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Query: UMLS:C0011849 (diabetes)
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The dyslipidaemic profile of diabetes greatly contributes to the increased cardiovascular risk associated with the disorder, and evidence from many intervention trials using statins, fibrates, nicotinic acid or a nicotinic acid-statin combination, indicates the substantial cardiovascular risk reduction to be gained from lipid modification. Several large statin trials have demonstrated the efficacy of cholesterol-lowering in individuals with coronary heart disease and raised low-density lipoprotein-cholesterol (LDL-C) (>or=130 mg/dL; >or=3.4 mmol/L), but for the 40% of patients whose LDL-C is within recommended limits, many of whom have low high-density lipoprotein-cholesterol (HDL-C), an alternative strategy is necessary if excess risk is to be minimized. The veterans affairs high-density lipoprotein cholesterol intervention trial (VA-HIT) proved the efficacy of the fibric acid derivative, gemfibrozil, to elevate HDL-C and reduce triglycerides, with a resulting 22% relative risk reduction for cardiovascular death or non-fatal myocardial infarction, and even greater reductions in individuals with insulin resistance and diabetes. Increased HDL-C was independently predictive of reduction in coronary heart disease. In the Coronary Drug Project, individuals with diabetes or insulin resistance derived as much as 70% cardiovascular risk reduction from the HDL-C elevations achieved with nicotinic acid therapy. The effects of lowering LDL-C and raising HDL-C are additive and predictive of total cardiovascular event reduction, and by using statin-nicotinic acid combination therapy, cardiovascular risk reductions as great as 90% are possible. Such combination strategies offer patients the greatest opportunity for improved cardiovascular health and are likely to become the treatment strategy of the future.
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PMID:What is the most effective strategy for managing diabetic dyslipidaemia? 1605 42

In the summer of 2004, an evidence-based update of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines for management of hypercholesterolemia was published. This detailed assessment of 5 major clinical trials, published since the ATP III report in 2001, was designed to provide guidance for physicians in decision making for patients at high risk and very high risk. We have tried to summarize this assessment by suggesting the following to clinicians: (1) Calculate global risk of coronary artery disease (CAD) to determine an overall strategy for cholesterol management. (2) Emphasize the benefits of diet, exercise, and weight control or therapeutic lifestyle change, especially in those with lifestyle risk factors. (3) Use 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (statins) as first-line drugs to reduce risk of CAD and stroke in those at moderate to high risk. (4) If statins are prescribed, use moderate doses that reduce plasma levels of low-density lipoprotein (LDL) cholesterol by > or = 30% to 40%. (5) Strongly consider statin therapy in those with diabetes (with the exception of severe hypertriglyceridemia). (6) Consider LDL cholesterol-lowering drug therapy for lipids in older patients at risk. (7) Consider adding either a fibrate or nicotinic acid in high-risk patients with elevated plasma triglyceride values or low levels of plasma high-density lipoprotein cholesterol after statin therapy has achieved the LDL cholesterol goal. (8) Continue to treat those at low risk in similar fashion as before. This update is to inform current physician judgment in this area. Further clinical trial data that may modify or extend these recommendations are eagerly awaited.
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PMID:Recent National Cholesterol Education Program Adult Treatment Panel III update: adjustments and options. 1609 45

The metabolic syndrome is a constellation of interrelated abnormalities that increase the risk for cardiovascular disease and progression to type 2 diabetes. The prevalence of this syndrome is increasing because of the 'obesity epidemic'. The National Cholesterol Education Program Adult Treatment Panel III defined practical criteria for the diagnosis of the metabolic syndrome and established the basic principles for its management. Also, the International Diabetes Federation recently proposed another definition. The metabolic syndrome is a secondary target for cardiovascular risk reduction. Clinicians should identify individuals with this condition, assess their cardiovascular risk and treat them by an aggressive and multifaceted approach. The most effective therapeutic intervention in patients with the metabolic syndrome should focus on modest weight reduction and regular physical activity. Adoption of a healthier diet and smoking cessation are necessary. Drug therapy may be needed to achieve recommended goals if therapeutic lifestyle changes are not sufficient. Low-density lipoprotein cholesterol is the primary target of therapy (new aggressive goals should be achieved). Statins are probably the drugs of choice. Fibrates and nicotinic acid are also useful options. Hypertension should be managed aggressively probably starting with an inhibitor of the renin-angiotensin system or a calcium channel blocker and adding a low dose of a thiazide diuretic if necessary. Aspirin should be administered if the cardiovascular risk is high. In the future acarbose, metformin, meglitinides and thiazolidinediones may be used in patients with the metabolic syndrome to delay the onset of type 2 diabetes and reduce cardiovascular risk. Such an intense and multifactorial approach is likely to reverse the bad prognosis associated with the metabolic syndrome.
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PMID:Diagnosis and management of the metabolic syndrome in obesity. 1624 14

Prolonged-release (PR) nicotinic acid (niacin) [Niaspan] is an oral, once-daily formulation of the lipid-modifying drug designed to produce less vasodilatory flushing than crystalline immediate-release (IR) nicotinic acid and less hepatotoxicity than previous sustained-release formulations of nicotinic acid.PR nicotinic acid appears to retain the same level of efficacy as crystalline IR nicotinic acid and be better tolerated than older nicotinic acid formulations. Nicotinic acid has beneficial effects on all traditional blood lipid and lipoprotein fractions and is the most effective agent for increasing high-density lipoprotein (HDL)-cholesterol (HDL-C) and reducing lipoprotein(a). The effects of PR nicotinic acid are often additive when used in combination with HMG-CoA reductase inhibitors (statins), making it a useful addition when lipid goals are not achieved with the usual statin monotherapy or when additional correction of a specific lipid abnormality is required. PR nicotinic acid also slows atherosclerotic progression and even appears to produce regression of atherosclerosis in patients on stable statin therapy. PR nicotinic acid is a logical drug choice for treating atherogenic dyslipidaemia commonly associated with type 2 diabetes mellitus and the metabolic syndrome, and has been shown to be effective in patients with diabetes without adversely affecting glycaemic control in the majority of patients. The incidence of vasodilatory flushing with PR nicotinic acid is lower than with IR nicotinic acid and it decreases substantially over time as tolerance develops. To date, there has been no clinically significant hepatotoxicity observed with PR nicotinic acid. Therefore, once-daily PR nicotinic acid appears to maximise the potential benefits of nicotinic acid, while minimising any historical tolerability or safety concerns.
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PMID:Prolonged-release nicotinic acid: a review of its use in the treatment of dyslipidaemia. 1639 85

The use of lipid-lowering drugs in diabetes is aimed primarily at reducing the large cardiovascular disease (CVD) risk burden experienced by this group of patients. Statin therapy has been shown to be highly efficacious in reducing CVD risk, both in those with and without prior CVD. Therefore, statins are the first-line lipid-lowering therapy in patients with diabetes. Patients with diabetes and established CVD should have low-density lipoprotein cholesterol (LDLC) lowered to at least 2.6 mmol/L (100 mg/dL) and, if possible, to 1.8 mmol/L (70 mg/dL). Those without prior CVD should have LDLC lowered to 2.6 mmol/L. Triglycerides should be kept less than 1.7 mmol/L (150 mg/dL) and high-density lipoprotein cholesterol (HDLC) above 1.15 mmol/L (40 mg/dL) in men and 1.2 mmol/L (46 mg/dL) in women. Additional therapy with fibrates or nicotinic acid may be needed to achieve these goals; the choice is determined by tolerance and side-effect profile. The use of nicotinic acid or fibrates on their own to achieve triglyceride or HDLC levels should be limited to those patients already at or near LDLC goals. Caution is warranted with combination therapy because muscle side effects, in particular, can increase. In type 1 diabetes, CVD risk is high but trial data are sparse. Where there is nephropathy, and where glycemic control is poor, there will often be a need for triglyceride and HDLC raising interventions as above. In the absence of these, lipid profile is often normal and focus should be on reducing CVD risk by statin therapy. If uncertainty about CVD risk status exists, consideration should be given to using CVD imaging modalities to inform intervention choice in younger patients.
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PMID:Treatment of lipid disorders in patients with diabetes. 1640 82

The metabolic syndrome appears to affect a significant proportion of the population and is associated with increased risk for development of cardiovascular disease as well as of type-2 diabetes. No single treatment for the metabolic syndrome as a whole yet exists. While the primary management of patients with the metabolic syndrome involves healthy lifestyle promotion, the atherogenic dyslipidemia is a primary target for cardiovascular disease risk reduction in these patients. Statin therapy provides effective reduction of LDL-cholesterol, which represents the primary therapeutic goal of lipid-lowering therapy in patients at risk for cardiovascular disease. Fibrates in turn are effective in normalizing lipid levels (mainly triglycerides and HDL-cholesterol) in patients with the metabolic syndrome and may improve insulin resistance. Whereas statins remain the drug of choice for patients who need to achieve the LDL-cholesterol goal, fibrate therapy may represent an alternative for those with low HDL-cholesterol and high triglyceride levels. The simultaneous use of fibrates could be indicated in patients whose LDL-cholesterol is controlled by statin therapy but whose HDL-cholesterol and/or triglycerides are still inappropriate. Such a combination, however, needs careful monitoring due to the potential hazard of adverse drug interactions. Nicotinic acid and ezetimibe may be useful agents for therapy, particularly when combined with statins. A number of emerging therapies offer potential as future options for the pharmacological treatment of metabolic syndrome.
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PMID:Hypolipidemic therapy for the metabolic syndrome. 1662 89

Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-(3)H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t=0-240 min), and hyperglycemia (10 mmol/l, t=240-360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA(1c) 10.9 +/- 0.4%, age 50 +/- 3 years, BMI 30 +/- 2 kg/m(2)) on at least two occasions with saline (NA- group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h = 31 +/- 6% suppression of EGP with hyperglycemia vs. NA- = 8 +/- 7%; P<0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h = 41 +/- 8% suppression of EGP; P = NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.
Diabetes 2006 Jun
PMID:Time-dependent effects of free fatty acids on glucose effectiveness in type 2 diabetes. 1673 40

Type 2 diabetes and atherosclerotic vascular disease develop in parallel. Prospective epidemiologic studies have shown a striking communality of major risk factors for both diseases. This raises the question of a "common soil". The traits of the metabolic syndrome including dyslipidemia, visceral obesity and hypertension are predictors of type 2 diabetes as well as coronary heart disease. The same applies to the environmental factors: overnutrition, physical inertia and smoking. Visceral obesity, insulin resistance and low-grade inflammation are known as major components of the common soil for metabolic syndrome and coronary heart disease. Depending on the quality of metabolic control diabetes will accelerate the progression of atherosclerosis via unstable plaque formation. The "common soil" concept provides a paradigm for an integrated therapeutic approach. This applies to a lifestyle intervention as well as a rational use of drugs in diseases of the metabolic syndrome. The medication should consider coexisting disorders of the metabolic syndrome to use pleiotropic effects. On the other hand, side effect such as the worsening of blood glucose levels caused by beta-blockers and diuretics should be avoided. The following medication should be preferred in context of the metabolic syndrome: oral antidiabetics such as acarbose, metformin and thiazolidinediones, antihypertensives such as ACE inhibitors and ARBs (angiotensin receptor blockers) and lipid-lowering drugs such as atorvastatin, rosuvastatin, and the modern nicotinic acid derivative Niaspan, respectively. The strategy using synergies in drug treatment can reduce polypharmacy and costs and improve the patients' compliance.
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PMID:[Metabolic syndrome: "common soil" for diabetes and atherosclerosis. Novel approaches to an integrated therapy]. 1677 May 62

Resorption inhibitors for cholesterol are commonly applied today in case of hypercholesterolemia in addition to statins. This combination therapy reduces the value of the LDL concentration by 50-60%. A target value of 100 mg/dl should be adjusted in case of high-risk patients in order to also decrease coronary risk. The significance of the triglycerides level is also becoming increasingly important, for it describes a high cardiovascular risk due to an increase of adiposity and diabetes. Such a dysfunction in storage and release of fatty lipids from triglycerides is treated dependent on severity: Patients with slightly elevated values (> 200 mg/dl) should change their habits (e.g. balanced diet, abstinance of alcohol, exercise) if necessary followed by application of fibrates, omega-3 fatty acids or nicotinic acid. These medicamentous measures are inevitable and must be applied immediately in case patients having values >1000 mg/dl.
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PMID:[Lipometabolic disorder--cholesterol and triglycerides]. 1701 80

The metabolic syndrome or cardiovascular dysmetabolic syndrome is characterized by obesity, central obesity, insulin resistance, atherogenic dyslipidemia, and hypertension. The major risk factors leading to this syndrome are physical inactivity and an atherogenic diet and cornerstone clinical feature is abdominal obesity or adiposity. In addition, patients usually have elevated triglycerides, low HDL cholesterol, elevated LDL cholesterol, other abnormal lipid parameters, hypertension, and elevated fasting blood glucose. Impaired fibrinolysis, increased susceptibility to thrombotic events, and raised inflammatory markers are also observed. Given that India has the largest number of subjects with type-2 diabetes in the world it can be extrapolated that this country also has the largest number of patients with the metabolic syndrome. Epidemiological studies confirm a high prevalence. Therapeutic approach involves intervention at a macro-level and control of multiple risk factors using therapeutic lifestyle approaches (diet control and increased physical activity, pharmacotherapy - anti-obesity agents) for control of obesity and visceral obesity, and targeted approach for control of individual risk factors. Pharmacological therapy is a critical step in the management of patients with metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. Anti-obesity drugs such as sibutramine and orlistat can be tried to reduce weight and central obesity and jointly control the metabolic syndrome components. Other than weight loss, there is no single best therapy and treatment should consist of treatment of individual components of the metabolic syndrome. Newer drugs such as the endocannabinoid receptor blocker,rimonabant, appear promising in this regard. Atherogenic dyslipidemia should be controlled initially with statins if there is an increase in LDL cholesterol. If there are other lipid abnormalities then combination therapy of statin with fibrates, nicotinic acid, or ezetimibe should be considered. For insulin resistance, drugs such as thiazolidinediones and renin-angiotensin system blockers are available. Available evidence suggests that angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBS) may be more beneficial for treatment of hypertension in patients with metabolic syndrome compared to others as these drugs also prevent development of diabetes. Patients with metabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothrombotic state and aspirin may be beneficial for primary prevention in these patients. The new developments in the treatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor (PPAR) agonists and cannabinoid receptor-1 antagonists, will broaden the horizons of the current treatment options. Fixed-dose combination polypharmacy using a single pill is an interesting concept that needs to be evaluated in long-term prospective trials in such patients.
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PMID:Management issues in the metabolic syndrome. 1721 77


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