The results from two other recent studies also support a strategy of intensive lipid lowering with statins in patients with diabetes. In specific, the treating to new targets (TNT) trial compared the effects of 10 vs. 80 mg atorvastatin over 5 years (32). A total of 10,001 patients with stable CHD and LDL cholesterol <130mg/dL (3.3mmol/L) were randomly assigned to the two aforementioned atorvastatin doses. The primary endpoint was the occurrence of a first major cardiovascular event (death from CHD, nonfatal-non-procedure-related MI, and resuscitation after cardiac arrest, fatal or nonfatal stroke). A primary event occurred in 8.7% of the subjects receiving 80 mg of atorvastatin and in 10.9% of those receiving 10 mg, representing a significant 22% relative risk reduction (p<0.001). A total of 1501 patients had diabetes. In this group a primary event occurred in 17.9% of the patients receiving atorvastatin 10 mg compared with 13.8% receiving atorvastatin 80 mg (=0.026). In specific, intensive therapy with atorvastatin 80 mg in patients with diabetes and CHD significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg. End-of-treatment mean LDL cholesterol levels were 2mmol/L (77mg/dL) and 2.5mmol/L (98.6mg/dL), respectively (33).

Another comparative statin trial in high risk patients was the pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 trial (PROVE IT-TIMI 22) (34). This trial randomized 4162 patients who had been hospitalized for an acute coronary syndrome to either pravastatin 40 mg d-1 or atorvastatin 80 mg d-1 18% of all patients had diabetes. The primary end point was death from any cause, MI, unstable angina requiring rehospitalisation, revascularisation, and stroke. After a mean follow-up of 2 years, atorvastatin therapy was associated with a 16% reduction in risk for the primary end point compared with pravastatin with a similar reduction (17%) seen in the subgroup of patients with diabetes.

While the aforementioned evidence from subgroup post-hoc analyses of major statin trials suggested a benefit from statin therapy in patients with diabetes there are only two statin trials investigating this question in a hypothesis-based prospective fashion thus specifically recruiting patients with diabetes. These are the collaborative atorvastatin diabetes study (CARDS) (35) and the atorvastatin study for prevention of coronary heart disease endpoints in non-insulin-dependent diabetes mellitus (ASPEN) (36). In CARDS the patients had relatively low LDL cholesterol (<160mg/dL, 4.14mmol/L), serum triglycerides <600mg/dL, (6.78mmol/L), no history of CVD, but >1 risk factor for CHD in addition to diabetes. At entry, patients were 40 to 75 years old. A total of 2838 patients were randomized in a doubleblind fashion to receive placebo or atorvastatin 10 mg/day. The combined primary endpoint was an acute CHD event, coronary revascularisation and stroke. The trial was originally planned for 5 years, but was terminated at 3.9 years, because of a substantial reduction in the incidence of cardiovascular events observed in the atorvastatin group (37% reduction compared to placebo). All cause mortality was reduced by 27%, although this finding achieved only borderline statistical significance (p=0.059). In order to prevent one major CVD event, 27 patients with diabetes would need to be treated for four years. When the parameters of the primary endpoint were assessed separately, atorvastatin therapy was associated with a 36% reduction in coronary events, a 31% reduction in coronary revascularisation procedures and a 48% reduction in stroke compared with placebo. There was also no evidence of heterogeneity by age, gender, baseline systolic blood pressure, retinopathy, albuminuria or smoking. Moreover these effects were independent from the baseline LDL cholesterol, HDL cholesterol or triglyceride concentrations. The authors of CARDS concluded that the question should not be whether all patients with type 2 diabetes warrant statin therapy, but if there are any patients at sufficiently low risk for this treatment to be withheld.

The just recently published ASPEN trial (36), however, failed to reproduce these findings. This combined primary and secondary prevention trial was a 4-year double-blind study involving 2410 patients with type 2 diabetes, which compared the effects of 10mg/day atorvastatin to placebo. The composite primary endpoint was similar to that of CARDS (cardiovascular death, nonfatal MI, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest and worsening or unstable angina requiring hospitaliza-tion). There was no difference found in the primary end point between the placebo and the atorvastatin group, a result that could be attributed, at least in part, to the high statin drop-in rate (26.9%) in the placebo group.

Fibrate Treatment for Patients With Diabetes

While there is considerable amount of evidence to support that the use of statins reduces LDL cholesterol in patients with diabetes and provides cardiovascular benefit, there is much less persuasive evidence regarding potential beneficial effects of fibrates.

The veterans affairs high-density lipoprotein intervention trial (VA-HIT) (37) was a secondary intervention trial in 2531 men younger than 74 years of age who had an established diagnosis of CHD with low HDL cholesterol levels of <40 mg/dL (1 mmol/L) and LDL cholesterol of <140 mg/dL (3.6 mmol/L). The subjects were randomized to receive gemfibrozil (1200 mg/day) or placebo. The primary outcome was death due to coronary causes or non fatal MI. Treatment with gemfibrozil resulted in a 22% reduction in the primary endpoint (p=0.006) for a mean follow-up period of 5.1 years. In a subgroup analysis, it was revealed that gemfibrozil induced a smaller increase in HDL cholesterol and a smaller decrease in TG in subjects with diabetes compared to non-diabetics (5% vs. 8% and 20% vs. 29%, respectively) (38). Interestingly, despite of the more limited improvement in the lipid profile in patients with diabetes, gemfibrozil use was associated with a greater risk reduction in the combined end points in the subjects with diabetes compared to the non-diabetic patients (32% vs. 18%, respectively). The reduction in CHD death was 41% and in stroke 40%. Moreover, among the non-diabetic patients, gemfibrozil was most effective in reducing major cardiovascular events in individuals having insulin values within the highest fasting plasma insulin (FPI) quartile, in specific 39 pU ml-1 (risk reduction 35%, p=0.04). In short, this study showed that in men with CHD and low HDL-C levels gemfibrozil significantly reduces the risk of major cardiovascular events.

In a subsequent analysis of VA-HIT data it was shown that the occurrence of new cardiovascular events and the benefit of fibrate therapy was much less dependent on the levels of HDL cholesterol or triglycerides than on the presence or absence of insulin resistance (39).

The St. Mary's Ealing, Northwick park diabetes cardiovascular disease prevention (SENDCAP) study (40) was a double-blind placebo-controlled primary prevention trial of 164 patients (117 men, 47 women) with diabetes and a mean age of 50.9 years, randomized to receive bezafibrate (400 mg daily) or placebo for a minimum of 3 years. No significant differences between the two groups were found in the progress of arterial disease measured by carotid and femoral artery ultrasound. However, those treated with bezafibrate had a significant reduction (p=0.01) in the combined incidence of ischemic changes on the resting ECG and documented MI.

The Diabetes atherosclerosis intervention study (DAIS) (41), a combined primary and secondary prevention trial, was designed to examine whether treatment with micronized fenofibrate (200 mg/day) would decrease the rate of progression of CHD in patients with diabetes. The study included 418 men and women between 40 and 65 years of age, in relatively good glycemic control (mean hemoglobin Aic 7.5%), with mild lipoprotein abnormalities

(the total cholesterol to HDL cholesterol ratio had to be four or higher) and at least one visible coronary lesion on angiography. Approximately 50% had a previous history of clinical CHD and 33% had previously undergone coronary interventions the primary endpoint was progression or regression of CHD on quantitative angiography. The subjects were randomly assigned to fenofibrate (n=207) or placebo (n=211) with an average follow-up period of 3.5 years. Serum triglycerides decreased by 29% and HDL cholesterol increased by 6% in the fenofibrate group during the study. The Fenofibrate treatment was associated with 40% less progression in minimum lumen diameter (p=0.029), 42% less progression in percentage diameter stenosis (p=0.2), and 25% less progression in mean segment diameter, but this change was not significant. The trial was not powered to examine clinical endpoints, but fewer endpoints were observed in the fenofibrate compared to the placebo group (38 vs. 50, respectively). The correlation between plasma lipids and angiographic changes was weak, suggesting the presence of lipid-independent effects of fenofibrate.

The Fenofibrate intervention and event lowering in diabetes (FIELD) (42) study was a multinational, randomized controlled trial with 9.795 participants aged 50 to 75 years, with type 2 diabetes and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, the patients (2131 with previous cardiovascular diseases and 7664 without) with a total cholesterol concentration of 115mg/dL (3mmol/L) to 250mg/dL (6.5mmol/L) and a total cholesterol to HDL cholesterol ratio of 4.0 or more or plasma triglycerides of 88-442 mg/ dL (1.5-5 mmol/L) were randomly assigned to micronized fenofibrate 200 mg daily (n=4.895) or placebo (n=4.900). The primary outcome was coronary events (CHD death or non-fatal MI); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, MI, stroke and coronary and carotid revascularisation). Over the 5 years duration of the study similar proportions in each group discontinued study medication (10% placebo vs. 11% fenofibrate) and more patients taking placebo (17%) than fenofibrate (8%, p<0.0001) started other lipid treatments, predominantly statins. 5.9% of patients on placebo and 5.2% of those on fenofibrate had a coronary event (relative reduction of 11%, HR 0.89, 95% CI 0.75-1.05, p=0.16). This finding corresponds to a significant 24% reduction in non-fatal MI (HR 0.76, 0.62-0.94, p=0.010) and a non-significant increase in CHD mortality (HR 1.19, 0.90-1.57, p=0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (HR 0.89, 0.80-0.99, p=0.035). This finding included a 21% reduction in coronary revascularisation (0.79, 0.68-0.93, p=0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p=0.18). Fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2% vs. 3.6%p=0.003). There was a slight increase in pancreatitis (0.5% vs. 0.8%, p=0.031) and pulmonary embolism (0.7% vs. 1.1%, p=0.022) but no significant other adverse effects. The authors concluded that fenofibrate does not significantly reduce the risk of the primary outcome of coronary events. It reduces, however, total cardiovascular events, mainly due to fewer non-fatal MIs and revascularisations. In summary, there was an overall non-significant 11% reduction in the primary end point of CHD events (a 25% reduction in those without previous cardiovascular disease and a non-significant 8% increase in those with previous CVD) and a significant 11% reduction in total cardiovascular disease events, mainly because of reductions in non-fatal MI and coronary revascularisations (total cardiovascular events fell by 19% in those without a history of cardiovascular disease and there was no effect in those with previous CVD). These differences in treatment effects between cardiovascular disease subgroups were of borderline significance (p=0.05 for CHD, p=0.03 for cardiovascular disease) and might be due to chance. Although there was a significant 24% reduction in nonfatal MI, there was a 19% increase (non-significant) in cardiac mortality, largely reflecting an increase in sudden cardiac deaths. Considering that the fenofibrate group also had a significant increase in pulmonary emboli, this increase in sudden deaths might be a matter of concern. While the higher rate of starting statin therapy in patients' allocated placebo might have masked a larger treatment benefit the FIELD trial does not give clear answers on the efficacy and safety of fenofibrate.

Eagerly awaited are the results of the Action to control cardiovascular risk in diabetes (ACCORD) trial (www.accordtrial.org/public/frames.cfm), a multicenter randomized trial in 10.000 patients with diabetes, 40 to 79 years of age. The subjects will be randomized for the purpose of assessing the prevention of major cardiovascular events (nonfatal MI, cardiovascular death and stroke) using a complex factorial design that includes intensive glycemic, lipid and blood pressure control and insulin resistance-lowering therapy. The lipid part of the study (n=5.800) will assess whether decreasing triglycerides and increasing HDL cholesterol reduces cardiovascular risk beyond the current strategy of optimal LDL cholesterol and glycemic control. The study is expected to be completed in June 2009.

In summary, statin trials in patients with diabetes provide much more convincing evidence of a substantial benefit than those with fibrates. The available evidence does not justify a recommendation for increased fibrate use in patients with diabetes, and do not support a benefit of fibrate therapy in patients already at target serum LDL cholesterol levels. However, fibrates may have a role in the treatment of diabetic patients with high triglycerides and low HDL cholesterol. If a fibrate is to be combined with a statin, fenofibrate should be preferred, since gemfibrozil seems to inhibit the glucuronidation (43) and therefore the elimination of statins, thus increasing the risk of myopathy (44).

Other Treatments

All patients should have medical nutrition therapy and dietary modification focused on reducing saturated fats and cholesterol intake. Weight loss and increased physical activity could also improve diabetic dyslipidemia (45).

Nicotinic acid increases HDL and decreases triglycerides, small dense LDL and Lp(a) (46), therefore it could represent an attractive treatment for diabetic dyslipidemia. However, because of early reports associating nicotinic acid with decreased insulin sensitivity (47), it has not been widely used in patients with diabetes. Subsequent studies showed that modest doses of nicotinic acid (750-2500 mg/day) have minimal effects on glycemia (48,49). Most of the data on the efficacy of nicotinic acid come from a trial carried out in the 1970s, the Coronary Drug Project, in men with established CHD. In that study, acute coronary events were reduced by 28% and total mortality by 11%. The study excluded patients on insulin but included 251 with fasting glucose levels in the diabetic range. There was no significant difference in the event rate reduction by baseline glucose level (50). The safety and efficacy of the combination of niacin with statins has been shown both for simvastatin (51) and atorvastatin (52).

The new cholesterol lowering drug, ezetimibe, is a cholesterol absorption inhibitor that, when used as monotherapy, decreases LDL cholesterol by about 20%. Recent studies have shown the that its combination with statins (53), fibrates (54) and niacin (55) in patients with diabetes seems to be efficacious and safe.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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