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)

Male Yucatan swine were allocated to four groups (n = 5-6 pigs per group): low fat (3%) fed control, high fat/2% cholesterol (CH) fed (HF), high fat/CH fed with alloxan-induced diabetes (DF) and DF pigs that were treated with atorvastatin (80 mg/day; DF+A). Pigs were fed two meals per day and daily insulin injections were used in diabetic pigs to maintain plasma glucose between 250 and 350 mg/dl. Diabetic dyslipidemic (DF) pigs exhibited greater coronary atherosclerosis and increased collagen deposition in internal mammary artery compared with normoglycemic hyperlipidemic pigs. Although total and LDL CH concentrations did not differ, triglyceride (TG) were increased in DF pigs and FPLC analysis indicated that the LDL/HDL CH ratio was significantly increased in DF compared with HF pigs. The LDL fraction of DF pigs contained larger, lipid enriched particles resembling IDL. Consumption of the high fat/CH diet caused a moderate increase in the percentage of 14:0 fatty acids in plasma lipids and this was compensated by small-moderate declines in several unsaturated fatty acids. There was a significant increase in phospholipid arachidonic acid in DF compared with HF pigs. Atorvastatin protected diabetic pigs from atherosclerosis and decreased total and VLDL TG, but exerted minimal effects on the FPLC lipoprotein and plasma fatty acid profiles and plasma concentrations of total and LDL CH, vitamin A, vitamin E, and lysophosphatidylcholine. Across all groups the plasma CH concentration was positively correlated with hepatic CH concentration. These findings suggest that atorvastatin's protection against coronary artery atherosclerosis in diabetes may involve effects on plasma VLDL TG concentration. Lack of major effects on other lipid parameters, including the LDL/HDL ratio, suggests that atorvastatin may have yet other anti-atherogenic effects, possibly directly in the vessel wall.
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PMID:Increased atherosclerosis in diabetic dyslipidemic swine: protection by atorvastatin involves decreased VLDL triglycerides but minimal effects on the lipoprotein profile. 1236 46

Treatment of HIV infection with potent combination antiretroviral therapy has resulted in major improvement in overall survival, immune function and the incidence of opportunistic infections. However, HIV infection and treatment has been associated with the development of metabolic complications, including hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia. Safe pharmacological treatment of these complications requires an understanding of the drug-drug interactions between antiretroviral drugs and the drugs used in the treatment of metabolic complications. Since formal studies of most of these interactions have not been performed, predictions must be based on our understanding of the metabolism of these agents. All HIV protease inhibitors are metabolised by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir is the most potent inhibitor of CYP3A4. Ritonavir and nelfinavir also induce a host of CYP isoforms as well as some conjugating enzymes. The non-nucleoside reverse transcriptase inhibitor delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4. Drug interaction studies have been performed with HIV protease inhibitors and HMG-CoA reductase inhibitors. Coadministration of ritonavir plus saquinavir to HIV-seronegative volunteers resulted in increased exposure to simvastatin acid by 3059%. Atorvastatin exposure increased by 347%, but exposure to active atorvastatin increased by only 79%. Conversely, pravastatin exposure decreased by 50%. Similar results have been obtained with combinations of simvastatin and atorvastatin with other HIV protease inhibitors. Thus, the lactone prodrugs simvastatin and lovastatin should not be used with HIV protease inhibitors. Atorvastatin may be used with caution. Although there are no formal studies available, calcium channel antagonists and repaglinide may have significant interactions and toxicity when used with HIV protease inhibitors because of their metabolism by CYP3A4. Sulfonylurea drugs utilise mainly CYP2C9 for metabolism, and this isoenzyme may be induced by ritonavir and nelfinavir with a resulting decrease in efficacy of the sulfonylurea. Losartan may have increased effect when coadministered with ritonavir and nelfinavir because of the induction of CYP2C9 and the expected increase in formation of the active metabolite, E-3174. Overall, well-designed drug-drug interaction studies at steady state are needed to determine whether antiretroviral drugs may be safely coadministered with many of the drugs used in the treatment of the metabolic complications of HIV infection.
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PMID:Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. 1240 66

The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d(3)-leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased (P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL(2) cholesterol (P < 0.001), HDL(3) cholesterol (P < 0.01), apoAI (P = 0.01), and apoAII (P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased (P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production (P < 0.001) and FCR (P = 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome.
Diabetes 2003 Mar
PMID:Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. 1260 23

Seven hypertriglyceridemic patients with type-2 diabetes were treated with atorvastatin (40 mg/day) for 2 months. Kinetics of apolipoprotein B100 (apoB100)-containing lipoproteins were determined before and after atorvastatin treatment and compared with data obtained in five normolipidemic volunteers. ApoB100 metabolism was studied using stable isotopes and multicompartmental modeling. Compared with normolipidemic obese subjects, type-2 diabetic patients had a higher apoB100 concentration in very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and low-density lipoproteins (LDL) (P < 0.005). Kinetic analysis showed an increase in the total apoB100 production rate (P < 0.005) related to VLDL apoB100 overproduction (P < 0.005). Patients were also characterized by a lower fractional catabolic rate (FCR) in VLDL (not significant) or IDL (P < 0.005) mainly related to a decrease in VLDL and IDL delipidation rate (P < 0.005). Catabolism of LDL was also lower in diabetic patients (P < 0.05). Atorvastatin treatment significantly decreased plasma triglycerides (P < 0.05), total and LDL cholesterol (P < 0.05), apoB100 in LDL, IDL, and VLDL (P < 0.05). Treatment significantly decreased total apoB100 production rate (P < 0.05), but only for VLDL (P < 0.05). Treatment normalized FCR in IDL and LDL (P < 0.05). We concluded that atorvastatin improved lipid abnormalities in type-2 diabetic patients not only by increasing the clearance of apoB100-containing lipoproteins but also by decreasing VLDL production.
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PMID:Effect of atorvastatin on apolipoprotein B100 containing lipoprotein metabolism in type-2 diabetes. 1268 43

Lipids may adversely affect renal function. The recently published MRC/BHF Heart Protection Study (HPS) subgroup analysis showed that simvastatin significantly reduced the fall in glomerular filtration rate in high-risk patients with and without diabetes mellitus. These findings are in line with those of smaller earlier studies, including the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Lipid lowering trials need to consider that changes in renal function may occur. Renal and ischaemic heart disease may progress in parallel and statins may be beneficial to both organs.
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PMID:Statins and renal function in patients with diabetes mellitus. 1460 84

This is a prospective evaluation of the effect of structured care of dyslipidemia with atorvastatin (strict implementation of guidelines) versus usual care (physician's standard of care) on morbidity and mortality of patients with coronary heart disease (CHD) and diabetes mellitus (DM). From 1600 consecutive CHD patients randomized to either form of care in the GREek Atorvastatin and CHD Evaluation Study (GREACE), 313 had DM: 161 in the structured care arm and 152 in the usual care arm. All patients were followed up for a mean of 3 years. In the structured care group, patients were treated with atorvastatin to achieve the National Cholesterol Education Program (NCEP) low-density lipoprotein cholesterol (LDL-C) treatment goal of <2.6 mmol/L (100 mg/dL). Primary endpoints were all-cause and coronary mortality, coronary morbidity, and stroke. In the structured care group, 156 patients (97%) were taking atorvastatin (10-80 mg/day; mean, 23.7 mg/day) throughout the study; the NCEP LDL-C treatment goal was reached by 150 patients (93%). Only 17% (n=26) of the usual care patients were on long-term hypolipidemic drug treatment and 4% (n=6) reached the NCEP LDL-C treatment goal. During the study, 46 of 152 (30.3%) CHD patients with DM on usual care experienced a major vascular event or died versus 20 of 161 (12.5%) patients on structured care; relative risk reduction (RRR) 58%, p<0.0001. RRR for all-cause mortality was 52%, p=0.049; coronary mortality 62%, p=0.042; coronary morbidity 59%, p<0.002; and stroke 68%, p=0.046. Event rate curves started deviating from the sixth treatment month and the RRR was almost 60% by the 12th month. RRRs remained at that level until the end of the study, when they became statistically significant. The cost/life-year gained with structured care was estimated at 6200 US dollars. In CHD patients with DM, structured care of dyslipidemia with atorvastatin to achieve the NCEP LDL-C treatment goal, reduces all-cause and coronary mortality, coronary morbidity, and stroke by more than one half within a 3-year period, in comparison to usual care. Clinical benefit is manifested as early as the sixth month of treatment.
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PMID:Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus. 1466 56

Dyslipidemia, characterized by elevated serum levels of triglycerides and reduced levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol, has been recognized in patients with human immunodeficiency virus (HIV) infection. It is thought that elevated levels of circulating cytokines, such as tumor necrosis factor-alpha and interferon-alpha, may alter lipid metabolism in patients with HIV infection. Protease inhibitors, such as saquinavir, indinavir and ritonavir, have been found to decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with a syndrome of fat redistribution, insulin resistance, and hyperlipidemia. Elevations in serum total cholesterol and triglyceride levels, along with dyslipidemia that typically occurs in patients with HIV infection, may predispose patients to complications such as premature atherosclerosis and pancreatitis. It has been estimated that hypercholesterolemia and hypertriglyceridemia occur in greater than 50% of protease inhibitor recipients after 2 years of therapy, and that the risk of developing hyperlipidemia increases with the duration of treatment with protease inhibitors. In general, treatment of hyperlipidemia should follow National Cholesterol Education Program guidelines; efforts should be made to modify/control coronary heart disease risk factors (i.e. smoking; hypertension; diabetes mellitus) and maximize lifestyle modifications, primarily dietary intervention and exercise, in these patients. Where indicated, treatment usually consists of either pravastatin or atorvastatin for patients with elevated serum levels of LDL-C and/or total cholesterol. Atorvastatin is more potent in lowering serum total cholesterol and triglycerides compared with other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but it is also associated with more drug interactions compared with pravastatin. Simvastatin and lovastatin are significantly metabolized by cytochrome P450 enzymes (CYP3A4) and are therefore not recommended for coadministration with protease inhibitors. A fibric acid derivative (gemfibrozil or fenofibrate) should be used in patients with primary hypertriglyceridemia. However, it must be kept in mind that protease inhibitors, such as nelfinavir and ritonavir, induce enzymes involved in the metabolism of the fibric acid derivatives and may, therefore, reduce the lipid-lowering activity of coadministered gemfibrozil or fenofibrate. In certain patients HMG-CoA reductase inhibitors may be used in combination with fibric acid derivatives but patients should be carefully monitored for liver and skeletal muscle toxicity. Select patients may experience improvements in serum lipid levels when their offending protease inhibitor(s) is/are exchanged for efavirenz, nevirapine, or abacavir; however each patient's virologic and immunologic status must be taken closely into consideration.
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PMID:Management of protease inhibitor-associated hyperlipidemia. 1472 85

Dyslipidaemia is common in patients with Type 2 diabetes and is held to be responsible for considerable CVD-related morbidity and mortality. Patients with Type 2 diabetes are at high risk from complications associated with atherosclerosis and should therefore receive preventive interventions. At the level of the adipocyte, impaired insulin action leads to increased rates of intracellular hydrolysis of triglycerides with the release of NEFA. The rise in NEFA provides substrate for the liver that, in the presence of impaired insulin action and relative insulin deficiency, is associated with complex alterations in plasma lipids: * Plasma VLDL levels are raised. (i). Increased VLDL levels are associated with post-prandial hyperlipidaemia that is compounded by impaired LPL activity. The latter may be independently associated with CAD. (ii). Remnant particles can deliver more cholesterol to macrophages than LDL-C particles. Thrombogenic alterations in the coagulation system also ensue from hypertriglyceridaemia. * Plasma HDL-C levels are reduced. (i). The reduction in cardioprotective HDL-C means a reduction of cholesterol efflux from the tissues--the first step in reverse cholesterol transport to the liver from peripheral tissues. (ii). The antioxidant and antiatherogenic activities of HDL-C are reduced when circulating levels are low. * LDL-C particles become small and dense. Small, dense LDL-C particles are held to be more atherogenic than their larger, buoyant counterparts because they (a) are more liable to oxidation and (b) may more readily adhere to and subsequently invade the arterial wall. The atherogenicity of LDL-C may also be enhanced by nonenzymatic glycation. Metabolic and lipid abnormalities can often be improved with lifestyle changes, including dietary modification, weight loss, smoking cessation and increased exercise. Although attainment of better glycaemic control may improve diabetic dyslipidaemia, pharmacological intervention is usually required. Several large-scale clinical trials, including 4S and more recently HPS, have clearly demonstrated the benefits of statins in reducing cardiovascular events. By virtue of their high absolute risk of CVD, many patients with Type 2 diabetes may achieve a greater risk reduction than their non-diabetic counterparts. For example, in 4S there was a 43% reduction in total mortality risk among patients with diabetes compared with 29% for non-diabetics and a reduced risk of MI by 55% vs. 32% for diabetic and non-diabetics, respectively. In the diabetic subgroup in HPS, there were reductions of approximately 25-30% in the risk of first major vascular events. More recently, the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was halted early because of a significant reduction in cardiovascular events compared with placebo. Surprisingly an analysis of subgroups failed to show significance among the diabetic population, although the sample size, shortened follow-up period and higher drop-in statin use among diabetics on placebo may have affected results. The Collaborative Atorvastatin Diabetes Study (CARDS), involving 2800 patients with Type 2 diabetes, was halted 2 years early in June 2003 because patients allocated atorvastatin had significant reductions in MI, stroke and surgical procedures compared with those receiving placebo. The UKPDS demonstrated that the appearance and progression of certain microvascular complications of Type 2 diabetes could be reduced by treatment directed at hyperglycaemia and hypertension. In addition, correction of dyslipidaemia in patients with diabetes is important in reducing the high toll from macrovascular disease. The subjects in the HPS had similar lipid profiles to the participants in UKPDS, suggesting that additional benefit would accrue from a therapeutic assault on the main cardiovascular risk factors simultaneously. We now have firm evidence that appropriate use of statins in patients with Type 2 diabetes can significantly reduce cardiovascular morbidity and mortality.
Diabetes Obes Metab 2003 Nov
PMID:Lipoprotein abnormalities and their consequences for patients with type 2 diabetes. 1498 18

Both in Western countries and in third world countries there is an increasing incidence of obesity. Obesity per se or insulin resistance associated with obesity may increase cardiovascular risk factors including dyslipidemia, hypertension and Type 2 diabetes. Over the past decade the understanding has increased of specific mediators in the hypothalamus that are involved in regulating food intake and body weight. In obese humans fasting plasma lipids can be normal but postprandial lipid metabolism is abnormal with an accumulation of triglyceride-rich remnant lipoproteins. In viscerally obese men chylomicron remnant catabolism was markedly decreased when compared with lean individuals. The decreased clearance of chylomicron remnants in viscerally obese subjects may be explained by competition between chylomicron remnants and the increased hepatic production of VLDL for clearance by low density lipoprotein receptors. Increased food intake in rodent models of obesity was shown to be associated with a delay in the catabolism of remnant lipoprotein particles. Prevention of hyperphagia was found to correct the impairment in the metabolism of remnant lipoproteins. Under fasting and food restricted conditions the improvement of remnant metabolism was associated with an increased oxidation of remnant lipids as determined by a novel stable isotope breath test. Anti-obesity and lipid lowering drugs have been used for the treatment of obesity. Inhibitors of cholesterol synthesis inhibitors (statins) have been shown to be effective in treating dyslipidemia. Inhibition of cholesterol synthesis with Atorvastatin was shown to improve chylomicron metabolism by increasing chylomicron remnant catabolism in obese subjects as assessed by the newly developed stable isotope breath test.
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PMID:Obesity and post-prandial lipid metabolism. Feast or famine? 1502 94

The management of dyslipidemia in adults with diabetes is receiving more attention. However, there is a paucity of large, prospective, randomized outcome trials designed for diabetic patients. Diabetic dyslipidemia is characterized by an increase in triglyceride levels, low high-density lipoprotein (HDL) cholesterol concentrations, and small, dense low-density lipoprotein (LDL) particles. The treatment goals include an LDL cholesterol less than 100 mg/dL, triglyceride level less than 150 mg/dL, and an HDL greater than 40 mg/dL for men and more than 50 mg/dL for women. In the Diabetic Atherosclerosis Intervention Study, fenofibrate resulted in a 42% less increase in the percent stenosis, as assessed by quantitative coronary arteriography. The Heart Protection Study documented the unambiguous benefit of simvastatin in reducing all-cause mortality among 5963 diabetic patients. The Lescol Intervention Prevention Study observed a reduction in major adverse cardiac events in diabetics undergoing percutaneous intervention who received fluvastatin. The Veterans Affairs HDL Cholesterol Intervention Trial reported a reduction in major coronary events among 627 diabetic patients with low HDL cholesterol who sustained a myocardial infarction. The Fenofibrate Intervention and Event Lowering in Diabetics (FIELD) Trial (n = 9795), the Action to Control Cardiovascular Risk in Diabetes (ACCORD, n = 10,000), the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non Insulin Dependent Diabetes Mellitus (ASPEN, n = 2421), and the Collaborative Atorvastatin Diabetes Study (CARDS, n = 2140) will provide the prospective outcome data that are needed for the management of patients. Combination drug therapy will be necessary to achieve treatment goals. Careful monitoring will be required to avoid myositis and hepatotoxicity.
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PMID:Clinical trials and lipid guidelines for type II diabetes. 1505 51


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