipoprotein (LDL), which is made up of small, dense, cholesterol-rich particles; low levels of high-density lipoprotein (HDL); and glycosylation of apolipoproteins. Optimal drug therapy for this lipid profile is controversial. To test whether a fibrinic acid derivative (gemfibrozil) or a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (lovastatin) would produce better results in these patients, a crossover study was performed. Gemfibrozil 600 mg twice daily and, after a washout period, lovastatin 20 to 40 mg twice daily were administered to nine patients with NIDDM. Gemfibrozil significantly decreased triglyceride, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) levels, the total cholesterol:HDL ratio, and the IDL plus VLDL;HDL ratio, and significantly increased levels of HDL, HDL2, and HDL3. Lovastatin significantly decreased levels of total cholesterol, calculated LDL, directly measured LDL, IDL, total triglycerides, VLDL, and the ratios of LDL:HDL, total cholesterol:HDL, and directly measured LDL:HDL and significantly increased total HDL and HDL3 levels. Gemfibrozil was significantly more effective than lovastatin in raising total HDL and HDL3 levels and in lowering the IDL plus VLDL:HDL ratio. Lovastatin was significantly more effective than gemfibrozil in lowering total cholesterol, LDL, directly measured LDL, and the LDL:HDL and directly measured LDL:HDL ratios. In the absence of malignant hypertriglyceridemia, an HMG-CoA reductase inhibitor, rather than a fibrinic acid derivative, is indicated for the treatment of patients with dyslipidemia associated with NIDDM and insulin resistance.
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PMID:A comparison of lovastatin, an HMG-CoA reductase inhibitor, with gemfibrozil, a fibrinic acid derivative, in the treatment of patients with diabetic dyslipidemia. 859 42


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