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

Review

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Introduction

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Proof-of-concept: effect of anti-inflammatory agents

3.

Approaches targeting

Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Dicle Univ. on 11/04/14 For personal use only.

IKK-b-NF-kB 4.

Approaches targeting TNF-a

5.

Approaches targeting IL-1

6.


7.

Approaches using AMPK activators

8.

Sirtuin activators

9.

Approaches using mammalian target of rapamycin inhibitors

10.

Approaches using C-C motif chemokine receptor 2 antagonists

11.

Combined therapies

12.

Conclusion

13.

Expert opinion

Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease Nathalie Esser, Nicolas Paquot & Andre J Scheen† †

University of Lie`ge and Division of Diabetes, Nutrition and Metabolic Disorders and Division of Clinical Pharmacology, Department of Medicine, Center for Interdisciplinary Research on Medicines (CIRM), Lie`ge, Belgium

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-a (etanercept, infliximab, adalimumab), IL-1b (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 b-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. Keywords: cardiovascular disease, inflammation, insulin resistance, IL-1, salsalate, TNF-a, type 2 diabetes mellitus Expert Opin. Investig. Drugs [Early Online]

1.

Introduction

The modern world is currently facing an epidemic of obesity and associated metabolic diseases, including metabolic syndrome (MetS) and type 2 diabetes (T2DM), all conditions leading to cardiovascular disease (CVD). These chronic diseases result from a combination of predisposing genes, epigenetic phenomena and an unhealthy environment. The global health and economic burden of T2DM has reached staggering proportions as current projections estimate that 592 million people will have diabetes by 2035 [1,2]. Almost two-third of them will die from a CVD, although the effect of blood glucose control on cardiovascular outcomes remains controversial [3]. The pathophysiology of T2DM is rather complex. 10.1517/13543784.2015.974804 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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N. Esser et al.

Article highlights. .

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Silent inflammation is now recognized as a key feature of cardiometabolic diseases associated to obesity and insulin resistance (IR), especially type 2 diabetes, MetS and cardiovascular diseases. The prevention and management of cardiometabolic diseases require a multifactorial approach in which targeting inflammation may represent a valuable add-on therapy. Several anti-inflammatory agents, used for inflammatory (rheumatologic) diseases, have been shown to reduce IR, improve glucose control and/or reduce cardiovascular risk. Better knowledge of the pathophysiological mechanisms responsible for tissue inflammation led to the development of pharmacological approaches especially monoclonal antibodies targeting TNF-a to dampen IR and IL-1b to ameliorate insulin secretion. Other pharmacological approaches using small molecules or monoclonal antibodies are currently in evaluation, especially agents targeting IL-6, AMPactivated protein kinase, sirtuin-1, mammalian target of rapamycin and C-C motif chemokine receptor 2. Long-term safety of most compounds is still poorly known so that the potential overall benefit/risk balance remains unclear. Recent randomized controlled trials have shown promising results, although overall the observed improvements appear rather modest. Further research in the field is needed before using anti-inflammatory agents to reduce the cardiometabolic risk in clinical practice.

This box summarizes key points contained in the article.

Insulin resistance (IR) in muscle and liver and b-cell failure represent the core pathophysiological defects in T2DM [4]. Overall, hyperglycemia develops when islet b-cells are deficient in producing sufficient insulin to overcome IR. Whereas a deleterious role of elevated free fatty acid levels has been emphasized for a long time, there is a growing body of evidence for the key-role of diffuse silent tissue inflammation to explain both IR and insulin secretory defects in T2DM (Figure 1) [5-7]. In presence of obesity, cellular and humoral inflammation is located not only in expanded fat (more particularly visceral adipose tissue), but also in skeletal muscle, in liver and in pancreatic islets, which may explain both tissue IR and b-cell progressive failure [8]. MetS is closely related to IR- [9], and both MetS (including atherogenic dyslipidemia with hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol and a higher proportion of small dense low-density lipoprotein [LDL] cholesterol) and T2DM are independent CVD risk factors (Figure 1) [1]. The initiation and progression of atherosclerotic lesions are currently understood to also have major inflammatory components that implicate both the innate and acquired immune systems [10]. NF-kB is a protein complex acting as a primary transcription factor and fast messenger to harmful cellular 2

stimuli, including inflammation. Current data suggest that NF-kB plays a critical role in all stages of atherosclerotic plaque evolution and targeting NF-kB signaling may provide new therapeutic strategies against atherogenic inflammatory process [11]. Furthermore, recent data support the hypothesis that inflammatory mediators of atherosclerosis may converge on the central role of TNF-a, IL-1 and IL-6 signaling pathways [12]. In a recent meta-analysis, several different pro-inflammatory cytokines (IL-6, IL-18, TNF-a) are each associated with coronary heart disease risk independent of conventional risk factors and in an approximately log-linear manner [13]. More particularly, accumulating evidence suggests that the inflammatory cytokine TNF-a plays a pivotal role in the disruption of macrovascular and microvascular circulation [14]. Furthermore, TNF-a may interfere with insulin signaling and has been implicated since many years as a causative factor in obesity-associated IR and the pathogenesis of T2DM [15,16], a finding that led to the investigation of anti-TNF therapies for the management of insulin-resistant patients [17,18]. Finally, the NLRP3 (‘Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain containing 3’) inflammasome appears to be an important sensor of metabolic dysregulation and controls obesity-associated IR and pancreatic b-cell dysfunction [19,20], and IL-1 appears to be a key player of the innate immune response and inflammation [21]. Consequently, IL-1 blocking strategies are specific pathway targeting therapies in autoinflammatory disorders [22] and may open new perspectives for the management of chronic diseases like T2DM (Figure 2) [23,24]. There are closed interactions between cytokines and inflammatory cells in islet dysfunction, IR and CVD [25]. Drugs that inhibit the various inflammatory pathways responsible for obesity-associated metabolic complications and atherosclerosis are the subject of current intensive research [26,27]. Indeed, the prominent role of inflammation paves the route for future anti-inflammatory therapies to prevent or treat T2DM and CVD, especially in the context of obesity and abdominal adiposity [12,28-33]. The aim of this narrative review is to describe the results obtained with anti-inflammatory agents when used to reduce IR and/or improve b-cell function, thus preventing or treating MetS and T2DM, or when investigated to ameliorate cardiovascular prognosis in high-risk patients. Some drugs are already on the market but for the treatment of other more classical inflammatory diseases, especially rheumatologic pathologies. Interestingly, they are currently investigated in pilot studies or Phase II-III trials to tackle cardiometabolic diseases. Other novel pharmacological agents are still in early clinical development. To identify relevant studies, an extensive literature search in MEDLINE was performed from 1990 to July 2014, with the following MESH terms: the generic terms anti-inflammatory agents, TNF-a, IL-1b, AMP-activated protein kinase (AMPK), sirtuin-1 (SIRT1)

Expert Opin. Investig. Drugs (2014) 24(2)

Anti-inflammatory agents to treat or prevent T2DM, MetS and CVD

Islet inflammation (inflammasome) Type 2 diabetes

Impaired insulin secretion

Hyperglycemia Arterial wall inflammation CRP Systemic inflammation

Liver dysfunction

Decreased insulin sensitivity

Atherothrombosis CVD

Dyslipidemia


Metabolic syndrome Adipose tissue

Tissue inflammation (inflammasome)

Myocardial infarct Stroke

Muscle

Figure 1. Role of inflammation in various target organs playing a key-role in the pathophysiology of type 2 diabetes and its associated metabolic abnormalities, leading to an increased risk of CVD. CRP: C-reactive protein; CVD: Cardiovascular disease.

Anakinra Monoclonal antibodies (*)

Type 2 diabetes

IL-1β

Hyperglycemia

Colchicine Methotrexate Etanercept TNF-α

Impaired insulin secretion

Liver dysfunction

Systemic inflammation

AMPK Decreased insulin sensitivity

Specific activators salsalate IκKβ-NFκB

Adipose tissue Muscle

Salsalate

Dyslipidemia

Rapamycin TNF-α IL-1 IL-6

mTOR

Atherothrombosis CVD IL-1

IL-6

Canakinumab

Tocilizumab

Metabolic syndrome

TNF-α

Etanercept, infliximab, adalimumab

IL-1β

Anakinra, monoclonal antibodies (*)

IL-6

Tocilizumab

SIRT-1

Synthetic activators (SRT 2104)

CCR-2

CCX 140-B, JNJ-41443532

Figure 2. Most important actors of inflammation used as potential targets for pharmacotherapy in type 2 diabetes, associated metabolic abnormalities and CVD. Note that the precise sites of action of the various compounds remain poorly known and to a large extent only speculative. (*) Monoclonal antibodies: Canakinumab, gevokinumab, LY2189102; AMPK: AMP-activated protein kinase; CCR2: C-C motif chemokine receptor 2; CVD: Cardiovascular disease; IKKb-NFb: I(kappa)B kinase-b nuclear factor-kappaB; mTOR: Mammalian target of rapamycin; SIRT-1: Sirtuin-1.

and each of the most important identified molecules (salsalate, etanercept, infliximab, adalimumab, anakinra, canakinumab, tocilizumab) combined with each of the following cardiometabolic pathologies: ‘atherosclerosis’, ‘CVD’,

‘T2DM’, ‘metabolic syndrome’ and ‘IR’ (Table 1). No language restrictions were imposed. Reference lists of original studies, narrative reviews and previous systematic reviews were also carefully examined.


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Table 1. Targets to reduce inflammation and molecules in current evaluation for the management of type 2 diabetes and/or cardiovascular disease. Molecular targets

Molecules

Route of administration (terminal elimination half-life)

Main target organs

Effects on glucose metabolism

IkKb-NFk-b inhibition

Salsalate

Oral (» 1 h)

TNF-a antagonists

Etanercept Infliximab Adalimumab Anakinra Canakinumab Gevokizumab LY2189102 Tocilizumab Metformin* CNX-012-570 ZLN024 (Resveratrol) SRT2104 Rapamycin (everolimus)

s.c. (3 -- 4 days) i.v. (8 -- 10 days) s.c. (10 -- 20 days) s.c. (4 -- 6 h) s.c., i.v. (17 -- 26 days) s.c. (22 days) s.c. (17 days) s.c. (11 -- 13 days) Oral (6 h) Only animal data Only animal data Oral (9 h) Oral (8 -- 24 h) Oral (»60 h)

Muscle Liver b-cell Muscle & adipose tissue

Decreased insulin clearance Improved insulin action Improved insulin secretion Improved insulin action

b-cell

Improved insulin secretion

CCX 140-B JNJ-41443532

Oral (»75 h) Oral (»8 h)


IL-1 receptor blockade IL-1b antagonists

IL-6 antagonists AMPK activators

SIRT-1 activators mTOR inhibitors CCR-2 antagonists

Improved insulin action Adipose tissue Liver

Improved insulin action Decreased hepatic glucose output

Adipose tissue

Improved insulin action

Artery

None

b-cell

Improved insulin secretion

Note that the precise sites of action of the various compounds remain poorly known and to a large extent only speculative. *Old molecule still used as first-line glucose-lowering agent with various actions, among which AMPK activation and mTOR inhibition. AMPK: AMP-activated protein kinase; CCR2: C-C motif chemokine receptor 2; IKKb-NFkb :I(kappa)B kinase-b nuclear factor-kappaB; i.v.: Intravenous; mTOR: Mammalian target of rapamycin; s.c.: Subcutaneous; SIRT-1 :Sirtuin-1.

Proof-of-concept: effect of anti-inflammatory agents 2.

Old anti-inflammatory agents have shown a potential of reducing cardiovascular events. Colchicine, an anti-inflammatory medication long used to treat gout and reduce disease invoked by uric acid crystals, is now understood also to suppress the crystal-recognizing NLRP-3 inflammasome and thus reduce levels of IL-1b. Intriguing results from a recent trial raised the possibility that low-dose colchicine may reduce cardiovascular event rates in patients with clinically stable coronary (hazard ratio: 0.33; 95% CI 0.18 -- 0.59; p < 0.001) [34]. Low-dose methotrexate is widely used as first-line treatment for patients with chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriasis and psoriatic arthritis. It reduces several inflammatory biomarkers including C-reactive protein (CRP), IL-6 and TNF-a in patients with rheumatologic disease, without affecting lipid levels, blood pressure, platelet function or measures of hemostasis [35]. Interestingly, among patients with RA or psoriasis, epidemiological data suggested that low-dose methotrexate reduces cardiovascular risk, although those patients tended to have higher classical vascular risk profiles. A recent meta-analysis found that patients with rheumatologic disease on methotrexate had a 21% lower risk of CVD events (relative risk 0.79, 95% CI 0.73 -- 0.87, p < 0.001) 4

compared with those on other disease-modifying antirheumatic drugs [36]. Based on this rationale, the Cardiovascular Inflammation Reduction Trial (CIRT) has been funded by the National Heart, Lung, and Blood Institute (Table 2) [37]. It will randomly allocate 7000 patients with prior myocardial infarction and either T2DM or MetS; patient groups known to have high risk on the basis of a persistent pro-inflammatory response will receive either low-dose methotrexate (target dose 15 -- 20 mg/week) or placebo over an average followup period of 3 -- 5 years. The CIRT primary end point is a composite of nonfatal myocardial infarction, nonfatal stroke and cardiovascular death. An important pre-specified secondary end point of CIRT is a reduction in the progression to diabetes (among those with metabolic syndrome) and reduced need for glucose-lowering agents (among those who are already diabetic). If positive, CIRT would confirm the proof-of-concept that targeting inflammation in cardiometabolic disease may be potentially beneficial. Thus, anti-inflammatory therapies raise hope for the prevention of CVD. However, caution is required, especially after the negative results of a large randomized placebocontrolled trial (15,828 patients with a median follow-up period of 3.7 years) recently published with darapladib (STABILITY: ‘Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy’). This molecule is a selective oral




Table 2. Ongoing prospective clinical trials investigating the effects of various anti-inflammatory approaches on cardiovascular outcomes in high-risk patients, including patients with MetS or T2DM. Trial name

Clinical trial.gov identifier

Molecule

Patients

N

Estimated completion date

CIRT [37] Cardiovascular inflammation reduction trial CANTOS [116] Canakinumab Anti-inflammatory thrombosis outcomes study ENTRACTE [12] Rheumatoid arthritis (RA) with cardiovascular (CV) outcomes study CLEVER-ACS [12] Controlled level EVERolimus in acute coronary syndromes

NCT 01594333

Methotrexate versus placebo

Coronary heart disease with T2DM or MetS

7000

2017

NCT 01327846

Canakinumab versus placebo

NCT 01331837

Tocilizumab versus etanercept

Stable post-myocardial »10,000 2017 infarction patients with elevated hs-CRP Rheumatoid arthritis and 3115 2016 cardiovascular risk factors

NCT 01529554

Rapamycin (everolimus) versus placebo

Patients with ST elevation 150 myocardial infarction (STEMI)

2015

hs CRP: High-sensitive C-reactive protein; MetS: Metabolic syndrome; T2DM: Type 2 diabetes mellitus.

inhibitor of lipoprotein-associated phospholipase A2 whose elevated activity has been shown to promote the development of vulnerable atherosclerotic plaques. Even if darapladib, as compared with placebo, reduced the rate of major coronary events (9.3 vs 10.3%; p = 0.045) and total coronary events (14.6 vs 16.1%; p = 0.02), it did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction or stroke in patients with stable coronary heart disease [38]. 3.

Approaches targeting IKK-b-NF-kB

Administration of salicylates was shown over a century ago to lower glucose levels in patients with diabetes. Later on, many in vitro and in vivo pharmacological studies have demonstrated a glucose-lowering effect of salicylates, especially salsalate [39]. The underlying mechanisms appear complex and only partially understood. The anti-inflammatory properties of high doses of aspirin and other salicylates are mediated in part by their specific inhibition of I(kappa)B kinase-b (IkK-b), thereby preventing activation by NF-kB of genes involved in the pathogenesis of the inflammatory response [40]. It has been shown that high doses of salicylates reverse hyperglycemia, hyperinsulinemia and dyslipidemia in obese rodents by sensitizing insulin-signaling metabolism [41]. Because activation or overexpression of IkK-b attenuated insulin signaling, whereas IkK-b inhibition reversed IR, IkK-b, rather than the cyclooxygenases, appears to be the relevant molecular target explaining the salicylate-induced improvement in glucose metabolism [41,42]. There is now compelling evidence that activation of the transcription of NF-kB and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic IR and b-cell dysfunction, although the molecular mechanisms involved are

incompletely understood. Recent epidemiological observations in humans and experimental data using systemic or hepatic blockade of receptor activator of NF-kB ligand (RANKL) signaling in genetic and nutritional mouse models of T2DM suggested that RANKL, a prototypic activator of NF-kB, contributes to this process [43]. Besides this action via IKK-b-NF-kB, it has also been shown that AMPK, which has a central role in controlling cellular energy expenditure, may mediate some metabolic effects of salicylate-based drugs (see below: Section 7) [44,45]. The therapeutic potential of high-dose aspirin and other salicylates is limited by bleeding risk. Salsalate, which is a nonacetylated form of salicylate, is an equipotent inhibitor of NF-kB but has a lower bleeding risk than aspirin [39]. It has been shown to be well tolerated at a daily dose around 3 g, with tinnitus as most common adverse event. Effects of salsalate in nondiabetic individuals A proof-of-principle study demonstrated that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in overweight individuals [46]. Compared with placebo, salsalate reduced fasting plasma glucose (FPG) by 13%, glycemic response after an oral glucose challenge by 20% and glycated albumin by 17% (Table 3). Although plasma insulin levels were unchanged, fasting and post-glucose C-peptide plasma levels decreased in the salsalate-treated subjects compared with placebo, consistent with improved insulin sensitivity and/or inhibition of insulin clearance. Adiponectin, a adipokin that improves insulin sensitivity and endothelial function, increased by 57% after salsalate compared with placebo, whereas circulating levels of CRP were reduced by 34% within the group of salsalate-treated subjects [46]. In another double-blind, placebo-controlled trial, obese nondiabetic individuals were randomized to salsalate or 3.1


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Table 3. Metabolic effects of salsalate in insulin-resistant patients, without (nondiabetic) or with type 2 diabetes. Ref.

Patient

Nondiabetic patients Overweight


[46]

Protocol

Duration (weeks)

N

Dose (g/day)

FPG* (%)

PPG* (%)

GA or HbA1c* (%)

IR index* (%)

RCT

4

11 9 26 28 Total 66 36 35 14 27 20 20

Placebo 4 Placebo 3 Placebo 3 Placebo 3-4 Placebo 3.5 Placebo 1.5

+5 -8z 0 -4.7z NA -11z +1 -5z +1 -7z -2 -14z

+6 -14z NS (2 h) z (overall) NA

-13 -17z NA

6 -2 NS

NA

NS

NA

-9 -1 +2 -1

NA NA -6 +3

NA -10z +6 +1 +2 -3 NA NA

9 7 9 8 27 27 27 27 140 146 30 30

3 4.5 Placebo 3.5-4 Placebo 3.0 3.5 4.0 Placebo 3.5 Placebo 3

-9z -19z +1 -15z +8.5 -12.3z -9.4z -10.4z +1.3 -8.5z +18 -14z

NA NA -1 -13z NA

-5 -19z 0 -21z 0 -4.6z -4.6z -6.4z +0.5 -4.3z +27 -8z

[47]

Obese

RCT

1

[48]

Prediabetic

RCT

12

[49]

IFG/IGT

RCT

12

[50]

Insulin-resistant

RCT

4

[51]

Prediabetic

RCT

12

Open Open RCT

2 2 4

T2DM patients Wash-out Wash-out Diet/Met/Su

[54] [54] [54] [55]

All drugs except insulin and TZD

RCT

12

[56]

Idem

RCT

48

[59]

Drug-naive

RCT

12

NA NA

-15z (GIR) -44z (GIR) NA NA

NA -15 -7

*Change versus baseline (expressed as relative percentage). z p < 0.05 versus placebo in RCT and versus baseline in open trial. FPG: Fasting plasma glucose; GA: Glycated albumin; GIR: Glucose infusion rate during a glucose clamp (reduction of IR assessed by a significant increase in GIR); HbA1c: Glycated hemoglobin; IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance (during an oral glucose tolerance test); IR: Insulin Resistance; Met: Metformin; NA: Not available; PPG: Postprandial glucose (after a meal or a glucose load); RCT: Randomized controlled trial; SU: Sulphonylurea; TZD: Thiazolidinedione.

placebo for 7 days [47]. Salsalate treatment resulted in decreased FPG and AUC plasma glucose concentrations during an oral glucose tolerance test and in increased rate of glucose disposal measured during a hyperinsulinemic euglycemic clamp (the gold standard dynamic test to assess insulin sensitivity) (Table 3). However, the effect of salsalate on glucose disposal disappeared after normalizing to increased insulin concentrations measured during the clamp, which suggests that the glucose-lowering potential of salsalate is mainly due to effects on insulin concentration rather than improved insulin action. In a double-blind, placebo-controlled clinical trial, persons who had prediabetes were randomly assigned to receive salsalate or placebo for 12 weeks. Salsalate treatment reduced FPG (-11%) and homeostasis model assessment IR index (HOMAIR: -10%), while homeostasis model assessment of b-cell function (HOMA-B) increased (+35%, p = 0.01 for all changes) (Table 3) [48]. Thus, treatment with salsalate can reduce IR, improve insulin secretion and improve glucose metabolism in subjects with prediabetes. However, the interpretation of HOMA-B may be misleading due to the reduced insulin clearance by salsalate. 6

In individuals with impaired fasting glucose and/or impaired glucose tolerance, FPG was significantly reduced by 6% by salsalate but did not change with placebo (Table 3) [49]. Declines in FPG were accompanied by declines in fasting C-peptide with salsalate. Again, insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% and adiponectin increased by 53% at the end of the study. However, glucose disposal did not change in either group. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue NF-kB activity declined in the salsalate group compared with placebo (-16 vs +42%, p = 0.005) but was not correlated with metabolic improvements [49]. In a recent double-blind placebo-controlled study, 4-week salsalate treatment in nondiabetic, insulin-resistant individuals improved fasting, but not postprandial, glucose and triglyceride concentrations. These improvements were associated with a significant decrease in insulin clearance rate without significant changes in insulin action or insulin secretion (Table 3) [50]. In another study performed in Indian prediabetic subjects, the reduction in FPG (without improvement in postprandial glucose levels) after 12 weeks of salsalate




(Table 3) was associated with an improvement of endothelial function reflected by a significant increase in forearm flowmediated dilation [51]. However, another randomized, double-blind, placebo-controlled crossover trial evaluated the effects of 4 weeks of high-dose salsalate (disalicylate) therapy on endothelium-dependent flow-mediated and endotheliumindependent vasodilation in a mixed population of healthy subjects, individuals with MetS and patients with atherosclerosis [52]. Surprisingly, endothelium-dependent flow-mediated vasodilation after salsalate therapy was impaired compared with placebo therapy in subjects with therapeutic salicylate levels (p < 0.02) but not in subjects with subtherapeutic levels. Thus, the action of salsalate on endothelium function is unclear. Finally, in a double-blind randomized trial within two distinct groups, that is, recently diagnosed diabetic patients (n = 46) and prediabetic subjects (n = 113) allocated in two arms of the intervention to receive 3 g salsalate or placebo for 12 weeks, salsalate could not change significantly biochemical markers of non-alcoholic fatty liver, a condition commonly characterized by local inflammation [53]. Effects of salsalate in T2DM patients In two open-label studies, both high (4.5 g/day) and standard (3.0 g/day) doses of salsalate reduced FPG and postchallenge glucose levels after 2 weeks of treatment in patients with T2DM [54]. Furthermore, salsalate increased glucose utilization during hyperinsulinemic euglycemic clamps, by ~ 50 and 15% at the high and standard doses, respectively, and insulin clearance was decreased with both salsalate doses. In a third, double-masked, placebo-controlled trial, 1 month of salsalate at maximum tolerable dose (inducing no tinnitus) improved FPG and postchallenge glucose levels (Table 3). Circulating free fatty acids were reduced, and plasma adiponectin levels increased in all treated subjects [54]. To confirm these preliminary resuts in longer studies, T2DM patients were randomly assigned to receive placebo or salsalate in various dosages for 14 weeks in addition to their current therapy (Table 3) [55]. Mean glycated hemoglobin (HbA1c) absolute changes were -0.36% (p = 0.02) at 3.0 g/ day, -0.34% (p = 0.02) at 3.5 g/day and -0.49% (p = 0.001) at 4.0 g/day compared with placebo. Higher proportions of patients in the three salsalate treatment groups experienced decreases in HbA1c levels of 0.5% or more from baseline. Other markers of glycemic control also improved in the three salsalate groups, as did circulating triglyceride and adiponectin concentrations [55]. These data were further confirmed in a larger (n = 286) and longer (48 weeks) placebo-controlled trial (TINSAL-2D) (Table 3) [56]. The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group (3.5 g/day) than in the placebo group (95% CI -0.53% to -0.21%; p < 0.001), despite more reductions in concomitant diabetes medications. Lower circulating leukocyte, neutrophil and lymphocyte counts reflect the anti-inflammatory effects of salsalate, whereas 3.2

adiponectin levels increased more in the salsate-treated group than in the placebo group [56]. TINSAL-T2D study also examined the impact of salsalate treatment on a wide variety of other parameters. Salsalate therapy was associated with a reduction in early but not late glycation end products [57]. In another study, HbA1c and FPG were reduced (by 0.46% and 1.6 mg/ml, respectively), together with a reduction of white blood cell count as marker of inflammation, in T2DM patients treated with salsalate 3.5 g/day versus placebo (Table 3) [58]. However, total and LDL cholesterol levels and urinary albumin excretion rate were slightly, but significantly, higher in the T2DM patients treated with salsalate compared with those treated with placebo. There was no difference in the mean change in either low-mediated, endotheliumdependent dilation and endothelium-independent, nitroglycerin-mediated dilation of the brachial artery between the groups treated with salsalate and placebo at 6 months [58]. Finally, in a randomized, double-blind, placebo-controlled 12-week trial recruiting newly diagnosed drug-naive patients with T2DM, salsalate (3 g/day) reduced FPG but increased fasting insulin levels, a finding again supporting a reduction in insulin clearance by salsalate [59]. HbA1c rose in the placebo group from 6.2 to 7.9% but decreased in the salsalate group from 6.1 to 5.6% (p < 0.04 for between-group comparison) (Table 3). HOMA-IR did not change but HOMA-B, reflecting B-cell function, significantly increased ~1.7-fold in the salsalate group. Even if these results should be interpreted with caution because of the reduction effect of salsalate on insulin clearance, these findings show that salsalate is effective in improving glycemic control in newly diagnosed naive patients with T2DM and the positive effects appears to result more from an improved b-cell function than from a reduction in IR. However, the optimal duration of treatment with salsalate and sustainability of its effect requires further study [59]. 4.

Approaches targeting TNF-a

The first description of the role of TNF-a in the pathophysiology of T2DM was reported > 20 years ago in rodents [60], and its deleterious effect on insulin sensitivity confirmed later on in humans [4,15,16,61]. The deleterious metabolic effects of TNF-a were recently analyzed in an acute study showing that low-dose TNF-a infusion alters glucose metabolism and b-cell function in healthy humans [62]. Anti-TNF-a therapies, using the TNF receptor:Fc fusion protein (etanercept) or specific monoclonal antibodies (infliximab, adalimumab), are widely used with success in various inflammatory diseases such as RA [18], psoriasis [63] and Crohn’s disease [64]. Of potential interest, in all these disorders, IR is present and in several studies it has been shown to be improved by medications targeting TNF-a. However, the possible cardiometabolic benefit of drugs targeting TNF-a should be weighed against known adverse effects associated with such pharmacological approaches (mainly risk of infection, the risk of tumor development appearing very low). Furthermore, cost of


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Table 4. Effects of anti-TNF-a therapies on insulin sensitivity in insulin-resistant patients: obese nondiabetic, patients with type 2 diabetes and patients with active RA. Ref.

Patients

Nondiabetic patients [65] Obese Insulin-resistant [66] MetS

Protocol

N

Drug

Duration

Insulin sensitivity

Other findings

Open

7

R045-2081

48 h

No effect (CLAMP)

RCT

28

Etanercept 50 mg s.c. weekly Placebo

4 weeks

No effect (FSIVGTT)

No change in substrate oxidation " adiponectin #CRP, #fibrinogen #IL-6

26 weeks

No effect (HOMA-IR)

#FPG " adiponectin No change in CRP, IL-6

24

Etanercept 50 mg twice weekly Placebo Etanercept 50 mg once weekly Placebo

Open

10

CDP571

4 weeks

No effect (KITT)

RCT

10

4 weeks

No effect (CLAMP)

10

Etanercept 25 mg twice weekly Placebo

No change fasting glucose, insulin, C-peptide #CRP and IL-6 No change in vasodilation b-cell function tended to improve

Open Open

5 45

Infliximab Infliximab

48 months 6 months

Improved (HOMA-IR) No effect (HOMA-IR, QUICKI)

Improvement (HOMA-IR, QUICKI) Improvement (CLAMP) Improvement (HOMA-IR) No effect (CLAMP)

28


[67]

MetS

RCT

16 24 28

T2DM patients [68] Obese + T2DM [69] Obese + T2DM

RA patients Insulin-resistant Nondiabetic

[73] [74]

52 weeks

[75]

Nondiabetic

Open

27

Infliximab

Acute

[76]

Nondiabetic

Open

8

Infliximab

6 weeks

[77]

Nondiabetic

Open

19

Infliximab

14 weeks

[78]

Open

9

Adalimumab

8 weeks

[79]

Nondiabetic Insulin- resistant Nondiabetic

Open

21

Infliximab

24 weeks

[80]

Nondiabetic

Open

61

49 Infliximab 11 Adalimumab 1 Etanercept

12 weeks

#CRP Reduction of insulin resistance (p < 0.01 in highest tertile)

Lipid profile alteration

No effect after 12 weeks Improvement after 24 weeks (HOMA-IR, QUICKI) Improvement (HOMA-IR, QUICKI)

CLAMP: Hyperinsulinemic euglycemic glucose clamp; CRP: C-reactive protein; FPG: Fasting plasma glucose; FSIVGTT: Frequently-sampled intravenous glucose tolerance test; HOMA-IR: Homeostasis model assessment of insulin resistance; KITT: Coefficient K of glucose disappearance during an insulin tolerance test; MetS: Metabolic syndrome; QUICKI: Quantitative insulin sensitivity check index; RA: Rheumatoid arthritis; RCT: Randomized controlled trial.

therapy may also be a barrier for the long-term clinical use of such pharmacological approaches. Pioneer studies in insulin-resistant subjects Pioneer human studies using TNF-a blockade, mostly with etanercept, failed to demonstrate beneficial effects on insulin sensitivity or glucose metabolism in various populations with IR but without overt inflammatory disease : insulin4.1

8

resistant obese subjects [65], individuals with MetS [66,67] and patients with T2DM (Table 4) [68,69]. However, these pilot studies comprised a limited number of individuals and were conducted only for a short-term period, except one in patients with MetS [67]. In the latter study, prolonged therapy with etanercept improved fasting glucose, increased the ratio of high molecular weight to total adiponectin and decreased soluble intracellular adhesion molecule-1 in obese subjects with




abnormal glucose homeostasis and significant subclinical inflammation. However, body composition, HOMA-IR, lipids, CRP and IL-6 were unchanged after 6 months [67]. Other pilot studies were clearly underpowered and not designed to allow definite conclusions about the potential of TNF-a antagonism in improving insulin sensitivity and glucose metabolism [21,23]. Nevertheless, neutralization of TNF-a in obese humans results in differential effects on critical adipokines and body composition indexes, which might explain the lack of effect on insulin sensitivity after TNF-a neutralization in obesity [70]. Further larger and longer studies are warranted, especially since several clinical reports showed that TNF-a antagonism treatment improves insulin sensitivity and/or lowers plasma glucose, together with a reduction of various inflammatory markers, in patients with inflammatory diseases, especially RA [17,18].

Metabolic studies in patients with inflammatory rheumatoid diseases

4.2

Patients with RA generally have IR accompanied by various metabolic alterations and have increased cardiovascular mortality, and a potential role of TNF-a has been suspected, although not fully demonstrated yet [71,72]. The scientific evidence published in the literature about a positive effect of TNF-a blockade in improving IR and associated metabolic disturbances in nondiabetic rheumatic patients has been reviewed [17,18]. Controversial results have been reported, and this heterogeneity may be explained by the various RA populations tested, the mode and duration of anti-TNF-a therapy and the modalities of assessment of insulin sensitivity (Table 4) [73-80]. Similar results were obtained in subjects with other inflammatory diseases as patients with ankylozing spondylitis [81] or psoriasis [63]. Even if many positive reports have been published in patients with RA [73,75-77,80], some studies were unable to demonstrate a positive impact of antiTNF-a therapy on insulin sensitivity or metabolic profile [74,78]. These negative results may suggest that although systemic blockade of TNF-a exerts an anti-inflammatory and anticachectic effect in RA patients, it does not seem to play a major role in IR [82]. Furthermore, finding of elevated levels of Soluble TNF Receptor Type II and IFN-g in patients with RA on anti-TNF-a suggests that this therapy does not completely suppress the underlying inflammatory process and the associated metabolic abnormatities that may promote atherogenesis [83]. However, epidemiological observations are encouraging. A retrospective study evaluated the impact of therapy with etanercept, adalimumab and methotrexate on MetS components in a cohort of psoriasis patients with a follow-up period of 24 months. Patients on etanercept and adalimumab showed a significant improvement of the MetS components (in detail, waist circumference, triglycerides, HDL cholesterol and FPG) as compared to the methotrexate group [84]. In another study among patients with RA or psoriasis, the

adjusted risk of T2DM was lower for individuals starting a TNF-a antagonist compared with initiation of other nonbiological disease-modifying antirheumatic drugs [85]. These data were confirmed in another cohort of RA patients for whom anti-TNF-a therapy was associated with a 51% reduction in risk of developing T2DM [86]. 4.3 Effects of anti-TNF-a therapy on vascular function and cardiovascular risk

RA patients experience increased CVD and mortality, and there is ample evidence showing that coagulation processes are active in RA. Large-scale, long-term studies have shown that anti-TNF-a treatment improves the clinical and laboratory measures of disease activity and reduces local and systemic inflammation. TNF-a blockade may therefore also reduce the impaired coagulation and cardiovascular risk associated with RA [72,87]. Patients with RA have abnormal endothelium-independent microvascular function that correlates with inflammation. It has been postulated that RA disease-related inflammation, especially TNF-a, contributes to endothelial dysfunction. However, endothelium dysfunction was not altered by short-term (4 weeks) anti-TNF-a therapy [88]. Classical CVD risk may influence endothelial function more than disease-related markers of inflammation in RA. These CVD risk factors and anti-TNF-a medication have different effects on microvascular and macrovascular endothelial function, suggesting that combined CVD prevention approaches may be necessary [89]. 5.


IL-1 family is a group of cytokines that play a central role in the regulation of immune and inflammatory responses [90]. They may also have important roles in endocrinology and in the regulation of responses associated with inflammatory stress, as observed in T2DM [91]. IL-1 may exert physiological or pathological effects depending on its amount and on the spatial and temporal patterns of its production [92]. The IL-1 family consists of two pro-inflammatory cytokines, IL-1a and IL-1b, and a naturally occurring anti-inflammatory agent, the IL-1 receptor antagonist (IL-1Ra) [90,91]. A growing body of evidence suggests that cytokines of the IL-1 family, particularly IL-1b, are involved in obesity-associated inflammation and possibly atherothrombotic process [92]. IL-1b is produced via cleavage of pro-IL-1b by caspase-1, which in turn is activated by a multiprotein complex called the inflammasome. The components of the NLRP3 inflammasome are involved in sensing obesity-associated danger signals, with caspase-1 seemingly the most crucial regulator [19]. All these mechanisms are operative in human adipose tissue and appear to be more pronounced in human visceral compared to subcutaneous tissue [19]. Repeated stress-induced IL-1b production in white adipose tissue may result in functional impairments


9


N. Esser et al.

that drive the development of stress-induced visceral obesity [93]. Studies using the IL-1Ra to block endogenous IL-1 in a variety of animal disease models suggested that IL-1 plays a key role in triggering the cascade of inflammatory responses that may induce metabolic abnormalities [94,21]. Glucose-induced b-cell production of IL-1b contributes to glucotoxicity in human pancreatic islets [95]. Intra-islet IL-1b activity governs islet inflammation and diminishes b-cell function and survival. An emerging hypothesis gains support from patients with T2DM in whom an imbalance in the amount of IL-1b agonist activity versus the specific countering by the naturally occurring IL-1Ra determines the outcome of islet inflammation [96]. Clearly, the IL-1 family of cytokines plays an important role in obesity-associated inflammation, IR and defective insulin secretion in T2DM, and IL-1b may represent a therapeutic target to reverse the detrimental metabolic consequences of obesity, including T2DM [97,98]. While treating inflammation by blocking IL-1 may be useful in a broad spectrum of diseases [99], IL-1b-targeted therapy has been evaluated in patients with MetS or T2DM [100]. Currently, long-lasting and specific IL-1b blocking antibodies are being evaluated in clinical trials and this may lead to a novel cytokine-based treatment for T2DM in the future [24,2]. So far, three IL-1-targeted agents have been approved for the treatment of inflammatory diseases : the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept (a hybrid molecule consisting of the extracellular domain of IL-1 receptor accessory protein and IL-1 receptor type 1 arranged inline and fused to the Fc-portion of IgG1) and the neutralizing monoclonal antiIL-1b antibody canakinumab. While anakinra and canakinumab were already tested in several trials in patients with MetS or T2DM, the effect of rilonacept on B-cell function was only investigated in animal models [101]. Various other highly specific IL-1b monoclonal antibodies are able to attenuate IL-1b pathway by different mechanisms [102]. Several of them, such as a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1a antibody, are currently evaluated in clinical trials [99]. Some have already been evaluated in patients T2DM (Table 5). Anakinra Anakinra is a recombinant human IL-1-receptor antagonist that is currently approved for moderate-to-severe RA that has been unresponsive to initial disease-modifying anti-rheumatic drugs therapy [103]. Anecdotal case reports supporting a favorable metabolic activity of the drug were reported. For instance, three patients affected by gout and T2DM were treated with anakinra (100 mg/day subcutaneously [s.c.]) after an unsatisfactory or incomplete response to classical anti-gout therapies. The remarkable clinical improvement in joint symptoms within 24 h and in glycemic control during a 6-month period gives anakinra a potential therapeutic role in the management of gout and T2DM [104]. 5.1

10

In a double-blind, parallel-group trial, 70 patients with T2DM were randomly assigned to receive 100 mg of anakinra s.c. once daily (q.d.) or placebo (Table 5) [105]. At 13 weeks, in the anakinra group, the HbA1c level was 0.46% lower than in the placebo group; C-peptide secretion was enhanced, and there were significant reductions in the ratio of proinsulin to insulin and in levels of IL-6 and CRP. IR, insulin-regulated gene expression in skeletal muscle, serum adipokine levels and the body mass index were similar in the two study groups [105]. To investigate the durability of these responses, 67 patients who completed initial treatment period were included in a double-blind 39-week follow-up study. IL-1 blockade with anakinra induced improvement of the proinsulin/insulin ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal [106]. This study showed that the blockade of IL-1 with anakinra reduced markers of systemic inflammation and improved glycemia and b-cell secretory function in a sustained manner. In a randomized, double-blind, crossover study, nondiabetic, obese subjects with the MetS received 150 mg anakinra s.c. q.d. or matching placebo for 4 weeks [107]. Although anakinra treatment resulted in a significantly lower level of inflammatory markers such as CRP concentrations and leukocyte numbers, insulin sensitivity assessed during an hyperinsulinemic euglycemic clamp was not significantly different after anakinra treatment compared with placebo. Nevertheless, the disposition index, a marker of insulin secretion adjusted for insulin sensitivity, increased significantly after anakinra therapy (Table 5). Thus, treatment with anakinra improves b-cell function but not insulin sensitivity in nondiabetic insulin-resistant subjects with MetS [107]. To assess the effect of blocking IL-1b on b-cell function, 16 participants with impaired glucose tolerance were treated with anakinra 150 mg daily for 4 weeks in a double-blind, randomized, placebo-controlled, crossover study [108]. Firstphase insulin secretion assessed during an hyperglycemic clamp improved after anakinra treatment compared to placebo (+20%, p = 0.03), and the insulinogenic index calculated during an oral glucose tolerance test was also higher (+27%, p = 0.036) after anakinra treatment. In contrast, anakinra had no effect on the insulin sensitivity index (Table 5) [108]. Using a quantitative modeling approach (combining ex vivo data of IL-1b effects on b-cell function and turnover with a disease progression model of the long-term interactions between insulin, glucose and b-cell mass in T2DM), it has been proposed that improved b-cell function, rather than bcell mass, is likely to explain the main IL-1b-blocking positive effects seen in current clinical data with anakinra [109]. Canakinumab Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1b by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex [110]. A 4-week, parallel-group study evaluated canakinumab (a single dose of 150 mg s.c.) in patients with 5.2


RCT, CO

IGT

[108]


T2DM, with cardiovascular risk

T2DM MET/INS

T2DM MET/SU/TZD

T2DM MET/SU

T2DM MET

RCT 181 95 181 92

16 181 92 181

15 93

16 28

17 32

17 33

28 27 33

34 35 19 19 16 16

N

16

4

4

4

13

Duration (weeks)

150 mg single dose Placebo 150 mg single dose Placebo 150 mg single dose Placebo 150 mg single dose Placebo 150 mg single dose Placebo 5 mg once monthy Placebo 15 mg once monthly Placebo 50 mg once monthly Placebo 150 mg once monthly Placebo

100 mg q.d. Placebo 150 mg q.d. Placebo 150 mg q.d. Placebo

Dose

+0.20 NS

-0.20 NS -0.30 NS

+0.26 NS

+0.54 p = 0.86

+0.03 p = 0.52

+0.03 p = 0.53

-0.17 p = 0.14 -0.65 p = 0.09

-0.6 p = 0.29 -0.12 p = 0.17 0 NS

FPG* mmol/l

+0.61 p < 0.05

+0.18 NS -0.43 NS

-0.08 NS

-0.40 NS

-0.52 NS

-0.78 NS

-0.01 NS -0.66 NS

NA

-1.3 p = 0.05 NA

PPG* mmol/l

-0.20 p = 0.5

-0.15 p = 0.2 -0.10 p = 0.1

-0.10 p = 0.9

NA

NA

NA

NA

NA

-0.46 p = 0.03 -0.05 p = 0.35 -0.1 p = 0.068

HbA1C* (%)

Unchanged

Unchanged

Unchanged

Unchanged

NA

NA

NA

NA

NA

Unchanged p = 0.58 Unchanged p = 0.15 Unchanged p = 0.29

IR (insulin resistance)*

Unchanged

Unchanged

Unchanged

NS Unchanged

Unchanged

NS Unchanged NS

Unchanged

Increased p = 0.04 Unchanged NS

Increased p = 0.05 Increased p = 0.04 Increased p = 0.03

ISR (Insulin secretion rate)*

*Change versus baseline (expressed as absolute difference). CO: Crossover; FPG: Fasting plasma glucose; HbA1c: Glycated hemoglobin; IGT: Impaired glucose tolerance; T2DM : Type 2 diabetes mellitus; Ins : Insulin; Met: metformin; NA: Not available; NS: Nonsignificant; PBO: Placebo; PPG: Postprandial glucose (after a meal or a glucose load); RCT: Randomized controlled trial; SU: Sulfonylurea; TZD: Thiazolidinedione; q.d.: Once daily.

[112] [113]

[111]

RCT

RCT, CO

METS

[107]

Canakinumab IGT

RCT

Protocol

T2DM

Patient

[105]

Anakinra

Ref.

Table 5. Metabolic effects of treatment targeting IL-1b in patients with T2DM, impaired glucose tolerance or MetS.



11

12


RCT

LY 2189102 [126] T2DM 12

12

12

Duration (weeks)

1.8 mg weekly Placebo 180 mg weekly Placebo

16 23 19 23

0.6 mg weekly Placebo

0.03 and 0.1 mg/kg single dose Placebo 0.3, 1 and 3 mg/kg single dose Placebo

1.5 mg/kg single dose Placebo 10 mg/kg single dose Placebo

Dose

21 23

17

17 35

36

45

34 45

23

N

-0.6 NS

-1.25 p < 0.05

-0.85 NS

NA

NA

-0.31 p = 0.038

-0.27 p = 0.097

FPG* mmol/l

-2.0 p = 0.021

-1.4 p = 0.021

-1.2 p = 0.021

NA

NA

NA

NA

PPG* mmol/l

-0.25 NA

-0.38 NA

-0.27 NA

NS

-0.85 p = 0.049

NA

NA

HbA1C* (%)

Unchanged p = 0.79

Unchanged p = 0.79

Unchanged p = 0.79

Unchanged

Unchanged

NA

NA

IR (insulin resistance)*

Slightly increased p = 0.117 Moderately increased p = 0.117 Markedly increased p = 0.117

Numerical increased p = 0.39 Unchanged NS

NA

NA

ISR (Insulin secretion rate)*

*Change versus baseline (expressed as absolute difference). CO: Crossover; FPG: Fasting plasma glucose; HbA1c: Glycated hemoglobin; IGT: Impaired glucose tolerance; T2DM : Type 2 diabetes mellitus; Ins : Insulin; Met: metformin; NA: Not available; NS: Nonsignificant; PBO: Placebo; PPG: Postprandial glucose (after a meal or a glucose load); RCT: Randomized controlled trial; SU: Sulfonylurea; TZD: Thiazolidinedione; q.d.: Once daily.

RCT

RCT

T2DM

[114]

Gevokinumab [120] T2DM

Protocol

Patient

Ref.

Table 5. Metabolic effects of treatment targeting IL-1b in patients with T2DM, impaired glucose tolerance or MetS (continued).


N. Esser et al.



impaired glucose tolerance or with T2DM treated with various background pharmacological approaches in whom hyperglycemia may trigger IL-1b-associated inflammation, leading to suppressed insulin secretion and b-cell dysfunction (Table 5). In patients with impaired glucose tolerance, canakinumab significantly increased insulin secretion and tended to decrease FPG. Although primary results were not statistically significant in T2DM patients, a trend towards improving insulin secretion rate relative to glucose supports the hypothesis that insulin secretion could be improved by blocking IL-1b [111]. In a large double-blind, Phase IIb trial, 556 men and women with well-controlled T2DM and high cardiovascular risk were randomly allocated to s.c. canakinumab at doses of 5, 15, 50 or 150 mg monthly or placebo [112]. Compared with placebo, canakinumab had modest but nonsignificant effects on the change in HbA1c, FPG and fasting insulin levels after 4 months of follow-up (Table 5). No consistent effects were seen on lipid parameters. By contrast, important and significant reductions in CRP, fibrinogen and IL-6 levels were observed at 4 months across the canakinumab dose range. Thus, canakinumab significantly reduces inflammation without major effect on lipid profile and only a trend for modest improvement of glucose metabolism [112]. The effects of canakinumab on glucose control and markers of insulin secretion and IR were analyzed in more details in a subsequent paper dealing with the same study [113]. There was no dose response detected between active canakinumab doses, but all doses numerically lowered HbA1c (primary end point) from baseline between 0.19 and 0.31% (placebo-unadjusted), with maximal effect noted in the 50 mg dose of canakinumab (-0.18% difference vs placebo; multiplicity-adjusted, p = 0.139). No other glycemic parameters (fasting and postprandial plasma glucose, fasting and postprandial insulin or C-peptide, HOMA-B and HOMA-IR) showed any meaningful changes by canakinumab therapy [113]. A multi-centre, randomized, double-blind, placebo-controlled, dose-escalation study was conducted in 231 patients with T2DM on a stable daily dose of metformin [114]. Patients were randomly assigned to receive a single intravenous dose of canakinumab 0.03, 0.1, 0.3, 1.5 or 10 mg/kg or placebo. Dose-related reductions in high-sensitive (hs) CRP were significantly greater with canakinumab compared with those with placebo at week 4. Significant reductions in hsCRP were maintained up to week 12 with the two highest doses of canakinumab (-0.8 mg/l with 1.5 mg/kg and -1.3 mg/l with 10 mg/kg; both, p < 0.05). A placebo-adjusted decrease in HbA1c of 0.31% at week 12 was reported with canakinumab 10 mg/kg (p = 0.038), and a reduction of 0.23% at week 4 was found with canakinumab 1.5 mg/kg (p = 0.011) but the difference failed to reach statistical significance at week 12 (Table 5) [114]. To assess the safety and tolerability of different doses of canakinumab versus placebo in patients with T2DM, data were pooled from three studies in 1026 T2DM patients with

different routes of administration, treatment regimens and follow-up duration. Canakinumab groups were categorized as low, intermediate, medium and high doses and compared with placebo. This pooled analysis demonstrated that canakinumab was safe and well tolerated over a treatment period up to 1.4 years at the four pooled doses evaluated, in agreement with safety findings reported in the individual studies [115]. These reassuring safety data open the route to a large long-term prospective controlled study with canakinumab. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) will evaluate whether IL-1b inhibition with canakinumb as compared with placebo can reduce rates of major CVD events among stable patients with coronary artery disease who remain at high vascular risk despite contemporary secondary prevention strategies (Table 2) [116]. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate round 10,000 stable postmyocardial infarction patients with persistent elevation of hsCRP (> 2 mg/l) to either placebo or to canakinumab at doses of 50, 150 or 300 mg every 3 months, administered s.c. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events. Of major interest, a critical secondary end point includes a slowing of diabetic progression (incidence of new onset diabetes) [116], in agreement with the recognition that diabetes is an inflammatory disorder driven in part by IL-1 activation [6]. If the trial meets its primary end point, CANTOS will confirm the critical role of IL-1b-mediated inflammation in the development of CVD and will introduce cytokine-directed therapy as a potential avenue for the treatment of atherosclerotic disease [117]. If the secondary metabolic end point is positive, CANTOS will confirm the causal role of IL-1b in the pathogenesis of islet dysfunction in the natural history of T2DM. Gevokinumab Gevokizumab (XOMA 052) is a potent anti-IL-1b antibody that negatively modulates IL-1b signaling through an allosteric mechanism. It decreases the association rate for binding of IL-1b to its receptor by altering the electrostatic surface potential of IL-1b, thus reducing the contribution of electrostatic steering to the rapid association rate [118]. Co-preincubation of IL-1b with gevokizumab in 3T3-L1 adipocytes neutralized nearly all of the inhibitory effects of IL-1b on insulin-induced activation of Akt phosphorylation, glucose transport and fatty acid uptake as well as on insulin-mediated downregulation of suppressor of cytokine signaling-3 expression [119]. In a placebo-controlled, dose-escalation study, gevokizumab improved glycemia, possibly via restored insulin production and action and reduced inflammation in patients with T2DM [120]. In the combined intermediate-high dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in HbA1c was 0.11, 0.44 (p = 0.017) and 0.85% (p = 0.049) 5.3


13


N. Esser et al.

after 1, 2 and 3 months, respectively, along with enhanced Cpeptide secretion, increased insulin sensitivity, and a reduction in CRP and spontaneous and inducible cytokines (Table 5). Because of its long half-life of 22 days, this therapeutic agent may be able to be used on a once-every-month or longer schedule [120]. The same group reported that IL-1b blockade with gevokizumab significantly reduced motor fatigue in patients with T2DM [121]. Because of these promising preliminary results, gevokizumab may open new prospects to treat not only inflammatory rheumatoid diseases but also other inflammatory diseases such as T2DM and CVD [122]. In rats, a single administration of gevokizumab 1 mg/kg improves endothelial regrowth and reduces neointima formation in rats following carotid denudation, at least in part through its beneficial effects on endothelial cells [123]. Furthermore, gevokizumab has been considered as a potential drug to protect b-cell against IL-1-induced inflammation in patients with type 1 diabetes [124]. LY2189102 LY2189102 is a high-affinity anti-IL-1b humanized monoclonal immunoglobulin G4 evaluated for efficacy in RA and T2DM. Population pharmacokinetics of LY2189102 were characterized using data from 79 T2DM subjects who received 13 weekly s.c. doses of LY2189102 (0.6, 18 and 180 mg) and 96 RA subjects who received 5 weekly intravenous doses (0.02 -2.5 mg/kg). Overall, LY2189102 pharmacokinetics is consistent with other therapeutic humanized monoclonal antibodies and is likely to support convenient s.c. dosing [125]. A Phase II study aimed to evaluate the efficacy, safety and tolerability of LY2189102 in patients with T2DM treated with diet and exercise, with or without antidiabetic agents [126]. Weekly subcutaneous LY2189102 for 12 weeks modestly reduced HbA1c (adjusted mean differences vs placebo: -0.27, -0.38 and -0.25% for 0.6, 18 and 180 mg doses, respectively) and FPG and postprandial glucose levels, and demonstrated significant antiinflammatory effects in T2DM patients with a significant reduction in inflammatory biomarkers, including hs-CRP and IL-6 (Table 5) [126]. Interestingly, at week 24, thus 12 weeks after the last dose, the reduction in HbA1c remained evident for the two highest doses (placebo-corrected changes: -0.59 and -0.43% for the 18 and 180 mg doses, respectively) but was partially reversed for the lowest dose group (placebocorrected changes: -0.18%). These findings argue for longlasting effects of IL-1 antagonism on glucose control in patients with T2DM. 5.4

6.


The role of IL-6 in the context of metabolism in health and disease appears rather complex. On the one hand, several studies implicated IL-6, known predominantly as a proinflammatory cytokine, as a co-inducer of the development of obesity-associated IR, which precedes the development of 14

T2DM. On the other hand, the identification of IL-6 as a myokine, a protein produced and secreted by skeletal muscle to fulfill paracrine or endocrine roles in the insulin-sensitizing effects following exercise, provides a contrasting and hence paradoxical identity of this protein in the context of metabolism [127]. Thus, IL-6 appears to be a pleiotropic cytokine that participates in normal functions of the immune system, hematopoiesis, metabolism, as well as in the pathogenesis of metabolic disorders and CVD. Of potential interest, largescale human genetic and biomarker data are consistent with a causal association between IL-6 receptor (IL-6R)-related pathways and coronary heart disease [128]. In a recent posthoc analysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, plasma IL-6 levels, but not CRP or fibrinogen levels, add significantly to the prediction of macrovascular events and mortality in individuals with T2DM who have baseline CVD or risk factors [129]. Both pro- and anti-inflammatory roles of IL-6 are possibly discriminated by the cascades of signaling transduction, namely classic and trans-signaling. Emphasis should be put on the distinct destinations diverged by these two arms of IL-6 signaling and the value of developing therapeutic strategies to specifically target the deleterious trans-signaling of IL-6 [130]. Blocking IL-6 trans-signaling could prevent inflammation, while activating membrane-bound signaling could promote insulin sensitivity [131]. Therefore, specific appropriate IL-6R blockade could provide a novel therapeutic approach to management of metabolic disease as T2DM and to prevention of coronary heart disease [132]. The successful treatment of certain autoimmune conditions with the humanized anti-IL-6R antibody tocilizumab has emphasized the clinical importance of cytokines that signal through the b-receptor subunit glycoprotein 130 [133]. Inhibition of IL-6 signaling with tocilizumab improved insulin sensitivity in humans with immunological disease [134], suggesting that elevated IL-6 levels in T2DM subjects might be causally involved in the pathogenesis of IR. Furthermore, tocilizumab decreased lipoprotein(a) serum levels, which might reduce the cardiovascular risk of human subjects [135]. Improvement of HbA1c during treatment with tocilizumab (8 mg/kg intravenously every 4 weeks) has been reported in patients with RA [136]. In a subgroup of 10 patients with T2DM, HbA1c decreased significantly after 1 month of tocilizumab treatment (from 7.17 to 6.35%, p < 0.01) and this effect persisted after 6 months (6.0%, p < 0.001) (Table 6). The reduction in HbA1c appeared earlier than the tapering of prednisolone dosage. In a subgroup of 29 nondiabetic patients, HbA1c was also slightly decreased after 6 months of therapy with tocilizumab (from 5.59 to 5.42%, p < 0.05) [136]. In another study, after only 6 weeks of tocilizumab treatment, HOMA-IR was improved in insulinresistant children with systemic juvenile idiopathic arthritis in the presence of unchanged glucocorticoid dose. These data support a mechanistic contribution of IL-6 to IR in




humans [134]. However, the effect of IL-6 on the insulin sensitivity in patients with T2DM seems rather complex [137] so that targeting this IL to promote insulin action remains questionable [131]. Targeting IL-6 may be also of potential interest to improve cardiovascular function. In experimental studies, beneficial effects exerted by adiponectin on cardiovascular functions were attributed, at least in part, to its direct modulation of the proinflammatory factor IL-6 [138]. In a pilot study, IL-6 inhibition with tocilizumab has been reported to improve endothelial function and reduces arterial stiffness [139]. ENTRACTE is an ongoing randomized, open-label clinical trial comparing the effects of IL-6R blockade with tocilizumab to TNF-a inhibition with etanercept on the rate of vascular events among 3000 patients with moderateto-severe RA and a history of coronary heart disease or multiple cardiovascular risk factors (Table 2) [12]. This study will also allow a more careful evaluation of the safety profile of this compound in such a population, especially the potential risk of infection. 7.

Approaches using AMPK activators

The identification of AMPK and its activation by exercise and fuel deprivation have led to studies of the effects of AMPK on IR, MetS and T2DM [140]. AMPK, a heterotrimeric protein complex with serine/threonine kinase activity, has a central role in controlling cellular energy expenditure and may impact glucose metabolism [141]. Furthermore, activation of AMPK has a number of potentially beneficial antiatherosclerotic effects including reducing adhesion of inflammatory cells to the blood vessel endothelium, reducing lipid accumulation and the proliferation of inflammatory cells caused by oxidized lipids, stimulation of gene expression responsible for cellular antioxidant defenses and stimulation of enzymes responsible for nitric oxide formation [142]. Taken together, these data suggest that activation and function of AMPK contribute to cardiometabolic health [142]. AMPK was shown in 2001 to be activated by metformin [141], currently the first-line drug for treatment for T2DM. At concentrations reached in plasma after administration of salsalate or of aspirin at high doses, salicylates also activate AMPK, an effect that may contribute to their favorable metabolic effects [143]. Thus, small-molecule-based activation of AMPK represents an attractive option for the management of metabolic disorders and vascular disease [144]. However, identification of AMPK subunits responsible for specific anti-inflammatory effects, a better molecular understanding of the mechanisms involved and the development of direct, highly specific AMPK activators will be necessary to fully exploit AMPK pathway activation while minimizing adverse reactions [144-146]. Only results in animal models are available yet (Table 6). CNX-012-570, a highly potent and orally bioavailable compound activating AMPK, has shown its potential to control hyperglycemia and hyperlipidemia as well as

to reduce body weight gain with an additional benefit of minimizing cardiovascular risk factors in both diet-induced obese mice and db/db mice models [147]. Treatment of db/ db mice with ZLN024, a novel small-molecule AMPK allosteric activator, improved glucose tolerance and reduced liver tissue weight as well as triacylglycerol and total cholesterol content [148]. These preliminary results in animals confirm that AMPK is an attractive therapeutic target for T2DM, obesity and MetS, but future clinical trials are required to test the benefit/risk balance of this new approach in patients with T2DM [145]. 8.

Sirtuin activators

Recent studies have indicated that the regulation of innate immunity and energy metabolism are connected together through an antagonistic crosstalk between NF-kB and SIRT1 signaling pathways [149]. Recent findings also suggested the existence of an AMPK-SIRT1 cycle that links the cell’s energy and redox states [140,150]. The dysregulation of these processes may predispose to disorders such as T2DM and atherosclerotic CVD and thus SIRT1, as AMPK, may be considered as a potential target for the therapy of these diseases [150]. SIRT1 was originally identified as a NAD+-dependent histone deacetylase, and its activity is closely associated with longevity under caloric restriction. SIRT1 mRNA and protein expression are suppressed in obese rodent and human white adipose tissue [151], while experimental reduction of SIRT1 in adipocytes and macrophages causes low-grade inflammation that mimics that observed in obesity. SIRT1 regulates adipose tissue inflammation by controlling the gain of proinflammatory transcription in response to inducers such as fatty acids, hypoxia and endoplasmic reticulum stress [152]. Thus, suppression of SIRT1 during overnutrition may be critical to the development of obesity-associated inflammation [153]. Of potential interest, in obese and T2DM women compared to normal-weight subjects, adipose SIRT1 expression correlated inversely with HOMA-IR and other IR-related parameters, while adipose SIRT1 and adiponectin mRNA expression correlated very strongly and positively. Thus, adipose tissue SIRT1 may play a key role in the regulation of whole body metabolic homeostasis in humans and downregulation of SIRT1 in visceral adipose tissue may contribute to the metabolic abnormalities that are associated with visceral obesity [151]. The overexpression of SIRT1 and several SIRT1 activators have beneficial effects on glucose homeostasis and insulin sensitivity in diabetic animal models. Therefore, SIRT1 may represent a new therapeutic target for the prevention of diseases related to IR and T2DM [154,155]. Natural activators of SIRT1: resveratrol In 2003, resveratrol, a natural polyphenolic compound, was discovered to be a small-molecule activator of SIRT1. Resveratrol also activates AMPK [156] and inhibits the 8.1


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NF-kB pathway [157]. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. In patients with T2DM, treatment with resveratrol regulates energy expenditure through increased skeletal muscle SIRT1 and AMPK expression [158]. To date, however, only limited clinical data are available that have systematically examined the health benefits of resveratrol in humans with or at risk of metabolic diseases [159]. A recent meta-analysis of 11 randomized controlled trials showed that resveratrol significantly improves glucose control and insulin sensitivity in persons with T2DM but does not affect glycemic measures in nondiabetic persons [160]. Another meta-analysis of six trials indicated that resveratrol consumption significantly decreases systolic blood pressure at the higher dose [161]. Nevertheless, despite the strong preclinical evidence of some positive cardiometabolic effects, studies to date have not shown resveratrol’s benefit in humans regarding cardiovascular outcomes [162]. Study variability and methodological issues limit interpretation of available results. Additional research, focusing on subjects with defined metabolic defects and using a range of doses, is needed to advance the field [163]. Synthetic activators of SIRT1 Small molecule activators of SIRT1 have been identified, which are structurally unrelated to resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates [164]. Compared with resveratrol, the synthetic SIRT1-activating compounds show greater potency (1000-fold stronger), solubility and target selectivity [165] SIRT1-activating compounds, which have been identified from a variety of chemical classes, provide health benefits in animal disease models [165]. In dietinduced obese and genetically obese mice, these compounds improved insulin sensitivity, lowered plasma glucose and increased mitochondrial capacity [166]. In Zucker fa/fa rats, hyperinsulinemic-euglycemic clamp studies demonstrated that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver [166]. These in vivo insulin-sensitizing effects were accompanied by a reduction in tissue inflammation markers and a decrease in the adipose tissue macrophage pro-inflammatory state [167]. These results define a novel role for SIRT1 as an important regulator of macrophage inflammatory responses in the context of IR and raise the possibility that targeting of SIRT1 might be a useful strategy for treating the inflammatory component of metabolic diseases such as T2DM [167]. In a pilot randomized, double-blind Phase I trial, oral doses of 0.5 or 2.0 g SRT2104, a selective small-molecule activator of SIRT1, or matching placebo were administered q.d. for 28 days in elderly healthy subjects. Serum cholesterol, LDL levels and triglycerides decreased with SRT2104 treatment but no significant changes in metabolic responses to an oral glucose tolerance test were observed. Interestingly, muscle 31P magnetic resonance spectroscopy data were consistent

with increased mitochondrial oxidative phosphorylation [168]. An improved lipid profile was also demonstrated with SRT2104 in otherwise healthy cigarette smokers, without demonstrable differences in vascular or platelet function [169]. Finally, treatment with SRT2104 did not result in improved glucose or insulin control after 28 days of therapy in patients with T2DM (Table 6) although this selective activator of SIRT1 improved glucose homeostasis and increased insulin sensitivity in animal models [170]. The authors hypothesized that this failure is likely due to the observed pharmacokinetics which were not dose proportional and had large between subject variability [170]. Thus, although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to potent and specific activation, and whether SIRT1 activators will ultimately prove safe and efficacious in humans [165]. Thus, the future of SIRT1 activators as potential medications remains questionable.

Approaches using mammalian target of rapamycin inhibitors

9.

8.2

16

Nutrients such as carbohydrates and lipids mainly exert their effects through the gene expression of sterol responsive binding protein 1 and 2 and the mammalian target of rapamycin (mTOR). mTOR is a core component of intracellular signaling for cellular growth, mRNA translation, metabolism and inflammation. Leptin directly activates resident macrophages to form ADRP (adipocyte differentiation-related protein)enriched lipid droplets and enhances eicosanoid production via a mechanism that is dependent on activation of the PI3K/mTOR pathway [171]. Administration of rapamycin effectively attenuated inflammation, inhibited progression and enhanced stability of atherosclerotic plaques in animal models [172]. Thus, mTOR inhibitors may play a protective role in atherosclerosis, especially in overweight/obese people [173]. Unfortunately, adverse effects associated with mTOR inhibitors such as dyslipidemia and hyperglycemia have recently been identified [173]. Rapamycin (everolimus) used in transplantation medicine has the potential to reduce inflammation via the mTOR pathways and thereby may exert effect on the progression of atherosclerosis [174]. The CLEVER-ACS (Controlled Level EVERolimus in Acute Coronary Syndromes) trial is currently recruiting patients with ST-segment elevation myocardial infarction to determine whether such an anti-inflammatory therapy will reduce infarct size, cardiac remodeling and clinical events in this patient population (Table 2) [12].

Approaches using C-C motif chemokine receptor 2 antagonists

10.

C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1, and its receptor, C-C motif



Table 6. Other new pharmacological approaches targeting IL-6, AMPK, SIRT1 and CCR2 to reduce inflammation and improve metabolic profile: effects after 4 weeks in patients with T2DM. Ref.

Molecule

IL-6 antagonists Tocilizumab AMPK activators [148] ZLN024 [147] CNX-12-570 SRT1 ACTIVATORS [170] SRT 2104


[136]

CCR2 Antagonists [179] CCX140-B

[180]

JNJ-41443532

Dose

N

FPG* mmol/l

PPG* mmol/l

HbA1c* %

HOMA-IR*

8 mg/kg once

10

NA

NA

-0.82z

NA

Positive results in rodents but no human data Positive results in rodents but no human data 250 mg/day 500 mg/day 1000 mg/day 2000 mg/day Placebo

41 43 40 43 43

-1.11 -0.52 -0.97 -0.15 -1.17

+2.9 +4.2 +3.7 +3.5 +3.6

-0.2 -0.1 0 NA -0.3

NA NA NA NA NA

5 mg/day 10 mg/day Placebo Pioglitazone 30 mg/day 500 mg/day 2000 mg/day Placebo Pioglitazone 30 mg/day

63 32 32 32 23 22 22 22

-0.24 -0.89 -0.59 -1.19 -0.46z -0.22 +0.76 -0.81z

-1.0 -1.6 -1.9 -6.4 -0.7z -0.3 +0.5 -1.0z

-0.09 -0.23z -0.09 -0.13 NA NA NA NA

-0.5 -1.9 -1.4 -1.9 +0.1 -0.4 +0.3 -1.5z

*Change versus baseline. z Significant difference versus placebo (p < 0.05). AMPK: AMP-activated protein kinase; CCR-2: C-C motif chemokine receptor 2; FPG: Fasting plasma glucose; HbA1c: Glycated hemoglobin l; HOMA-IR: Homeostasis model assessment insulin resistance index; NA: Not available; PPG: Postprandial glucose (assessed after a meal -- [170] -, during an OGTT -- [179] -- or over a 23 h mean period -- [180]).

chemokine receptor 2 (CCR2), play important roles in various inflammatory diseases. CCR2 is central for the migration of monocytes into inflamed tissues. Recently, it has been reported that the CCL2/CCR2 pathway also has an important role in the pathogenesis of MetS through its association with obesity and related systemic complications [175]. Indeed, CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic IR and plays a role in the maintenance of adipose tissue macrophages and IR once obesity and its metabolic consequences are established [175]. Therefore, CCR2 antagonists have been developed as potential therapies of such metabolic conditions [176]. Pharmacological inhibition of CCR2 in animal models of T2DM can reduce inflammation in adipose tissue, alter hepatic metabolism and ameliorate multiple diabetic parameters [177]. In diabetic transgenic human CCR2 knock-in mice, the CCR2 antagonist CCX140-B resulted in decreased levels of FPG and fasting insulin, normalization of HOMA-IR values, and decreased numbers of adipose tissue inflammatory macrophages [178]. CCX140-B has recently been shown to reduce FPG and HbA1c levels in patients with T2DM in a pilot double-blind, randomized placebocontrolled 4-week clinical trial [179]. FPG showed a CCX 140-B dose-dependent decrease, with the 10 mg dose showing a quite similar decrease to pioglitazone 30 mg. HbA1c least-square mean changes from baseline to week 4 with placebo, CCX 140-B 5 mg, CCX 140-B 10 mg and

pioglitazone 30 mg were -0.09, -0.09, -0.23 (p = 0.045 vs placebo) and -0.13% (NS vs placebo), respectively (Table 6). Similarly, administration of JNJ-41443532 (250 and 1000 mg q.d.), another orally bioavailable CCR2 antagonist, resulted in modest improvement in glycemic parameters in patients with T2DM in a 4-week, double-blind, placebocontrolled, randomized, multi-centre study, with again pioglitazone 30 mg as an active comparator [180]. The trend to improvement of glycemic control -- assessed by FPG and 23-h weighted mean glucose level -- (slightly better with 250 mg than with 1000 mg) may be due to improvement in b-cell function as suggested by the significant increase in the HOMA-B index with the 250 mg twice daily dose (placebo-subtracted difference : +13.7; p = 0.018), with only a minimal non-significant effect on HOMA-IR; this finding contrasted with what was observed with pioglitazone that significantly reduced HOMA-IR (Table 6). The drug JNJ-41443532 was generally well tolerated and further studies in humans are under way. 11.

Combined therapies

There are good reasons to combine different antiinflammatory drugs in future treatment strategies of T2DM [31,181]. Indeed, T2DM is a complex disease, whose treatment generally requires a combination of several drugs that target insulin secretion, insulin action or insulin-independent


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N. Esser et al.

mechanisms [182,183]. Many inflammatory pathways are involved in the pathogenesis of the disease, and it is unlikely that a single drug will be able to modulate all of them. Some treatments seem to be more effective in improving insulin secretion (anti-IL-1b), while others may impact primarily insulin-sensitive tissues (salsalate, anti-TNF-a). Finally, by combining drugs that have a similar target via modulation of different pathways, the amount of adverse effects may be reduced since the off-target effects of the various drugs differ [31]. Recent human data showed that T-cell-derived IL-22 amplifies IL-1b-driven inflammation in human adipose tissue and identified IL-1b and the T cell cytokine IL-22 as key players of a paracrine inflammatory pathway previously unidentified in adipose tissue, with a pathological relevance to obesity-induced T2DM [184]. These results provide an additional rationale for targeting IL-1b in obesity-linked T2DM and may have important implications for the conception of novel combined anti-IL-1b and anti-IL-22 immunotherapy in human obesity and T2DM [184]. 12.

Conclusion

There is a growing body of evidence that metabolic diseases that accompanied abdominal obesity, like MetS and T2DM, and lead to CVD, are associated with activation of the innate immune system in various tissues. Abnormalities are characterized by elevated proinflammatory factors (TNF-a, IL-1, IL-6), decreased anti-inflammatory factors (adiponectin) and the presence of activated immune cells (macrophages, T lymphocytes). Because inflammation is present in tissues implicated in insulin sensitivity (adipose tissue, skeletal muscle, liver), contributing to worsen IR, and is also present in pancreatic islets, where it can induce b-cell dysfunction and death via intra-islet IL-1b activity, inflammation may play a crucial role in the pathophysiology of T2DM. Furthermore, atherosclerosis, which is accelerated and more pronouced in patients with MetS and T2DM and responsible for a high morbidity and mortality rate in this population, is also characterized by increased silent inflammation, reflected by elevated hs-CRP levels, especially in the arterial wall. Old (salicylates, especially salsalate) and new compounds (essentially monoclonal antibodies), which are able to tackle various inflammation targets, have already been tested in clinical trials in patients with IR, MetS or T2DM. Whereas initial studies focused on anti-TNF-a therapies (etanercept, infliximab, adalimumab) with rather disappointing results (perhaps due to not well-designed protocols), more recent approaches rather involve other targets, mainly IL-1 (especially IL-1b) and IL-6, with preliminary encouraging results reported with anakinra, canakinumab and tocilizumab. Other strategies using small molecules acting as AMPK activators, SIRT1 activators or CCR2 antagonists are also in current investigation. Larger and more prolonged trials are under way to confirm the working hypothesis that targeting 18

inflammation with specific anti-inflammatory agents may have a place in the prevention and/or management of CVD as primary end point and T2DM as secondary end point. 13.

Expert opinion

The modern world is facing an epidemic of diabesity and CVD complications. Adiposopathy, especially in the visceral adipose tissue, is closely associated with humoral and cellular inflammatory processes that lead to a chronic silent inflammation. This inflammation, which implicates several cytokines, may contribute to increase IR in key insulin-sensitive tissues such as the skeletal muscles and liver, reduce b-cell function (and possibly mass) with secondary progressive insulin secretion defects and accelerate atherogenesis and thrombosis. The main clinical consequences are the development of MetS, T2DM and CVD. Currently, most pharmacological approaches for the management of hyperglycemia in T2DM are only symptomatic as they aim at improving insulin secretion and/or insulin signaling, without tackling the inherent cause of these defects. Of potential interest, it has been demonstrated that inflammation plays a major role in both impaired insulin secretion (local inflammation in the pancreatic islets) and action (inflammation in the adipose tissue, muscles and liver). Similarly, prevention and treatment of CVD require a multifactorial approach targeting most important risk factors such as smoking, dyslipidemia and hypertension, but again without directly addressing the intimate mechanism responsible for atherothrombosis. Yet, inflammation in the arterial wall is now recognized as a key feature of atherosclerosis. If inflammation plays a causal role in all these cardiometabolic diseases, successfully targeting inflammation may represent a major advance in the management of chronic diseases such as T2DM and CVD. It still remains an important medical need because of the persistent huge burden associated with these chronic diseases despite numerous diverse and expensive pharmacological approaches used in daily clinical practice. If anti-inflammatory agents might be successful in modifying the natural history of the disease, especially in protecting bcell in patients at risk of or with early-phase T2DM -- as disease-modifying antirheumatic drugs for the treatment of RA -, such novel strategies will indeed represent a major breakthrough in medicine. However, several questions remain in the development of anti-inflammatory drugs for the treatment of T2DM and CVD. Overall, these include the comparative efficacy versus other strategies, the safety of the drug and, last but not least, the cost of treatment. Current available data obtained with the various anti-inflammatory agents so far, and described in detail in this review, generally support the concept. However, although promising, results are far from being impressive yet. This may be due to the heterogeneity of the population tested, the short duration of follow-up in many trials and/or the modalities of anti-inflammatory approaches used.




Furthermore, to assess the magnitude by which drugs decrease glycemia, it is important to consider the starting level of blood glucose. Several studies of anti-inflammatory drugs were carried out in patients with near-normal HbA1c levels, which limits the potential to uncover the maximum glucoselowering effect. Interestingly, one potential advantage of anti-inflammatory agents is that they are not associated with a higher risk of hypoglycemia, a complication that is a major brake in the attainment of optimal glucose control with classical antidiabetic medications. It is also possible, although it remains to be proven, that by combining various anti-inflammatory drugs, broader and more efficacious therapeutic strategies could be developed. The rationale supporting this strategy relies on the variety and complexity of underlying mechanisms linking silent inflammation and IR or insulin secretory defect, on the one hand, chronic diseases such as obesity, MetS, T2DM and CVD, on the other hand. For instance, some antiinflammatory treatments (such as anti-IL-1b agents) seem to be more effective at improving insulin secretion, whereas others (such as anti-TNF agents and salsalate) may primarily affect insulin-sensitive tissues. To test this hypothesis, the planned INFLACOMB trial has the ambitious goal to compare various anti-inflammatory strategies using one single agent (either an anti-TNF-a or an anti-IL-1b or salsalate), a dual therapy (anti-TNF-a + salsalate, anti-IL-1b + salsalate or anti-TNF-a + anti-IL-1b) or a triple therapy (antiTNF-a + anti-IL-1b + salsalate), compared with a single, dual or triple placebo. T2DM is a slowly progressing chronic disease, and the life expectancy of many diabetic patients is increasing. Accordingly, the long-term safety of therapeutic agents is crucial. Several anti-inflammatory drugs that are being evaluated for the treatment of T2DM are already in use for other indications, so safety data are already available. It has be proven among patients with other inflammatory diseases, like RA, psoriasis, Crohn’s disease, that long-term treatment with systemic anti-inflammatory agents can be accomplished safely. In particular, clinical experience indicates that it is possible to tackle inflammation and modulate the immune system, without increasing excessively the risk of infection or cancer and without undue toxicity. Finally, the cost of antidiabetic drugs is a major issue. As the number of individuals with diabetes increases worldwide,

an increasing proportion of healthcare budgets will be required to manage and treat this disease. However, the most expensive part in diabetes expenditures appears to be hospital admissions for the treatment of complications, not glucose-lowering medications. These hospital costs could be decreased by the increased use of more efficient antidiabetic drugs. Furthermore, some anti-inflammatory approaches have already demonstrated long-lasting effects, which may allow interval between drug administrations. Finally, if tackling inflammation not only improves glucose control but also reduces cardiovascular risk, the overall cost-benefit balance may become more favorable. It is also conceivable that wider use of some specific expensive anti-inflammatory agents may result in a reduction of the cost of these novel pharmacological approaches in the future. In conclusion, anti-inflammatory therapies in the setting of chronic disorders such T2DM and CVD pose substantive challenges. The inflammatory system is simultaneously redundant, compensatory and crucial for survival. The remarkable complexity of the immune system makes it difficult to target a single pathway for the prevention of cardiometabolic diseases. Nevertheless, the next few years will see publication of several trials directly testing the inflammatory hypothesis of atherosclerosis. Additional information will be also available regarding the risk of development or progression of T2DM. The core results of these trials will tell us a great deal about whether anti-inflammatory therapies will eventually become a cornerstone in the management of obesity-linked metabolic diseases such as T2DM and atherosclerosis-driven cardiovascular complications. If positive, this may lead to a new paradigm in the management of cardiometabolic diseases with the perspective of using anti-inflammatory agents and innovative cytokine-based therapies.

Declaration of interest AJ Scheen has received lecture/advisor fees from AstraZeneca/ BMS, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi-Aventis and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.


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Affiliation Nathalie Esser1 MD PhD, Nicolas Paquot1 MD PhD & Andre J Scheen†2 MD PhD † Author for correspondence 1 University of Liege and Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, Virology and Immunology Unit, GIGA-ST, CHU Lie`ge, Lie`ge, Belgium 2 Professor, University of Lie`ge and Division of Diabetes, Nutrition and Metabolic Disorders and Division of Clinical Pharmacology, Department of Medicine, Center for Interdisciplinary Research on Medicines (CIRM), CHU, Sart Tilman (B35) B-4000 LIEGE 1, Belgium Tel: +32 4 3667238; Fax: +32 4 3667068; E-mail: andre.scheen @ chu.ulg.ac.be

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