Cooling down inflammation in type 2 diabetes: how strong is
the evidence for cardiometabolic benefit?
Maria Ida Maiorino1 • Giuseppe Bellastella1 • Dario Giugliano1 • Katherine Esposito2
Received: 11 April 2016 / Accepted: 17 May 2016
Springer Science+Business Media New York 2016
Abstract Chronic inflammation is supposed to be an
important mediator of cardiometabolic dysfunctions seen
in type 2 diabetes. In this mini-review, we collected evi￾dence (PubMed) from randomized controlled trials
(through March 2016) evaluating the effect of anti-in-
flammatory drugs on indices of glycemic control and/or
cardiovascular events in people with type 2 diabetes.
Within the last 25 years, many anti-inflammatory drugs
have been tested in type 2 diabetes, including hydroxy￾chloroquine, anti-tumor necrosis factor therapies (etaner￾cept and infliximab), salsalate, interleukin-1 antagonists
(anakinra, canakinumab, gevokizumab, LY2189102), and
CC-R2 antagonists. Despite being promising, the observed
effects on HbA1c or glucose control remain rather modest
in most clinical trials, especially with the new drugs. There
are many trials underway with anti-inflammatory agents to
see whether patients with cardiovascular diseases and/or
type 2 diabetes may have clinical benefit from marked
reductions in circulating inflammatory markers. Until now,
a large trial with losmapimod (a p38 inhibitor) among
patients with acute myocardial infarction, including one/
third of diabetic patients, showed no reduction in the risk of
major ischemic cardiovascular events. Further evidence is
warranted in support of the concept that targeting inflam￾mation pathways may ameliorate glycemic control and also
reduce cardiovascular complications in type 2 diabetes.
Keywords Inflammation Type 2 diabetes Anti￾inflammatory drugs Glycemic control Cardiovascular
At the end of the last century, Hotamisligil and Spiegelman
[1, 2] opened the way to the inflammation–insulin resis￾tance connection. They demonstrated the presence of
Tumor Necrosis Factor (TNF) in adipose tissue and its
direct role in inducing insulin resistance in mice. This link
has represented more than an interesting hypothesis in
Medicine, given that many metabolic conditions, including
obesity, metabolic syndrome, and type 2 diabetes, are
thought to be states of chronic inflammation. Needless to
say, all these metabolic abnormalities are strictly tied
together, which gave further support to the concept of a
‘‘common soil’’ linking chronic inflammation to metabolic
disorders. Visceral obesity was thought to be the starting
condition through the release of inflammatory cytokines,
including TNF, which may facilitate insulin resistance and
possibly hyperglycemia in predisposed people. The last,
but not the least, part of the inflammatory circle came from
the evidence that increased inflammatory activity plays a
critical role in the development of atherogenesis and pre￾dispose-established atherosclerotic plaques to rupture [3].
Therefore, chronic inflammation was supposed to be an
important mediator of cardiometabolic dysfunctions seen
in obesity, metabolic syndrome, and type 2 diabetes [4].
& Maria Ida Maiorino
[email protected]
1 Department of Medical, Surgical, Neurological, Metabolic
Sciences and Aging, Endocrinology and Metabolic Diseases
Unit, Second University of Naples, Piazza L. Miraglia n 2,
80138 Naples, Italy
2 Department of Clinical and Experimental Medicine, Second
University of Naples, Naples, Italy
DOI 10.1007/s12020-016-0993-7
Cardiometabolic benefit of reducing inflammation
in type 2 diabetes
After more than 20 years from those seminal studies [1, 2],
what does it remain of the inflammatory hypothesis of
metabolic diseases, particularly of type 2 diabetes? The
hypothesis has been explored in humans mainly by tar￾geting inflammation with specific drugs in patients with
type 2 diabetes; as supporting observations, studies in
people with inflammatory rheumatoid diseases have also
been performed. In a general perspective, the inflammatory
connection of type 2 diabetes should be satisfied when
specific interventions (a) reduce the circulating inflamma￾tory markers; (b) ameliorate the glycemic control of dia￾betes, via an improvement of insulin resistance, insulin
secretion or both; and (c) decrease cardiovascular events.
In this narrative review, we collected evidence coming
from randomized controlled trials (RCTs) that assessed the
effect of anti-inflammatory drugs on indices of glycemic
control (glucose, HbA1c) and/or cardiovascular events in
type 2 diabetes. We identified relevant studies through an
extensive literature search in MEDLINE through March
2016, with the following terms: type 2 diabetes, nonin￾sulin-dependent diabetes, anti-inflammatory drugs, cardio￾vascular outcomes, clinical trial, and glycemic control. No
language restrictions were imposed. Reference lists of
original studies, and previous reviews were also carefully
Anti-inflammatory drugs and glycemic control
Hydroxychloroquine (HCQ)
HCQ exerts its action through many mechanisms, includ￾ing inhibition of phagocytosis, antigen presentation, and
chemotaxis, and by decreasing the production of pro-in-
flammatory cytokines, inhibition of matrix metallopro￾teinases, and blocking T and B cell receptors, and toll-like
receptor signaling [5, 6]. In addition, HCQ has been sug￾gested to have beneficial effect on lipids, coagulation, and
diabetes which may contribute to lower the high cardio￾vascular risk in Systemic Lupus patients. We found three
randomized trials [7–9] lasting 6–18 months, with a dou￾ble-blind procedure in two [7, 9], assessing the role of
HCQ in insulin-resistant, treatment refractory (insulin,
sulfonylurea, or both)-patients with type 2 diabetes
(Table 1). The results were satisfactory or very satisfactory
as the HbA1c response was similar to that seen with other
antidiabetic agents, like pioglitazone [9], or ranged from 1
to 3 % decrease in HbA1c in a way similar to that of
insulin [7].
Interestingly, the use of HCQ in rheumatoid arthritis has
been associated with a decreased risk of developing dia￾betes: 77 % reduced risk among those taking the drug for
more than 4 years, compared to those who had not taken it
[10]. Moreover, in a retrospective cohort of 1266 patients
with rheumatoid arthritis from 2001 to 2013 [11], treatment
with HCQ was independently associated with a 72 %
reduction in all incident cardiovascular (CV) events.
Anti-TNF therapies
Anti-TNF therapies, using the TNF receptor:Fc fusion
protein (etanercept) or specific monoclonal antibodies (in-
fliximab), are widely used in various inflammatory diseases
such as rheumatoid arthritis [12], psoriasis [13], and
Crohn’s disease [14]. The various studies performed until
now with the aim to obtain amelioration of insulin resis￾tance and hence hyperglycemia by blocking the TNF sys￾tem yielded negative results not only in people with type 2
diabetes [15, 16] (Table 1), but also in nondiabetic, insulin￾resistant subjects [17]. The absence of any consistent effect
on insulin sensitivity by anti-TNF therapies has been dis￾appointing, considering that the whole story started from
the hypothesis that TNF could be a major mediator of
insulin resistance. More or less convincing reasons have
been put forward to explain these negative results,
including dosing duration, choice of population, the pres￾ence of more powerful determinants of insulin sensitivity,
or a dissociation between TNF-mediated effects on
inflammation and insulin resistance in humans. As it hap￾pened with the lack of benefit of anti-TNF therapy for heart
failure [18], the TNF hypothesis for type 2 diabetes is not
supported by the results of specific studies.
In a retrospective cohort study of 47,193 patients with
rheumatoid arthritis, the risk of acute myocardial infarction
was elevated by 30 % among anti-TNF initiators overall
(etanercept and infliximab) compared with abatacept or
tocilizumab initiators [19].
More than a century ago, high doses of sodium salicylate
(C5 g/d) were first demonstrated to alleviate symptoms in
diabetic patients having presumably type 2 diabetes [20], as
Ebstein in 1876 and then Williamson in 1901 concluded
that sodium salicylate could diminish greatly the sugar
excretion. Salsalate, which has been used to treat inflam￾matory conditions, such as rheumatoid arthritis,
osteoarthritis, and other rheumatologic conditions, is a
strong inhibitor of the NF-jB pathway [21]. Salicylates
have been shown to inhibit IjB kinase, thereby inhibiting
the NF-jB cascade and decreasing the production of
inflammatory cytokines (i.e., IL-6, TNF, and CRP) and
decreasing insulin resistance [22].
As demonstrated in recent trials (Table 1), the use of
salsalate therapy, at doses of 3–4.5 g daily, has the ability
to lower insulin resistance and reduce the levels of glucose,
triglycerides, and free fatty acid concentrations, with
minimal side effects [23, 24]. The two RCTs with salsalate
demonstrated a benefit of 0.33 % HbA1c in type 2 diabetes
compared with placebo, but they failed to have improve￾ments in endothelium-dependent and -independent dila￾tions of the brachial artery [25]. Unlike aspirin, salsalate is
not acetylated, it is not a cyclo-oxygenase inhibitor and
does not impact upon bleeding times or platelet aggrega￾tion. Whether or not salsalate might reduce cardiovascular
event rates is unknown.
Interleukin-1 antagonism
Under the influence of higher glycemic levels, islets mac￾rophages start to produce inflammatory cytokines, includ￾ing IL-1b, which contributes to the impairment in
pancreatic secretory function by increasing the b-cell
apoptosis rate [26].
Table 1 RCTs of anti-inflammatory drugs in type 2 diabetes
Drug/author Type of study Subjects studied Duration Results
Hydroxycholoquine (HCQ)
Quatraro et al. [7] RCT 19 T2D patients (HCQ) 6 months HbA1c lower than placebo (3.3 %)
DB 19 T2D patients (placebo) (P = 0.001)
Gerstein et al. [8] RCT 67 T2D patients (HCQ) 18 months HbA1c lower than placebo (1.02 %)
68 T2D patients (placebo) (P\0.05)
Pareek et al. [9] RCT 135 T2D patients (HCQ) 24 weeks HbA1c decrease 0.87 % (P \0.05)
DB 32 T2D patients (PIO)
Ofei et al. [15] RCT 10 T2D patients (CDP571) 4 weeks No effect on glucose and insulin sensitivity
DB 11 T2D patients (saline)
Dominguez et al. [16] RT 20 T2D patients (etanercept) 4 weeks No effect on insulin sensitivity
OP Same patients as controls
Salsalate (SAL)
Goldfine et al. [23] RCT 27 T2D patients (SAL) 14 weeks HbA1c lower (0.340.49 %) in the SAL vs
placebo group (P\0.001)
DB 27 T2D patients (placebo)
Goldfine et al. [24] RCT 148 T2D patients (SAL) 48 weeks HbA1c lower 0.33 % in the SAL versus
placebo group (P\0.02)
DB 140 T2D patients (placebo)
IL-1-receptor antagonists
Larsen et al. [27] RCT 34 T2D pts (Anakinra) 13 weeks HbA1c 0.46 % lower than placebo group
(P = 0.03)
DB 36 T2D pts (placebo)
Ridker et al. [30] RCT 377 T2D pts (Canakinumab) 4 months Modest and non significant effect on HbA1c
(-0.2 %)
DB 179 T2D pts (placebo)
Cavelti-Weder et al. [31] RCT 16 T2D pts (Gevokizumab) 3 months HbA1c 0.85 % lower than placebo group
(P = 0.049)
17 T2D pts (placebo)
Sloan-Lancaster et al. [32] RCT 56 T2D pts (LY2189102 12 weeks HbA1c 0.48 % lower than placebo group
(P = NR)
DB 23 T2D pts (placebo)
CC-R2 antagonists
Di Prospero et al. [33] RCT 21 T2D pts (NJ-41443532) 4 weeks FG 20 mg/dl lower than placebo (P = 0.038)
DB 22 T2D pts(placebo)
RCT randomized controlled trial; DB double-blind; T2D type 2 diabetes; FG fasting glucose; NR not reported
C–C motif chemokine receptor-2 (CCR2)
Anakinra is a recombinant human interleukin-1 receptor
antagonist, the first to be used in clinical practice. The first
study [27] that tested the metabolic effect of IL-1b inhi￾bition with Anakinra in type 2 diabetes reported benefits on
both hyperglycemia and secretory function of insulin
associated with reduced C-reactive protein (CRP) levels
(Table 1). Additional 12 independent clinical studies [28]
have demonstrated that IL-1 antagonism has the potential
to improve glycemia in patients with type 2 diabetes.
However, the magnitude of the effects is often a matter of
Canakinumab binds to human IL-1b, blocking interac￾tion of this cytokine with its receptors, an effect that should
in turn reduce circulating levels of IL-6 and hepatic pro￾duction of CRP and fibrinogen [29]. In a phase IIb, ran￾domized trial (556 men and women) [30], monthly doses of
canakinumab over 4 months had a modest but nonsignifi-
cant effect on HbA1c and glucose, with no effect on lipids
(LDL and HDL cholesterol) among the well-controlled
(baseline HbA1c = 7.4 %) diabetic patients being at high
risk of cardiovascular disease (Table 1). Yet, in this same
study population, canakinumab was highly effective at
reducing CRP, IL-6, and fibrinogen levels.
Gevokizumab is a recombinant human-engineered
monoclonal antibody that binds and neutralizes human IL-
1b. In a placebo-controlled study [31], a total of 98 patients
were randomly assigned to placebo (17 subjects) or
gevokizumab (81 subjects). In the combined intermediate￾dose group (single doses of 0.03 and 0.1 mg/kg), the mean
placebo-corrected decrease in glycated hemoglobin was
0.85 % after 3 months (N = 16 subjects, P = 0.049)
(Table 1), along with enhanced C-peptide secretion,
increased insulin sensitivity, and a reduction in CRP levels.
LY2189102 is a humanized monoclonal antibody (IgG4)
that binds to IL-1b with high affinity and neutralizes its
activity. In a phase II, randomized, double-blind, and pla￾cebo-controlled study [32], subcutaneous LY2189102
administered weekly for 12 weeks in patients with type 2
diabetes reduced HbA1c levels at 12 weeks (-0.38 % with
the 18 mg dose) and inflammatory biomarkers, including
CRP and IL-6 (Table 1).
CC-R2 antagonists
C–C chemokine ligand 2 (CCL2) also known as monocyte
chemoattractant protein-1, and its receptor, C–C motif
chemokine receptor 2 (CCR2), play important roles in
various inflammatory diseases. In a 4-week, double-blind,
placebo-controlled, and randomized, multicenter study
[33], 89 patients were randomized to receive either 250- or
1000-mg of JNJ-41443532, an orally bioavailable, selec￾tive, reversible antagonist of CCR CCR2 antagonist, twice
daily; 30-mg of pioglitazone once daily (reference arm); or
placebo. There was a modest yet significant decrease in
23-h-weighted mean glucose (Table 1).
Anti-inflammatory drugs and cardiovascular
The Emerging Risk Factors Collaboration [34] was a meta￾analysis of individual records from 160,309 people without
history of vascular disease from 54 long-term prospective
studies; the study found a positive association between
CRP and vascular risk, at the same level of that associated
with an increase in either blood pressure or cholesterol.
Despite the robust epidemiological evidence, it remains
unknown whether inhibition of inflammation per se will
lower vascular event rates. Moreover, the optimal agent for
trials testing the inflammatory hypothesis of atherosclerosis
should be able to reduce inflammatory biomarkers, such as
CRP, IL-6, and fibrinogen, with minimal effects on lipids
and other CV risk factors.
There is a great expectation from the results of Canaki￾numab Antiinflammatory Thrombosis Outcomes Study
(CANTOS) as regards whether patients with cardiovascular
diseases and type 2 diabetes may benefit from an anti-IL-1b
treatment [35]. The declared aim of CANTOS was to
address directly the potential for canakinumab to reduce
incident cardiovascular events in a secondary prevention
population with a persistent proinflammatory response.
Another NHLBI-sponsored trial (Cardiovascular Inflam￾mation Reduction Trial—CIRT) is evaluating the role of
low-dose methotrexate as a potential anti-inflammatory
agent to suppress cardiovascular event rates [36]. Moreover,
large-scale Phase III trials are now underway with agents
that lead to marked reductions in IL-6 and CRP (such as
canakinumab and methotrexate), as well as with agents that
impact on diverse non-IL-6-dependent pathways, disrupting
the first step of the arachidonic acid pathway of inflam￾mation through the inhibition of the phospholipase A2 (such
as varespladib and darapladib) [37].
In the meantime, a trial with losmapimod, a selective,
reversible, competitive inhibitor of p38 MAPK with onset as
early as 30 min after oral dosing has come to an end [38].
Activation of p38 MAPK leads to amplification of the
inflammatory cascade through enhanced production of mul￾tiple cytokines, including TNF, IL-1, and IL-6, metallopro￾teinases, and cyclooxygenase. This large RCT was prompted
by the findings of a randomized trial of 526 patients hospi￾talized with non-ST-elevation myocardial infarction
(NSTEMI), in which losmapimod, administered prior to per￾cutaneous coronary intervention, attenuated the acute increase
in markers of inflammation (CRP and IL-6) at 72 h [39].
In the LATITUDE-TIMI 60 [38], patients were ran￾domized to either twice-daily losmapimod (7.5 mg;
n = 1738) or matching placebo (n = 1765) and were
treated for 12 weeks and followed up for an additional
12 weeks. Among patients with acute myocardial infarc￾tion, the use of losmapimod compared with placebo did not
reduce the risk of major ischemic cardiovascular events,
although it reduced levels of CRP at 4 weeks and at the end
of the treatment period at 12 weeks. The trial included one/
third (33 %) of diabetic patients in each arm.
There is a considerable increase in the interest among the
researchers about anti-inflammatory therapies in the setting
of chronic disorders such as type 2 diabetes and CV dis￾eases. However, because inflammation acts along multiple
and redundant pathways, the identification of an appro￾priate target may be difficult. The current interest is
apparently directed toward new drugs targeting inflamma￾tion which are innovative molecules acting at different
stages of the inflammatory cascade. It has been hypothe￾sized that the immune system is intimately linked to
metabolism disorders [40]: accordingly, patients with dia￾betes may benefit from IL-1b or TNF blockade which
focuses on pathologically activated pathways responsible
for the disease. However, this hypothesis has to be con-
firmed by further studies specifically designed to test the
effect of immune-modulating drugs on diabetes and the
associated CV risk. Paradoxically, the drugs that until now
have demonstrated the more robust effect on glycemic
control in type 2 diabetes are the oldest ones, such as HQC
and salsalate. HCQ has the most abundant evidence for
metabolic benefit, with the longest trial so far performed
and the largest number of patients. The newer, costly, and
innovative drugs have yet to demonstrate their value in
both metabolic and CV outcomes in type 2 diabetic
patients. The old, cheap medications could be a useful and
cost-efficient option in the treatment of specific individuals
with treatment-refractory type 2 diabetes; however, larger
and longer clinical trials are needed to convince the med￾ical community of their benefits on treatment and preven￾tion of type 2 diabetes, as well as on its CV complications.
Compliance with ethical standards
Conflict of Interest D. G. and K. E. received speaker fees from Lilly,
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