Diabetes combination studies

Very extensively studied, but many of the reports describe single-dose studies or multiple-dose studies in healthy subjects (only a few are cited here), which do not give a clear picture of what may be expected in diabetic patients. Those studies that have concentrated on diabetics indicate that the control of the diabetes is not usually adversely affected by calcium-channel blockers, although isolated cases with diltiazem, nicardipine and nifedipine have been reported.Similarly, there appear to be no important pharmacokinetic interactions with any of the combinations studied. However, if an otherwise unexplained worsening of diabetic control occurs it may be prudent to consider the use of a calcium-channel blocker as a possible cause. Therefore, in general, no particular precautions normally seem necessary. 

Ascorbic acid also forms soluble chelate complexes with iron (142—145). It seems ascorbic acid has no effect on high iron levels found in people with iron overload (146). It is well known, in fact, that ascorbic acid in the presence of iron can exhibit either prooxidant or antioxidant effects, depending on the concentration used (147). The combination of citric acid and ascorbic acid may enhance the iron load in aging populations. Iron overload may be the most important common etiologic factor in the development of heart disease, cancer, diabetes, osteoporosis, arthritis, and possibly other disorders. The synergistic combination of citric acid and ascorbic acid needs further study, particularly because the iron overload produced may be correctable (147). 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

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 long-term toxic effects of lithium, such as nephrogenic diabetes insipidus, which has been calculated to occur in up to 5% of patients, and the rare possibility of lithium combined with neuroleptics being neurotoxic, has stimulated the research for other drug treatments. However, apart from the neuroleptics, these drugs have not been studied as extensively in the treatment of acute mania, but are worthy of consideration because of their reduced side effects. 

There is a disputed effect on carbohydrate metabolism, but it is at most mild and there is certainly no precipitation of diabetes in healthy women. Carbohydrate metabolism was unaffected by medroxyprogesterone in one study in which there was modest impairment of glucose tolerance among users of levonorgestrel-containing, low-dose combined oral contraceptives and progestogen-only tablets (18). 

In the United Kingdom Prospective Diabetes Study a subgroup of patients taking sulfonylurea therapy to which metformin was added appeared to have had excess mortality. Data from 263 general practices in the UK were analysed 8488 patients took a sulfonylurea initially, to which metformin was added in 1868 (25). The crude mortality rates per 1000 person years were 59 and 40 respectively. Metformin was used initially in 3099 patients and a sulfonylurea was added in 867. The crude mortality rates per 1000 person years were 25 and 20 respectively. These results suggest there is no increased mortality risk with a combination of a sulfonylurea and metformin. 

Schatz H, Schoppel K, Lehwalder D, Schandry R. Efficacy, tolerability and safety of nateglinide in combination with metformin. Results from a study under general practice conditions. Exp Clin Endocrinol Diabetes 2003 111 262-6. 

Gulliford M, Latinovic R. Mortality in type 2 diabetic subjects prescribed metformin and sulphonylurea drugs in combination cohort study. Diabetes Metab Res Rev... 

Olsson J, Lindberg G, Gottsater M, Lindwall K, Sjostrand A, Tisell A, Melander A. Increased mortality in Type II diabetic patients using sulphonylurea and metformin in combination a population-based observational study. Diabetologia 2000 43(5) 558-60. 

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