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Query: UMLS:C0011849 (diabetes)
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Statins have become a cornerstone of treatment for dyslipidaemia primarily due to their marked lowering of low-density lipoprotein cholesterol (LDL-C). Studies show that statin treatment typically reduces relative risk of cardiovascular disease by 24-37%, regardless of age, sex, prior history of coronary heart disease (CHD), or other co-morbid conditions. There is also a growing body of evidence that statins can be effective in people whose LDL-C is not considered elevated under current guidelines. In both the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and the Collaborative Atorvastatin Diabetes Study (CARDS), participants randomised to atorvastatin (10 mg/day) experienced at least a one-third reduction in major cardiovascular events, even though at baseline, their LDL-C was within the normal range. Other studies have also provided evidence that more intensive lipid-lowering regimens could provide additional clinical benefits. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, the first active-control clinical trial of CHD progression, an intensive lipid-lowering regimen using atorvastatin (80 mg/day) decreased atherogenic lipoproteins and atheroma volume in patients with established CHD, compared with a moderate regimen using pravastatin (40 mg/day). Furthermore, relative to baseline, there was no measurable atheroma progression in the atorvastatin group. While statin therapy does offer significant clinical benefit, 60-70% of major cardiovascular events are still not prevented, which underscores the need for alternative interventions. Targeting inflammatory mediators of atherosclerosis such as C-reactive protein (CRP), as well as combination therapy to simultaneously raise high-density lipoprotein cholesterol (HDL-C) and lower LDL-C, are among the promising new strategies for primary and secondary prevention of atherosclerotic disease. This article will summarise data concerning use of statins in patients without markedly elevated LDL-C. The issue of the ideal LDL-C target will also be considered before addressing future treatment options for dyslipidaemia.
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PMID:Statins and LDL-cholesterol lowering: an overview. 1613 36

Patients with diabetes mellitus are at higher risk for cardiovascular events than those without diabetes. Furthermore, patients with diabetes have a characteristic 'lipid triad' of low high-density lipoprotein-cholesterol (HDL-C) levels, high triglyceride levels, and normal or slightly raised low-density lipoprotein-cholesterol (LDL-C) levels, with a preponderance of small, dense LDL-C particles. Current guidelines on preventing cardiovascular disease recognize the need not only to reduce LDL-C levels, but also to increase HDL-C and decrease triglyceride levels in diabetic patients. Some clinical trials of HMG-CoA reductase inhibitors (statins) have included large populations of diabetic patients. In some of these trials (such as 4S [Scandinavian Simvastatin Survival Study], CARE [Cholesterol and Recurrent Events] trial, and the HPS [Heart Protection Study]), HMG-CoA reductase inhibitor treatment significantly reduced cardiovascular events in diabetic patients, whereas in other trials (ALLHAT-LLT [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial], ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial]) the reductions were not significant. In CARDS (Collaborative Atorvastatin Diabetes Study), the first large HMG-CoA reductase inhibitor study to enroll only patients with type 2 diabetes, atorvastatin reduced cardiovascular events by 37% (p=0.001) compared with placebo. Fibric acid derivatives (fibrates), which are agonists of peroxisome proliferator-activated alpha receptors, exert their effects by altering the transcription of genes encoding proteins that control lipoprotein metabolism. Fibric acid derivatives are a valuable tool in the treatment of dyslipidemia in patients with diabetes, as they reduce plasma triglyceride levels by 30--50%, increase HDL-C levels by 10--15%, and shift the distribution of LDL subfractions towards larger, less atherogenic particles. The DAIS (Diabetes Atherosclerosis Intervention Study), which was conducted exclusively in patients with type 2 diabetes, found that fenofibrate reduces the progression of angiographic coronary artery disease. The VA-HIT (Veterans Affairs Cooperative Studies Program HDL-C Intervention Trial) showed that gemfibrozil reduced cardiovascular events in subgroups of diabetic patients. A large clinical event study, FIELD (Fenofibrate Intervention and Event Lowering in Diabetes), which is currently being completed, will provide further information on the value of fenofibrate for the reduction of cardiovascular risk in patients with diabetes.
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PMID:A new perspective in the treatment of dyslipidemia : can fenofibrate offer unique benefits in the treatment of type 2 diabetes mellitus? 1618 99

Despite meaningful progress in the identification of risk factors and the development of highly effective clinical tools, deaths from cardiovascular disease continue to increase worldwide. Sparked by an obesity epidemic, the metabolic syndrome and the rising incidence of type 2 diabetes have led to an upsurge of cardiovascular risk. Although pharmacologic treatments with the statin class of drugs have reduced cholesterol levels and lowered mortality rates, several large controlled clinical trials, including the Scandinavian Simvastatin Survival Study, the Cholesterol and Recurrent Events trial, the Air Force/Texas Coronary Atherosclerosis Prevention studies, and Long-term Intervention with Pravastatin in Ischemic Disease study, have indicated that cardiovascular events continue to occur in two thirds of all patients. Follow-up studies, such as the Heart Protection Study and the Pravastatin or Atorvastatin Evaluation and Infection Therapy/Thrombolysis In Myocardial Infarction-22 trials, reinforced these earlier results. Although therapy with gemfibrozil, a fibric acid derivative, showed reduced occurrence of cardiovascular events in the Helsinki Heart Study and the Veterans Affairs HDL Intervention Trial, results of other studies, e.g., the Bezafibrate Intervention Program and the Diabetes Atherosclerosis Intervention study, showed less encouraging results. Although lifestyle modifications, such as improved diet and increased exercise levels, benefit general health and the metabolic syndrome and insulin resistance in particular, most people continue to resist changes in their daily routines. Thus, physicians must continue to educate their patients regarding an optimal balance of drug therapy and personal behavior.
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PMID:The forgotten majority: unfinished business in cardiovascular risk reduction. 1619 35

The metabolic syndrome and type 2 diabetes mellitus are both becoming more prevalent, and both increase the risk of cardiovascular disease. Many patients are not receiving appropriate treatment for the type of dyslipidemia that commonly occurs in these disorders--the so-called 'atherogenic lipid triad' of high serum triglyceride levels, low serum high-density lipoprotein cholesterol (HDL-C) levels, and a preponderance of small, dense, low-density lipoprotein cholesterol (LDL-C) particles. All of the processes involved in atherogenesis can be exacerbated by insulin resistance and/or the metabolic syndrome. Hypertriglyceridemia is a strong predictor of coronary heart disease. There is also an inverse relationship between serum levels of HDL-C and triglycerides in diabetic patients, with low serum HDL-C levels possibly representing an independent risk factor for cardiovascular disease. Small, dense, LDL-C particles are also highly atherogenic as they are more likely to form oxidized LDL and are less readily cleared. Insulin resistance, which is central to the metabolic syndrome and type 2 diabetes mellitus, leads to high levels of very low-density lipoprotein (VLDL), which contain a high concentration of triglycerides, resulting in high serum triglyceride levels and low serum HDL-C levels. Even though modification of the atherogenic lipid triad is probably one of the most effective methods of reducing cardiovascular risk, therapy for diabetic dyslipidemia is often directed to first lowering serum LDL-C levels with a HMG-CoA reductase inhibitor. This may leave substantial excess risk for cardiovascular disease in patients with these types of dyslipidemia. The results of recent trials evaluating HMG-CoA reductase inhibitors have been mixed, with two showing no significant effect on cardiovascular outcomes in subgroups of diabetic patients. The recent CARDS (Collaborative Atorvastatin Diabetes Study) showed that atorvastatin can reduce cardiovascular events in a trial specifically designed for a diabetic population, though the population had to have at least one other risk factor in addition to diabetes mellitus. Fibric acid derivatives, such as fenofibrate, bezafibrate and gemfibrozil, are potentially well suited to the treatment of dyslipidemia that is generally associated with type 2 diabetes mellitus and the metabolic syndrome, as they are usually more effective than HMG-CoA reductase inhibitors for normalizing serum levels of HDL-C and triglycerides. Promising results have been obtained from several trials of fibric acid derivatives including the BIP (Bezafibrate Infarction Prevention) study and the VA-HIT (Veterans Affairs Cooperative Studies Program HDL-C Intervention Trial; gemfibrozil). The FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, a clinical outcomes trial specifically designed to evaluate fenofibrate in a large population of patients with type 2 diabetes mellitus, many of whom have the metabolic syndrome, is underway. The FIELD trial results should shed light on the efficacy and safety of fenofibrate in reducing cardiovascular morbidity in diabetic and metabolic syndrome patients and on the safety profile of combination therapy with fenofibrate and a HMG-CoA reductase inhibitor.
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PMID:Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome. 1625 26

The objective of this study was to determine the proportion of Greek patients referred to outpatient clinics for dyslipidemia who achieved the low-density lipoprotein cholesterol (LDL-C) goal defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines, using lifestyle changes, lipid-lowering drug treatment (LLDT), or both. Adult patients with dyslipidemia, who had been receiving a hypolipidemic diet and/or LLDT for at least 3 months were assessed in a multicenter study performed at 66 sites across Greece. Patients were followed up for an additional 3-month treatment period. Lipid levels were recorded at baseline and at the end of the study. The primary endpoint was the proportion of patients achieving their individual LDL-C target at the end of the study, according to their coronary heart disease (CHD) risk status or its equivalents, as defined by the NCEP-ATP III guidelines. Multivariate logistic models were used to identify determinants of undertreatment. The study included 2,660 adults (20-75 years) from 7 regions of Greece. Of the evaluable sample (n = 2,211; men 51%; mean age 62 +/-9 years) 81% were receiving LLDT (96% with statins and 3% with fibrates), 44% had a history of CHD, 61% arterial hypertension, 36% diabetes, and 26% a family history of premature CHD. Overall, 6% were at low CHD risk, 30% at medium CHD risk, and 63% at high CHD risk. At the end of the study, 26% of all patients and 30% of those receiving LLDT achieved the NCEP-specified LDL-C target levels. The percentage of patients at LDL-C goal according to CHD risk status was: low risk 67% (95% CI = 59-75), medium risk 29% (95% CI = 26-33), and high risk 20% (95% CI = 18-22). Statins proved to be more effective than fibrates (p <0.0001). Atorvastatin-treated subjects (n = 1,222, mean dose 19 mg/day) attained the LDL-C target (31% of the cases) at a higher rate than those receiving other LLDT (n = 574, 26% at target, p <0.01) or not receiving drug treatment (n = 415, 8%, p <0.001). This outcome was more evident in the high-CHD risk group (n = 1,402, 26% with atorvastatin vs 16% with other LLDT and 3% not receiving LLDT attained the LDL-C goal, ANOVA, p <0.001). The majority of dyslipidemic patients receiving LLDT, mainly those with high-CHD risk, are not achieving the NCEP LDL-C target. This is mainly explained by inadequate dose titration to ensure target goals are met. Promoting healthy lifestyle and appropriate LLDT (potent statins with sufficient dose titration) must be implemented to ensure that patients attain LDL-C treatment goals and thus benefit from the reduction in individual CHD risk.
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PMID:The control of dyslipidemia in outpatient clinics in Greece (OLYMPIC) Study. 1632 50

The incidence of type 2 diabetes mellitus is expected to increase dramatically over the next decade. Patients with type 2 diabetes are at a much greater risk for cardiovascular disease (CVD) than are nondiabetic individuals. Consequently, the treatment of CVD risk factors is a healthcare priority in this patient population. Dyslipidemia is a major cardiovascular (CV) risk factor in patients with type 2 diabetes, and it is characterized by elevated triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels, and a preponderance of small, dense low-density lipoprotein (LDL) particles. Subgroup analyses of clinical trial data suggest that treatment of the entire range of lipid abnormalities may reduce CV risk in this patient population. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the best therapy for LDL cholesterol reduction. A number of statin trials have shown significant CV risk reduction through LDL cholesterol lowering in subgroups of patients with diabetes. The recently published Collaborative Atorvastatin Diabetes Study (CARDS), a placebo-controlled trial conducted solely in patients with type 2 diabetes, terminated 2 years earlier than its anticipated length owing to the significant reduction in number of CV events observed in patients randomized to receive low-dose atorvastatin versus placebo. These results suggest that low-dose statin therapy with atorvastatin results in significant reduction of CV events in patients with type 2 diabetes without prior CVD or high LDL cholesterol levels. Based on this evidence, patients with type 2 diabetes may be candidates for statin therapy regardless of LDL cholesterol level and in the absence of a previous CV event.
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PMID:Benefits of lipid-lowering therapy in patients with type 2 diabetes mellitus. 1635 2

The study has been designed to investigate the effect of Bis-(maltolato) oxovanadium (BMOV), an inhibitor of protein tyrosin phosphatase (PTPase), in diabetes mellitus and hyperhomocysteinemia induced vascular endothelial dysfunction. Streptozotocin (55 mg kg(-1), i.v.) and methionine (1.7% w/w, p.o., 4 weeks) were administered to rats to produce diabetes mellitus (serum glucose >140 mg dl(-1)) and hyperhomocysteinemia (serum homocysteine>10 microM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) were estimated to assess oxidative stress. Atorvastatin has been employed in the present study as standard drug to improve vascular endothelial dysfunction. BMOV (0.2 mg/ml in drinking water) or atorvastatin (30 mg kg(-1), p.o.) in diabetic and hyperhomocysteinemic rats significantly reduced serum glucose and homocysteine concentration. BMOV or atorvastatin markedly improved acetylcholine induced endothelium dependent relaxation, vascular endothelial lining, serum nitrite/nitrate concentration and serum TBARS in diabetic and hyperhomocysteinemic rats. However, this ameliorative effect of BMOV has been prevented by l-NAME (25 mg kg(-1), i.p.), an inhibitor of NOS or by glibenclamide (5 mg kg(-1), i.p.), a blocker of ATP sensitive K(+) channels. Therefore, it may be concluded that BMOV induced inhibition of PTPase may activate eNOS due to opening of ATP sensitive K(+) channels and consequently reduce oxidative stress to improve vascular endothelial dysfunction.
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PMID:Inhibition of protein tyrosin phosphatase improves vascular endothelial dysfunction. 1644 49

The present study has been designed to investigate the effect of fasudil (Rho-kinase inhibitor) in diabetes mellitus (DM) and hyperhomocyteinemia (HHcy) induced vascular endothelial dysfunction (VED). Streptozotocin (55 mg kg(-1), i.v., once only) and methionine (1.7% w/w, p.o., daily for 4 weeks) were administered to rats to produce DM (serum glucose >140 mg dl(-1)) and HHcy (serum homocysteine >10 microM) respectively. VED was assessed using isolated aortic ring, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) concentration was estimated to assess oxidative stress. Atorvastatin has been employed in the present study as standard agent to improve vascular endothelial dysfunction. Fasudil (15 mg kg(-1) and 30 mg kg(-1), p.o., daily) and atorvastatin (30 mg kg(-1), p.o., daily) treatments significantly attenuated increase in serum glucose and homocysteine but their concentrations remained markedly higher than sham control value. Fasudil and atorvastatin treatments markedly prevented DM and HHcy-induced (i) attenuation of acetylcholine induced endothelium-dependent relaxation, (ii) impairment of vascular endothelial lining, (iii) decrease in serum nitrite/nitrate concentration, and (iv) increase in serum TBARS. It may be concluded that fasudil prevented DM and HHcy-induced VED partially by decreasing serum glucose and homocysteine concentration due to inhibition of Rho-kinase. Moreover, inhibition of Rho-kinase by fasudil and consequent prevention of oxidative stress may have directly improved VED in diabetic and hyperhomocysteinemic rats. The Rho-kinase appears to be a pivotal target site involved in DM and HHcy-induced VED.
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PMID:Involvement of Rho-kinase in experimental vascular endothelial dysfunction. 1644 2

Plasma phospholipid transfer protein (PLTP) plays an important role in lipoprotein metabolism. PLTP activity is elevated in patients with diabetes, a condition with strongly elevated risk for coronary heart disease. The aim of this study was to test the hypothesis that statins reduce PLTP activity and to examine the potential role of apolipoprotein E (apoE). PLTP activity and apoE were measured in patients with type 2 diabetes from the DALI (Diabetes Atorvastatin Lipid Intervention) Study, a 30-week randomized double-blind placebo-controlled trial with atorvastatin (10 and 80 mg daily). At baseline, PLTP activity was positively correlated with waist circumference, HbA(1c), glucose, and apoE (all P < 0.05). Atorvastatin treatment resulted in decreased PLTP activity (10 mg atorvastatin: -8.3%, P < 0.05; 80 mg atorvastatin: -12.1%, P < 0.002). Plasma apoE decreased by 28 and 36%, respectively (P < 0.001). The decrease in apoE was strongly related to the decrease in PLTP activity (r = 0.565, P < 0.001). The change in apoE remained the sole determinant of the change in PLTP activity in a multivariate model. The activity of PLTP in type 2 diabetes is decreased by atorvastatin. The association between the decrease in PLTP activity and apoE during statin treatment supports the hypothesis that apoE may prevent PLTP inactivation.
Diabetes 2006 May
PMID:Plasma phospholipid transfer protein activity is decreased in type 2 diabetes during treatment with atorvastatin: a role for apolipoprotein E? 1664 10

To study the effect of atorvastatin on recurrence of atrial fibrillation (AF) after electrical cardioversion (EC), 48 patients with AF lasting 48 hours who were scheduled for EC were randomized to the atorvastatin (group I) and control (group II) groups. Six patients in group I (25%) and 2 patients in group II (8.3%) had spontaneous conversion before EC (p >0.05). The end point was the recurrence of AF during 3 months of follow-up. Eighteen patients in group I (12.5%) and 11 patients in group II (45.8%) had recurrence (p = 0.01, log-rank test). With the Cox proportional model, the predictors of recurrence included a body mass index of 25 to 30 kg/m2 (relative risk [RR] 0.07, 95% confidence interval [CI] 0.008 to 0.59), body mass index > or = 30 kg/m2 (RR 0.24, 95% CI 0.08 to 0.72), AF duration of > or = 3 months (RR 0.28, 95% CI 0.09 to 0.83), diabetes mellitus (RR 0.34, 95% CI 0.12 to 0.98), and left atrial diameter of > or = 45 mm (RR 0.23, 95% CI 0.07 to 0.74). Atorvastatin was associated with a significantly reduced risk of developing AF (unadjusted RR 0.23, 95% CI 0.064 to 0.82, p = 0.024). This association remained significant after adjustment for these predictors (adjusted RR 0.19, 95% CI 0.052 to 0.72, p = 0.01). High-sensitivity C-reactive protein levels at baseline were not different between the 2 groups (p = 0.92). Although the high-sensitivity C-reactive protein levels decreased significantly 48 hours after EC compared with the baseline levels in group I (2.82 +/- 1.46 vs 2.56 +/- 1.3 mg/dl, p = 0.02), no significant change occurred in group II (2.87 +/- 0.8 vs 2.84 +/- 0.8 mg/dl, p = 0.09). In conclusion, atorvastatin decreased the recurrence rate of AF after EC.
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PMID:Effect of atorvastatin on the recurrence rates of atrial fibrillation after electrical cardioversion. 1705 54


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