Clinical Briefs

By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville. Dr. Kuritzky is a consultant for Sucampo Pharmaceuticals, Takeda, Boehringer Ingelheim; and is a consultant and on the speaker's bureau for Novo Nordisk, Lilly, Daiichi Sankyo, Forest Pharmaceuticals, Cephalon, Novartis, and Sanofi Aventis.

Prediabetes therapy and beta-cell function

Source: Hanley AJ, et al. Effect of rosiglitazone and ramipril on {beta}-cell function in people with impaired glucose tolerance or impaired fasting glucose. Diabetes Care 2010;33:608-613.

Prediabetes (PDM) is defined as either impaired fasting glucose (FBG = 100-125 mg/dL), impaired glucose tolerance (IGT; 2-hour post-load glucose = 140-199 mg/dL), or supranormal but not diabetic A1c (A1c = 5.7-6.4). Untreated pDM predictably progresses to frank DM at a rate of about 7%-10% per year. Numerous interventions have been shown to alter the progression from pDM to diabetes, including diet, exercise, metformin, acarbose, orlistat, and thiazolidinediones; this year, nateglinide, an insulin secretagogue, was not confirmed to delay progression from pDM to diabetes.

Hopefully, treatments to prevent diabetes will also impact beta-cell function favorably, rather than simply compensate for progressive metabolic decline. The DREAM trial (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) randomized 5269 pDM subjects to ramipril and/or rosigliatoze. A substudy of DREAM (n = 982) had measurements of beta-cell function at baseline and periodically during the 3-year (median) follow-up, as well as measurements of progression from pDM to DM.

Subjects randomized to ramipril did not experience any meaningful change in beta-cell function. In contrast, rosigliatoze-treated subjects enjoyed substantial improvements in beta-cell function. Benefits were less in pDM subjects who only manifest IFG compared with IGT or both.

In addition to reducing beta cells induced by glucotoxicity, thiazolidinediones lower free fatty acid levels, which may favorably affect beta-cell apoptosis.

Maximize benefits of metformin in DM2

Source: Brown JB, et al. Secondary failure of metformin monotherapy in clinical practice. Diabetes Care 2010;33:501-506.

To date, controlled trials indicate that no matter what pharmacotherapy is used to control glucose in type 2 diabetes (DM2), one can anticipate a progressive loss of control over time. Loss of efficacy is termed secondary failure: An initially effective medication later becomes insufficient to maintain control. To me this seems too harsh an indictment of pharmacotherapy, since even if the medication continues with similar action over long time periods, confounders such as weight gain, inherent disease progression, and addition of confounding comorbidities might make it appear as if the medication is failing, when in reality, counterbalancing forces are increasing.

In any case, Brown et al performed an observational cohort study of DM2 subjects (n = 1799) initially treated with metformin monotherapy successfully (i.e., able to maintain an A1c < 7.0 without adding a second agent). Secondary failure was defined as either the addition of a second agent, or an increase of A1c above 7.0 while still on monotherapy. Subjects who required additional therapy within the first 6 months of metformin treatment were regarded as primary failure, and were excluded from this analysis.

In subjects able to maintain good control with initial metformin monotherapy, secondary failure occurred at a rate of 17% per year. Predictors of higher failure rates included longer duration of diabetes before treatment and higher baseline A1c at initiation of treatment. These data suggest that early initiation of treatment, especially when A1c is not yet markedly elevated, results in greater durability of metformin efficacy.

Onychomycosis: Long-term follow-up

Source: Piraccini BM, et al. Long-term follow-up of toenail onychomycosis caused by dermatophytes after successful treatment with systemic antifungal agents. J Am Acad Dermatol 2010;62:411-414.

Although onychomycosis (ONCM) is often considered a cosmetic problem, some patients suffer significant disability due to foot pain, and difficulty wearing shoes. The treatment course for toenail ONCM is lengthy and costly. There are few data on long-term follow-up to ascertain recurrence rates, although prevailing opinion suggests recurrence is common.

Piraccini et al performed a prospective study of ONCM patients (n = 73) who had been treated with pulse therapy (treatment 1 week/month for 6 months) with terbinafine or itraconazole. After clinical cure, subjects were prospectively followed for 7 years. Cure was defined as normalized clinical appearance and negative fungus culture.

Patients were seen every 6 months during follow-up. Overall, recurrence developed in 16.4% of subjects. Each case of recurrence involved the same organism identified in the original infection. However, the recurrence rate for itraconazole was 3-fold greater than terbinafine. Terbinafine is widely regarded as the treatment of choice for toenail ONCM; this trial suggests superior durability of cure for terbinafine when compared with itraconazole.