Anti-inflammatory agents to treat or prevent type 2 diabetes,metabolic syndrome and cardiovascular disease

Introduction: There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease (CVD). These observations suggest that pharmacological strategies, which reduce inflammation, may be therapeutically useful in treating obesity, type 2 diabetes and associated CVD.

Area covered: The article covers novel strategies, using either small molecules or monoclonal antibodies. These strategies include: approaches targeting IKK-b-NF-kB (salicylates, salsalate), TNF-α (etanercept, infliximab, adalimumab), IL-1β (anakinra, canakinumab) and IL-6 (tocilizumab), AMP-activated protein kinase activators, sirtuin-1 activators, mammalian target of rapamycin inhibitors and C-C motif chemokine receptor 2 antagonists.

Expert opinion: The available data supports the concept that targeting inflammation improves insulin sensitivity and β-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity.     

Relationship of plasma salicylate levels to pain relief with two different Salicylates

Summary

In a preliminary open study of salsalate (3 g daily for 4 weeks) in 61 patients with rheumatoid arthritis or osteoarthrosis, it was found that although the drug produced satisfactory analgesia in 64% of patients, the incidence of side-effects was high (57% of patients): most were symptoms of salicylism and probably related to the high plasma salicylate levels achieved. In a second open study, 20 patients with osteoarthrosis were treated for 4 weeks with 250?mg diflunisal twice daily and then crossed over to salsalate (3 g daily) for a further 2 weeks. The results of subjective assessments of pain relief showed that both drugs produced satisfactory analgesia, and neither was associated with a significant level of gastro-intestinal bleeding. During the diflunisal treatment period there were no reports of salicylism, and plasma salicylate levels were very much lower than those measured after salsalate. The pain-relieving effects of both drugs, assessed from patient preference for one or the other treatment, were unrelated to the plasma salicylate levels and it is suggested that plasma levels may have more relationship to the incidence of side-effects than with therapeutic effects.     

Pharmacokinetics of salsalate and salicylic acid in normal and diabetic rats

The pharmacokinetics (PK) of salsalate (SS) and salicylic acid (SA) was assessed in normal Wistar and diabetic Goto‐Kakizaki rats. Three PK studies were conducted: (1) PK of SA in normal rats after intravenous dosing of SA at 20, 40, 80 mg/kg. (2) PK of SS and SA in normal rats after oral dosing of SS at 28, 56, 112 mg/kg. (3) PK during 4 months feeding of SS‐containing diet in both normal and diabetic rats. The disposition of SS and SA were evaluated simultaneously using a pharmacokinetic model comprising several transit absorption steps and linear and nonlinear dual elimination pathways for SA. The results indicated that the nonlinear elimination pathway of SA only accounted for a small fraction of the total clearance (< 12%) at therapeutic concentrations. A flat profile of SA was observed after oral dosing of SS, particularly at a high dose. The possible reasons for this flat profile were posed. During the SS‐diet feeding, the diabetic rats achieved lower blood concentrations of SA than normal rats with a higher apparent clearance (CL/F), possibly due to incomplete (47%) bioavailability. Such CL/F decreased with age in both diabetic and normal rats. The effect of diabetes on SA pharmacokinetics may necessitate increased dosing in the future usage of SS in diabetes. Copyright © 2012 John Wiley & Sons, Ltd.     

双水杨酸酯通过抑制内质网应激缓解高脂饮食小鼠的高血糖状态

目的：研究并探讨双水杨酸酯（Salsalate,SAL）对高脂饮食喂养的小鼠血糖水平的影响。方法：高脂饮食联合0.5%双水杨酸酯共同饲养8周龄C57BL/6J雄性小鼠40天,行胰岛素耐量试验（ITT）及葡萄糖耐量试验（GTT）,提取肝脏总RNA及蛋白,检测内质网应激通路（CHOP、ERDJ4、GRP78和GRP94）的基因蛋白表达水平。结果:SAL组小鼠随机血糖水平低于对照组（pP <0.05）,且GTT提示糖耐量更好,但两组空腹胰岛素水平无统计学差异,且ITT提示两者胰岛素刺激后血糖变化未见明显差异;SAL组小鼠肝脏组织GRP78和GRP94的基因表达水平较对照组减低（pP<0.05）,SAL组小鼠肝脏组织CHOP、ERDJ4、GRP78和GRP94的蛋白表达水平较对照组减低（pP<0.05）。结论:双水杨酸酯通过抑制内质网应激通路缓解高脂饮食小鼠的高血糖状态,且这一过程不依赖于胰岛素作用。     

Use of Salsalate to Target Inflammation in the Treatment of Insulin Resistance and Type 2 Diabetes

Objectives: Chronic subacute inflammation is implicated in the pathogenesis of insulin resistance and type 2 diabetes. Salicylates were shown years ago to lower glucose and more recently to inhibit NF‐κB activity. Salsalate, a prodrug form of salicylate, has seen extensive clinical use and has a favorable safety profile. We studied the efficacy of salsalate in reducing glycemia and insulin resistance and potential mechanisms of action to validate NF‐κB as a potential pharmacologic target in diabetes. Methods and Results: In open label studies, both high (4.5 g/d) and standard (3.0 g/d) doses of salsalate reduced fasting and postchallenge glucose levels after 2 weeks of treatment. Salsalate increased glucose utilization during euglycemic hyperinsulinemic clamps, by approximately 50% and 15% at the high and standard doses, respectively, and insulin clearance was decreased. Dose‐limiting tinnitus occurred only at the higher dose. In a third, double‐masked, placebo‐controlled trial, 1 month of salsalate at maximum tolerable dose (no tinnitus) improved fasting and postchallenge glucose levels. Circulating free fatty acids were reduced and adiponectin increased in all treated subjects. Conclusions: These data demonstrate that salsalate improves in vivo glucose and lipid homeostasis, and support targeting of inflammation and NF‐κB as a therapeutic approach in type 2 diabetes.