Targeting Inflammation Using Salsalate in Patients With Type 2 Diabetes: Effects on Flow-Mediated Dilation (TINSAL-FMD)

Abstract

OBJECTIVETo test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSWe conducted an ancillary study to the National Institutes of Health–sponsored, multicenter, randomized, double-masked, placebo-controlled trial evaluating the safety and efficacy of salsalate in targeting inflammation to improve glycemia in patients with T2D. Flow-mediated, endothelium-dependent dilation (FMD) and endothelium-independent, nitroglycerin-mediated dilation (NMD) of the brachial artery were assessed at baseline and 3 and 6 months following randomization to either salsalate 3.5 g/day or placebo. The primary end point was change in FMD at 6 months.RESULTSA total of 88 participants were enrolled in the study, and data after randomization were available for 75. Patients in the treatment and control groups had similar ages (56 years), BMI (33 kg/m2), sex (64% male), ethnicity, current treatment, and baseline HbA1c (7.7% [61 mmol/mol]). In patients treated with salsalate versus placebo, HbA1c was reduced by 0.46% (5.0 mmol/mol; P < 0.001), fasting glucose by 16.1 mg/dL (P < 0.001), and white blood cell count by 430 cells/µL (P < 0.02). There was no difference in the mean change in either FMD (0.70% [95% CI −0.86 to 2.25%]; P = 0.38) or NMD (−0.59% [95% CI −2.70 to 1.51%]; P = 0.57) between the groups treated with salsalate and placebo at 6 months. Total and LDL cholesterol were 11 and 16 mg/dL higher, respectively, and urinary albumin was 2.0 µg/mg creatinine higher in the patients treated with salsalate compared with those treated with placebo (all P < 0.009).CONCLUSIONSSalsalate does not change FMD in peripheral conduit arteries in patients with T2D despite lowering HbA1c. This finding suggests that salsalate does not have an effect on vascular inflammation, inflammation does not cause endothelial dysfunction in T2D, or confounding effects of salsalate mitigate favorable effects on endothelial function.

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“…Our results do not address the potential therapeutic efficacy of longer-term, lower-dose salsalate treatment in this or other groups. In contrast to short-term salsalate administration in the present study and previous investigation in overweight/obese adults [16], recent work in patients with type 2 diabetes [30] and coronary artery disease [37] found no improvements in FMD with longer-term administration of salicylate-based compounds (salsalate and sulfasalazine, respectively). These differences may result from differences in compounds and dosing, concurrent use of medications such as statins, ACE inhibitors and/or metformin that improve endothelial dysfunction, or different etiologies of endothelial dysfunction among these groups.…”

“…In agreement with our previous observations and those of others [16, 30, 31], in the present study salsalate administration reduced endothelial NF-κB expression, but did not affect circulating inflammatory markers. Collectively, these results suggest that the improvements in EDD are a result of reduced local endothelial rather than systemic inflammation.…”

Is the risk of cardiovascular disease altered with anti‐inflammatory therapies? Insights from rheumatoid arthritis

“…Notwithstanding the potential benefits on fasting glycemia, salsalate treatment consistently appears to increase either low-density lipoprotein (LDL) or total cholesterol levels. 10, 11, 13, 27, 28 Furthermore, in patients with T2D, treatment with TZDs also appears to alter circulating cholesterol concentrations 29 and lipoprotein particle size, 30 which may be specific to the type of TZD used. For example, rosiglitazone seems to increase total and LDL cholesterol, whereas pioglitazone does not alter total or LDL cholesterol and increases high-density lipoprotein (HDL).…”

Macrophage activation in human diseases

“…Effects of several anti-inflammatory drugs on insulin resistance have already been analyzed in different clinical studies among them salicylates, TNF-␣ inhibitors and PPAR␥ agonists. While salicylates and TNF-␣ inhibitors significantly decrease the systemic concentration of pro-inflammatory cytokines in humans they have only a moderate positive effect on insulin resistance [82,83]. The PPAR␥ agonists pioglitazone on the other hand significantly decreases insulin resistance and seems to additionally be an efficacious drug for psoriasis [84].…”