Fibrates diabetes

Fibrates are being combined with statins to expand their potential in the dyslipidemia market. A recent clinical study examined the effects of rosuvastatin (10) and fenofibrate as mono and combination therapy in hyperlipidemic diabetic patients [43]. In late 2006, large scale Phase III clinical trials of rosuvastatin in combination with a next-generation fibrate, ABT 335, were initiated for evaluation of safety and efficacy in patients with mixed dyslipidemia. 

The fibrates are mainly used to treat two hyperlipi-demias, familial hypertriglyceridemia (type IV) and dysbetalipoproteinemia (type III). They are also useful in the treatment of hypertriglyceridemia associated with type II diabetes (secondary hyperlipidemia). The fibrates are the drugs of choice in treating hypertriglyceridemias, particularly those associated with low levels of HDL cholesterol. The fibrates additionally appear to... 

Primary increases of VLDL also reflect a genetic predisposition and are worsened by factors that increase the rate of VLDL secretion from liver, ie, obesity, alcohol, diabetes, and estrogens. Treatment includes addressing these issues and the use of fibrates or niacin as needed. Marine omega-3 fatty acids are a valuable adjuvant. 

Fibrates are highly bound to albumin and displace other similarly bound drugs. This can affect treatment with sulfonylureas. Hypoglycemia occurred in a diabetic patient taking glibenclamide plus gemfibrozil (170). 

Klein J, Ott V, Schutt M, Klein HH. Recurrent hypoglycae-mic episodes in a patient with Type 2 diabetes under fibrate therapy. J Diabetes Complications 2002 16(3) 246-8. 

Although it is not exactly clear how much these agents can reduce the risk of a major cardiac event (e.g., infarction, stroke), these drugs will probably remain the first choice for people with certain hyper-lipidemias (e.g., increased triglycerides). These drugs are likewise advocated for mixed hyperlipidemias that are common in metabolic disorders such as type 2 diabetes mellitus (see Chapter 32).32,141 Certain fibrates can be used with other drugs, such as statins, to provide more comprehensive pharmacologic control of certain lipid disorders.30,147... 

Erectile dysfunction (ED), the inability to achieve or maintain a penile erection sufficient to permit satisfactory sexual intercourse, is estimated to affect over 100 million men worldwide, with a prevalence of 39% in those of 40 years. Its numerous causes include cardiovascular disease, diabetes mellitus and other endocrine disorders, alcohol and substance abuse, and psychological factors (14%). While the evidence is not conclusive, drug therapy is thought to underlie 25% of cases, notably from antidepressants (SSRI and tricyclic), phenothiazines, cypro-terone acetate, fibrates, levodopa, histamine H -receptor blockers, phenytoin, carbamazepine, allopurinol, indomethacin, and possibly adrenoceptor blockers and thiazide diuretics. 

History. In the course of investigations on the fibrate class of hypolipidemic agents at Takeda (179, 180), a series of 5-(4-alkoxybenzyl)-2,4-thiazolidinediones were shown to reduce insulin resistance in genetically diabetic and obese animals. Ciglitazone (15), which became the prototypeforthis class... 

Despite its proven benefit in the control of blood glucose, PPARy agonists have been associated with an increased incidence of myocardial infarction and death from cardiovascular causes [71]. Numerous companies are therefore working actively on specific PPARa modulators, and a number of discovery and preclinical programs have been initiated with the aim of improving potency and selectivity compared to the fibrates. PPARa-selective compounds that are currently under development are shown in Figure 13.9. With the exception of K-lll (for a recent review, see Ref. [72]), which is developed for the treatment of type 2 diabetes mellitus, the development of all known PPARa activators is focused on lipid metabolism. 

Treatment targets for drcnlating levels of LDL-cholesterol and triglycerides can in most cases rather easily be achieved with statins, ezemtibine, fibrates and omega-3 fatty acids. In contrast, it is much more difficult to improve the low serum level of HDL-cholesterol as a prominent CVD risk factor in type 2 diabetes. Some hope is given to several novel drug candidates [39]. 

RCTs supporting the benefits of fibrate therapy is not consistent. Gemfibrozil was used in the Helsinki Heart Study, a primary prevention trial in men with raised non-HDL-cholesterol [55], and the Veterans Administration HDL Intervention Trial, VAHIT, a secondary CVD prevention trial in men with low HDL-cholesterol and relatively normal LDL [56], These studies showed significant positive benefit for the drug overall and in diabetic subgroups. However, the populations studied in these trials also respond well to statin therapy [43], In the Bezafibrate Infarction Prevention Trial, a CVD secondary prevention trial [57], there was a trend... 

It has been an attractive option to use combination therapy of statin and fibrate when HDL remains low but there is no data from RCTs to support this approach. It is ironic that gemfibrozil with the best outcome data should not be used in this context given drug interactions. The results of the FIELD trial with fenofibrate as sole therapy were disappointing [59] however, a combination trial with fenofibrate and statin in type 2 diabetes, the ACCORD study, is in progress. 

Colhoun H. After FIELD should fibrates be used to prevent cardiovascular disease in diabetes Lancet. 2005 366 1829-1831. 

ACCORD (Action for Central CV-risk in Diabetes) ACCORD investigators NIH/NHLBI/ NIDDK (a) Better Hbalc, and/or (b) better SBP, and/or (c) use of feno-fibrate + statin vs. statin alone. T2 DM patients (10,251) 2010... 

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