Anti-Inflammatory Strategies to Prevent Diabetic Cardiovascular Disease I Jialal1 and S Devaraj2 (1)Laboratory for Atherosclerosis and Metabolic Research , UC Davis Medical Center, Sacramento CA and (2) Baylor College of Medicine, Houston, Texas Correspondence: [email protected]
Introduction Diabetes is a pro-inflammatory state and inflammation is crucial in the genesis of vascular complications. Whilst there are many anti-inflammatory strategies, most of which have been shown to reduce inflammation in diabetes, there is sparse data on reduction in cardiovascular events (CVE). To date, the only anti-inflammatory strategies that have been shown to reduce CVE in diabetes include statins, ARBs, metformin and pioglitazone. We also discuss the role of novel emerging therapies.
Several studies have demonstrated increased circulating and cellular biomarkers/biomediators of inflammation in diabetic patients establishing that diabetes is a pro-inflammatory state (1). Also, in diabetic patients, the prototypic marker of inflammation, C-reactive protein, predicts cardiovascular events (CVE). Furthermore, the recent Look-AHEAD Study failed to show a benefit of therapeutic lifestyle changes on cardiovascular outcomes after a mean follow-up of 9.6 years despite a reduction in weight, blood pressure and glycated hemoglobin. Thus, it appears that there needs to be a greater focus on pharmacotherapy with anti-inflammatory activity to reduce CVE in diabetes given the pivotal role of inflammation in the pathogenesis of diabetic vasculopathies (1). In this commentary, we briefly review therapies that possess both antiinflammatory effects and reduce CVE in diabetics and also anti-inflammatory therapies that have yet to demonstrate a reduction in CVE in diabetes. With regards to the former group of drugs, the best data appears to be with the statin group of drugs. A meta-analysis of studies including 18,686 diabetic patients demonstrated a significant 21 percent reduction in CVE and 13 % reduction vascular mortality (2). This class of drugs has been shown to reduce both LDL-cholesterol and exhibit anti-inflammatory effects. In patients with diabetes compared to placebo, simvastatin reduced both circulating and cellular biomarkers of inflammation (3). Since the reduction in CVE includes ischemic stroke, a reduction of inflammation could be advanced as a plausible mechanism explaining in part the beneficial effects. Another drug that has been shown to have anti-inflammatory effects and reduce CVE in diabetic patients is Metformin. In the UKPDS study in overweight (>120 percent of ideal body weight) diabetic patients there was a significant reduction in CVE and mortality with metformin This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/cpt.105 This article is protected by copyright. All rights reserved.
compared to placebo and metformin has been shown to have anti-inflammatory effects in diabetic patients (5). Blockade of the renin-angiotensin system with angiotensin -converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to reduce CVE in diabetic patients. Since Angiotensin 11 induces both oxidative stress and inflammation, it is not surprising that ARBs and to a lesser extent ACEs reduce biomarkers of inflammation (5, 6). Hence some of the benefit of these drugs can also be attributed to their anti-inflammatory effects. The thiazolidinedione, pioglitazone, following engagement of PPARS –gamma has been shown reduce insulin resistance and inflammation in diabetics (5, 7). As reviewed by Yau et al, pioglitazone ameliorates atherosclerosis progression in both the carotid and coronary circulation and reduces CVE (secondary and not primary end-point in the PROACTIVE study). (7) Some of this benefit could be ascribed to its anti-inflammatory effects. However, since therapy results in fluid retention which increases the risk of heart failure especially in high risk patients, more so when combined with insulin therapy, this risk needs to taken into account against its potential benefits when considering pioglitazone as a therapy. There is thus a great need for other more selective PPAR –gamma agonists/modulators which do not cause fluid retention and are relatively safer since these drugs are excellent insulin sensitizers. Recently modulators of the incretin system (GLP-1 receptor agonists and DPP-4-Inhibitors) have been ushered in as part of the diabetic armamentarium. In addition to reducing glucose levels, both fasting and post-prandial, these drugs demonstrate anti-inflammatory effects in diabetic patients (8). However, the final arbiter with respect to this class of drugs reducing CVE will be the ongoing clinical trials. The largest amount of data with regards to the effect of the novel cytokine blockade therapies in diabetes is studies involving IL-1 inhibition. Anakinra is a non-glycosylated form of the human IL1 receptor antagonist. In a randomized, placebo controlled study of Anakinra therapy in diabetic patients for 13 weeks, in addition to improved insulin secretion and glycemic control, there were significant decreases in CRP and IL-6 levels [5]. Furthermore, 39 weeks after treatment discontinuation, Anakinra responders showed a benefit on insulin secretion and biomarkers of inflammation (5). However, IL-1RA has a short half-life (4-6 hrs) and this would need 1- 2 daily injections and it blocks both IL-alpha and beta. The implication of blocking IL1-alpha for long durations remains to be determined. Gevokizumab, an IL-1 beta specific antibody, in addition to reducing glycated hemoglobin, significantly reduced systemic inflammatory markers. Similarly, Canakinumab, a neutralizing IL-1b antibody, in short term studies, appear to improve HbA1c along with a reduction in CRP. However, long term effects of these antibodies and their safety profiles need to be established in currently ongoing randomized clinical trials such as the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), which will test the effect of IL-1β inhibition on CVE and new onset T2DM in patients with high hsCRP levels. (9). Importantly , anti-IL-1 therapies do not have a deleterious effect on the lipid profile. TNF was the first cytokine that was shown to have a role in insulin resistance in rodents. (5) However, this important observation has not been confirmed by clinical studies. Etanercept is a
This article is protected by copyright. All rights reserved.
dimeric fusion protein with an extracellular ligand binding domain of the Human Tumor Necrosis Factor Receptor (TNFR) linked to the Fc component of human IgG1. The first two clinical trials testing the role of TNF inhibition on insulin sensitivity used a single dose of a TNF antagonist in a small number of patients with diabetes and obesity for a short duration (ten and seven patients for 4 weeks and 2 days, respectively). These studies failed to detect statistically significant effects. (5) Prolonged (6-month) TNF inhibition was subsequently studied in obese individuals without diabetes and resulted in a statistically significant decrease in fasting glucose and an increase in adiponectin. Therefore, although it is likely that prolonged antagonism of TNF will be potentially beneficial in diabetes, a large long term clinical trial of TNF antagonism is warranted in patients with type 2 diabetes testing both its anti-inflammatory effects and potential reduction in CVE since it appears to have a deleterious effect on the lipid profile . Salsalates exert their anti-inflammatory effect via inhibition of the NF-κB pathway, (10). They have systematically conducted studies spanning animal models to Phase III clinical trials. In an open label study, salsalate, a prodrug form of salicylate, reduced fasting and post-challenge glucose levels and increased glucose utilization in euglycemic, hyperinsulinemic clamp studies (5, 10). In another study, salsalate, when compared with placebo, significantly reduced fasting glucose by 13%, glycemic response after an oral glucose challenge by 20%, and glycated albumin by 17%. Whilst insulin levels were unchanged, CRP levels decreased and adiponectin levels increased. These findings prove that salsalate reduces glycemia and attenuates inflammation in overweight individuals. Two multicenter, placebo-controlled studies were subsequently performed. In both a 14-week and a 48-week follow-up study, there was a 0.5% decrease in placebo corrected glycated hemoglobin and improvement in other markers of glycemic control [5, 10]. This was accompanied by decreased leukocyte count , little effect on CRP but an increase in adiponectin levels; however effects on CVE were not assessed. Salsalate may be an effective and cheap drug to improve glycemic control. However, caution needs to be exercised since there were small but significant increases in LDL-cholesterol and increased urinary albumin excretion and long-term cardiovascular and renal safety need to be determined. Also, in TINSAL-T2D, salsalate therapy was associated with a reduction in early but not late advanced glycation end products and there was a paradoxical increase in pentosidine levels suggesting a possible increase in oxidative stress [11]. The NIH sponsored TINSAL-T2D trial will eventually determine long term safety of salsalate with respect to cardiovascular safety. Other exciting but more preliminary strategies that impact inflammation include inhibition of IL6 (which appears to have a deleterious effect on the lipid profile), lipoxygenases, upregulation of Sirtuin 1,inhibition of histone deacetylases, low dose methotrexate therapy etc., but much work is needed in the clinical arena before any firm conclusions can be drawn about safety and reduction of CVE in diabetics. In conclusion, ameliorating inflammation in diabetes with novel therapeutics can be a very fruitful additional strategy to reduce CVE provided long term safety is established.
This article is protected by copyright. All rights reserved.
References: 1. Devaraj S et al. Diabetes is a proinflammatory state: a translational perspective. Expert Rev Endocrinol Metab. 5, 19-28 (2010). 2. Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 371, 117-25 (2008). 3. Jialal I, et al. . Concomitant reduction of low-density lipoprotein-cholesterol and biomarkers of inflammation with low-dose simvastatin therapy in patients with type 1 diabetes. J Clin Endocrinol Metab.92,3136-40 (2007). 4. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 352, 854-65 (1998). 5. Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 13, 465-76 (2014). 6. Raimondo D D et al Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Infllamation . Cuuent Pharamaceutical Design 18,4385-4413, (2012). 7. Yau H et al. The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. Curr Diab Rep. 13, 329-41(2013). 8. Dhindsa S and Jialal I Potential Anti-Atherosclerotic Effects of Dipeptidyl peptidase -4 inhibitors in T2DM Current Diabetes Reports 14,1-7(2014). 9. Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J35(27), 1782-91 (2014). 10. Goldfine A et al. Salicylate(Salsalate) in patients with Type2 Diabetes : A randomized Trial Ann Intern Med.159,1-129(2013). 11. Barzilay JI et al. The impact of salsalate treatment on serum levels of advanced glycation end products in Type 2 diabetes. Diab Care. 37,1083-9 (2014).
This article is protected by copyright. All rights reserved.
Introduction Diabetes is a pro-inflammatory state and inflammation is crucial in the genesis of vascular complications. Whilst there are many anti-inflammatory strategies, most of which have been shown to reduce inflammation in diabetes, there is sparse data on reduction in cardiovascular events (CVE). To date, the only anti-inflammatory strategies that have been shown to reduce CVE in diabetes include statins, ARBs, metformin and pioglitazone. We also discuss the role of novel emerging therapies.
Several studies have demonstrated increased circulating and cellular biomarkers/biomediators of inflammation in diabetic patients establishing that diabetes is a pro-inflammatory state (1). Also, in diabetic patients, the prototypic marker of inflammation, C-reactive protein, predicts cardiovascular events (CVE). Furthermore, the recent Look-AHEAD Study failed to show a benefit of therapeutic lifestyle changes on cardiovascular outcomes after a mean follow-up of 9.6 years despite a reduction in weight, blood pressure and glycated hemoglobin. Thus, it appears that there needs to be a greater focus on pharmacotherapy with anti-inflammatory activity to reduce CVE in diabetes given the pivotal role of inflammation in the pathogenesis of diabetic vasculopathies (1). In this commentary, we briefly review therapies that possess both antiinflammatory effects and reduce CVE in diabetics and also anti-inflammatory therapies that have yet to demonstrate a reduction in CVE in diabetes. With regards to the former group of drugs, the best data appears to be with the statin group of drugs. A meta-analysis of studies including 18,686 diabetic patients demonstrated a significant 21 percent reduction in CVE and 13 % reduction vascular mortality (2). This class of drugs has been shown to reduce both LDL-cholesterol and exhibit anti-inflammatory effects. In patients with diabetes compared to placebo, simvastatin reduced both circulating and cellular biomarkers of inflammation (3). Since the reduction in CVE includes ischemic stroke, a reduction of inflammation could be advanced as a plausible mechanism explaining in part the beneficial effects. Another drug that has been shown to have anti-inflammatory effects and reduce CVE in diabetic patients is Metformin. In the UKPDS study in overweight (>120 percent of ideal body weight) diabetic patients there was a significant reduction in CVE and mortality with metformin This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/cpt.105 This article is protected by copyright. All rights reserved.
compared to placebo and metformin has been shown to have anti-inflammatory effects in diabetic patients (5). Blockade of the renin-angiotensin system with angiotensin -converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to reduce CVE in diabetic patients. Since Angiotensin 11 induces both oxidative stress and inflammation, it is not surprising that ARBs and to a lesser extent ACEs reduce biomarkers of inflammation (5, 6). Hence some of the benefit of these drugs can also be attributed to their anti-inflammatory effects. The thiazolidinedione, pioglitazone, following engagement of PPARS –gamma has been shown reduce insulin resistance and inflammation in diabetics (5, 7). As reviewed by Yau et al, pioglitazone ameliorates atherosclerosis progression in both the carotid and coronary circulation and reduces CVE (secondary and not primary end-point in the PROACTIVE study). (7) Some of this benefit could be ascribed to its anti-inflammatory effects. However, since therapy results in fluid retention which increases the risk of heart failure especially in high risk patients, more so when combined with insulin therapy, this risk needs to taken into account against its potential benefits when considering pioglitazone as a therapy. There is thus a great need for other more selective PPAR –gamma agonists/modulators which do not cause fluid retention and are relatively safer since these drugs are excellent insulin sensitizers. Recently modulators of the incretin system (GLP-1 receptor agonists and DPP-4-Inhibitors) have been ushered in as part of the diabetic armamentarium. In addition to reducing glucose levels, both fasting and post-prandial, these drugs demonstrate anti-inflammatory effects in diabetic patients (8). However, the final arbiter with respect to this class of drugs reducing CVE will be the ongoing clinical trials. The largest amount of data with regards to the effect of the novel cytokine blockade therapies in diabetes is studies involving IL-1 inhibition. Anakinra is a non-glycosylated form of the human IL1 receptor antagonist. In a randomized, placebo controlled study of Anakinra therapy in diabetic patients for 13 weeks, in addition to improved insulin secretion and glycemic control, there were significant decreases in CRP and IL-6 levels [5]. Furthermore, 39 weeks after treatment discontinuation, Anakinra responders showed a benefit on insulin secretion and biomarkers of inflammation (5). However, IL-1RA has a short half-life (4-6 hrs) and this would need 1- 2 daily injections and it blocks both IL-alpha and beta. The implication of blocking IL1-alpha for long durations remains to be determined. Gevokizumab, an IL-1 beta specific antibody, in addition to reducing glycated hemoglobin, significantly reduced systemic inflammatory markers. Similarly, Canakinumab, a neutralizing IL-1b antibody, in short term studies, appear to improve HbA1c along with a reduction in CRP. However, long term effects of these antibodies and their safety profiles need to be established in currently ongoing randomized clinical trials such as the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), which will test the effect of IL-1β inhibition on CVE and new onset T2DM in patients with high hsCRP levels. (9). Importantly , anti-IL-1 therapies do not have a deleterious effect on the lipid profile. TNF was the first cytokine that was shown to have a role in insulin resistance in rodents. (5) However, this important observation has not been confirmed by clinical studies. Etanercept is a
This article is protected by copyright. All rights reserved.
dimeric fusion protein with an extracellular ligand binding domain of the Human Tumor Necrosis Factor Receptor (TNFR) linked to the Fc component of human IgG1. The first two clinical trials testing the role of TNF inhibition on insulin sensitivity used a single dose of a TNF antagonist in a small number of patients with diabetes and obesity for a short duration (ten and seven patients for 4 weeks and 2 days, respectively). These studies failed to detect statistically significant effects. (5) Prolonged (6-month) TNF inhibition was subsequently studied in obese individuals without diabetes and resulted in a statistically significant decrease in fasting glucose and an increase in adiponectin. Therefore, although it is likely that prolonged antagonism of TNF will be potentially beneficial in diabetes, a large long term clinical trial of TNF antagonism is warranted in patients with type 2 diabetes testing both its anti-inflammatory effects and potential reduction in CVE since it appears to have a deleterious effect on the lipid profile . Salsalates exert their anti-inflammatory effect via inhibition of the NF-κB pathway, (10). They have systematically conducted studies spanning animal models to Phase III clinical trials. In an open label study, salsalate, a prodrug form of salicylate, reduced fasting and post-challenge glucose levels and increased glucose utilization in euglycemic, hyperinsulinemic clamp studies (5, 10). In another study, salsalate, when compared with placebo, significantly reduced fasting glucose by 13%, glycemic response after an oral glucose challenge by 20%, and glycated albumin by 17%. Whilst insulin levels were unchanged, CRP levels decreased and adiponectin levels increased. These findings prove that salsalate reduces glycemia and attenuates inflammation in overweight individuals. Two multicenter, placebo-controlled studies were subsequently performed. In both a 14-week and a 48-week follow-up study, there was a 0.5% decrease in placebo corrected glycated hemoglobin and improvement in other markers of glycemic control [5, 10]. This was accompanied by decreased leukocyte count , little effect on CRP but an increase in adiponectin levels; however effects on CVE were not assessed. Salsalate may be an effective and cheap drug to improve glycemic control. However, caution needs to be exercised since there were small but significant increases in LDL-cholesterol and increased urinary albumin excretion and long-term cardiovascular and renal safety need to be determined. Also, in TINSAL-T2D, salsalate therapy was associated with a reduction in early but not late advanced glycation end products and there was a paradoxical increase in pentosidine levels suggesting a possible increase in oxidative stress [11]. The NIH sponsored TINSAL-T2D trial will eventually determine long term safety of salsalate with respect to cardiovascular safety. Other exciting but more preliminary strategies that impact inflammation include inhibition of IL6 (which appears to have a deleterious effect on the lipid profile), lipoxygenases, upregulation of Sirtuin 1,inhibition of histone deacetylases, low dose methotrexate therapy etc., but much work is needed in the clinical arena before any firm conclusions can be drawn about safety and reduction of CVE in diabetics. In conclusion, ameliorating inflammation in diabetes with novel therapeutics can be a very fruitful additional strategy to reduce CVE provided long term safety is established.
This article is protected by copyright. All rights reserved.
References: 1. Devaraj S et al. Diabetes is a proinflammatory state: a translational perspective. Expert Rev Endocrinol Metab. 5, 19-28 (2010). 2. Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 371, 117-25 (2008). 3. Jialal I, et al. . Concomitant reduction of low-density lipoprotein-cholesterol and biomarkers of inflammation with low-dose simvastatin therapy in patients with type 1 diabetes. J Clin Endocrinol Metab.92,3136-40 (2007). 4. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 352, 854-65 (1998). 5. Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 13, 465-76 (2014). 6. Raimondo D D et al Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Infllamation . Cuuent Pharamaceutical Design 18,4385-4413, (2012). 7. Yau H et al. The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. Curr Diab Rep. 13, 329-41(2013). 8. Dhindsa S and Jialal I Potential Anti-Atherosclerotic Effects of Dipeptidyl peptidase -4 inhibitors in T2DM Current Diabetes Reports 14,1-7(2014). 9. Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J35(27), 1782-91 (2014). 10. Goldfine A et al. Salicylate(Salsalate) in patients with Type2 Diabetes : A randomized Trial Ann Intern Med.159,1-129(2013). 11. Barzilay JI et al. The impact of salsalate treatment on serum levels of advanced glycation end products in Type 2 diabetes. Diab Care. 37,1083-9 (2014).
This article is protected by copyright. All rights reserved.
