OBJECTIVETo assess the efficacy of in-shoe orthoses that were designed based on shape and barefoot plantar pressure in reducing the incidence of submetatarsal head plantar ulcers in people with diabetes, peripheral neuropathy, and a history of similar prior ulceration.RESEARCH DESIGN AND METHODSSingle-blinded multicenter randomized controlled trial with subjects randomized to wear shape- and pressure-based orthoses (experimental, n = 66) or standard-of-care A5513 orthoses (control, n = 64). Patients were followed for 15 months, until a study end point (forefoot plantar ulcer or nonulcerative plantar forefoot lesion) or to study termination. Proportional hazards regression was used for analysis.RESULTSThere was a trend in the composite primary end point (both ulcers and nonulcerative lesions) across the full follow-up period (P = 0.13) in favor of the experimental orthoses. This trend was due to a marked difference in ulcer occurrence (P = 0.007) but no difference in the rate of nonulcerative lesions (P = 0.76). At 180 days, the ulcer prevention effect of the experimental orthoses was already significant (P = 0.003) when compared with control, and the benefit of the experimental orthoses with respect to the composite end point was also significant (P = 0.042). The hazard ratio was 3.4 (95% CI 1.3–8.7) for the occurrence of a submetatarsal head plantar ulcer in the control compared with experimental arm over the duration of the study.CONCLUSIONSWe conclude that shape- and barefoot plantar pressure–based orthoses were more effective in reducing submetatarsal head plantar ulcer recurrence than current standard-of-care orthoses, but they did not significantly reduce nonulcerative lesions.

This article is available online at http://www.jlr.org Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in the Western world ( 1 ). Elevated levels of LDL-cholesterol (LDL-C) have consistently shown a positive association with the development of CVD, justifying the current therapeutic strategies to prevent CVD primarily by the use of statins. Members of this drug class inhibit HMG-CoA reductase (HMGR), the rate-limiting enzyme for de novo cholesterol synthesis, thereby leading to decreased LDL-C ( 2-4 ). While the benefi ts of statins have been documented ( 2 ), many individuals on statin therapy still remain at a higher risk of developing CVD. It is possible this residual risk is a result of other metabolic syndrome (MetS) risk factors characterized by dyslipidemia and insulin resistance and is also in part due to statin intolerance ( 5-7 ) and noncompliance often related to statininduced myalgia ( 8, 9 ). Statins are effective at decreasing LDL-C and CVD; however, frequent muscle-related side effects limit dosage and impede maximal risk reduction in dyslipidemic patients ( 10 ). Furthermore, recent evidence suggests that high-dose statins may increase the risk of developing type 2 diabetes (T2D) ( 11 ), further justifying the need for alternative therapeutic interventions that have statin-like effects for lowering LDL-C and are designed to Abstract ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid ␤ -oxidation. However, the molecular mechanism(s) mediating these activities remained undefi ned.

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