The presence of cardiovascular disease (CVD) in Type 1 diabetes largely impairs life expectancy. Hyperglycemia leading to an increase in oxidative stress is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In Type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycemic episodes are considered to adversely influence cardiac performance. Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of Type 1 diabetes. Future therapies may also include glucagon-like peptide (GLP)-based treatment therapies. Pilot studies with GLP-1-analogues have been shown to reduce insulin requirements.
Type 1 diabetes; Cardiovascular disease
Hypoglycaemia has been associated with increased cardiovascular (CV) risk and mortality in a number of recent multicentre trials, but the mechanistic links driving this association remain ill defined. This review aims to summarize the available data on how hypoglycaemia may affect CV risk in patients with diabetes.
This was a systematic review of available mechanistic and clinical studies on the relationship between hypoglycaemia and cardiovascular risk. Study outcomes were compiled from relevant articles, and factors contributing to hypoglycaemia-mediated CVD and its complications are discussed.
Six recent comprehensive clinical trials have reinforced the critical importance of understanding the link between hypoglycaemia and the CV system. In addition, 88 studies have indicated that hypoglycaemia mechanistically contributes to CV risk by increasing thrombotic tendency, causing abnormal cardiac repolarization, inducing inflammation, and contributing to the development of atherosclerosis. These hypoglycaemia-associated risk factors are conducive to events such as unstable angina, non-fatal and fatal myocardial infarction, sudden death, and stroke in patients with diabetes.
Emerging data suggest that there is an impact of hypoglycaemia on CV function and mechanistic link is multifactorial. Further research will be needed to ascertain the full impact of hypoglycaemia on the CV system and its complications.
Hypoglycaemia; Cardiovascular risk; Arrhythmia; Continuous glucose monitoring; Randomized controlled trials
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in people with diabetes and therefore managing cardiovascular (CV) risk is a critical component of diabetes care. As incretin-based therapies are effective recent additions to the glucose-lowering treatment armamentarium for type 2 diabetes mellitus (T2D), understanding their CV safety profiles is of great importance. Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with beneficial effects on CV risk factors, including weight, blood pressure and lipid profiles. Encouragingly, mechanistic studies in preclinical models and in patients with acute coronary syndrome suggest a potential cardioprotective effect of native GLP-1 or GLP-1 receptor agonists following ischaemia. Moreover, meta-analyses of phase 3 development programme data indicate no increased risk of major adverse cardiovascular events (MACE) with incretin-based therapies. Large randomized controlled trials designed to evaluate long-term CV outcomes with incretin-based therapies in individuals with T2D are now in progress, with the first two reporting as this article went to press.
Type 2 diabetes mellitus; Cardiovascular safety; Incretin; GLP-1; GLP-1 receptor agonists; DPP-4 inhibitors
Circulatory and tissue renin-angiotensin systems (RAS) play a central role in cardiovascular (CV) and renal pathophysiology, making RAS inhibition a logical therapeutic approach in the prevention of CV and renal disease in patients with hypertension. The cardio- and renoprotective effects observed with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) monotherapy, together with the availability of a direct renin inhibitor (DRI), led to the investigation of the potential benefits of dual RAS inhibition. In small studies, ARB and ACE inhibitor combinations were shown to be beneficial in patients with CV or renal disease, with improvement in surrogate markers. However, in larger outcome trials, involving combinations of ACE inhibitors, ARBs or DRIs, dual RAS inhibition did not show reduction in mortality in patients with diabetes, heart failure, coronary heart disease or after myocardial infarction, and was in fact, associated with increased harm. A recent meta-analysis of all major trials conducted over the past 22 years involving dual RAS inhibition has clearly shown that the risk-benefit ratio argues against the use of dual RAS inhibition. Hence, the recent evidence clearly advocates against the use of dual RAS inhibition, and single RAS inhibition appears to be the most suitable approach to controlling blood pressure and improving patient outcomes.
Angiotensin-converting enzyme (ACE) inhibitors; Angiotensin II receptor blockers; Blood pressure; Cardiovascular disease; Dual renin-angiotensin system inhibition; Direct renin inhibitors; Outcomes; Renal disease
Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family implicated in the control of appetite and satiety. GLP-1 has insulinotropic, insulinomimetic, and glucagonostatic effects, thereby exerting multiple complementary actions to lower blood glucose in subjects with type 2 diabetes mellitus. A major advantage over conventional insulin is the fact that the insulinotropic actions of GLP-1 are dependent upon ambient glucose concentration, mitigating the risks of hypoglycemia. Recently, the crucial role of GLP-1 in cardiovascular disease has been suggested in both preclinical and clinical studies. The experimental data indicate GLP-1 and its analogs to have direct effects on the cardiovascular system, in addition to their classic glucoregulatory actions. Clinically, beneficial effects of GLP-1 have also been demonstrated in patients with myocardial ischemia and heart failure. GLP-1 has recently been demonstrated to be a more effective alternative in treating myocardial injury. This paper provides a review on the current evidence supporting the use of GLP-1 in experimental animal models and human trials with the ischemic and non-ischemic heart and discusses their molecular mechanisms and potential as a new therapeutic approach.
GLP-1; Insulin resistance; Heart; Cardiovascular disease; Diabetes
Dyslipidemia is a major risk factor for cardiovascular (CV) disease – the primary cause of death, worldwide. Although reducing levels of low-density lipoprotein-cholesterol can significantly reduce CV risk, a high level of residual risk persists, especially in people with obesity-related conditions, such as metabolic syndrome and type 2 diabetes mellitus. Peroxisome proliferator-activated receptor alpha- (PPARα-) agonists (e.g. fibrates), play a central role in the reduction of macro- and microvascular risk in these patients. However, the currently available fibrates are weak (PPARα-agonists) with limited efficacy due to dose-related adverse effects. To address this problem, a new generation of highly potent and selective PPARα-modulators (SPPARMα) is being developed that separate the benefits of the PPARα-agonists from their unwanted side effects. Among these, aleglitazar (a dual PPARα/γ agonist) and GFT505 (a dual PPAR α/δ agonist) have recently entered late-phase development. Although both compounds are more potent PPARα-activators than fenofibrate in vitro, only aleglitezar is more effective in lowering triglycerides and raising high-density lipoprotein-cholesterol (HDL-C) in humans. However, it is also associated with a potential risk of adverse effects. More recently, a highly potent, specific PPARα-agonist (K-877) has emerged with SPPARMα characteristics. Compared to fenofibrate, K-877 has more potent PPARα-activating efficacy in vitro, greater effects on triglycerides- and HDL-C levels in humans, and a reduced risk of adverse effects. If successful, K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual CV risk associated with metabolic syndrome and type 2 diabetes.
Peroxisome proliferator-activated receptor; Fibrate; SPPARM; K-877; Cardiovascular; Diabetes; Metabolic syndrome
Metformin is, if not contraindicated and if tolerated, usually preferred over other antidiabetic drugs for the first line treatment of type-2 diabetes. The particular decision on which antidiabetic agent to use is based on variables such as efficacy, cost, potential side effects, effects on weight, comorbidities, hypoglycemia, risk, and patient preferences. However, there is no guidance how to consider these in the selection of antidiabetic drug treatment. In this work, we aimed to summarize available evidence and tried to give pragmatic treatment recommendations from a clinical practice perspective.
There are clear contraindications for some drugs in those with impaired renal and liver function and precautions in those with heart failure for the use of metformin (NYHA III-IV) and glitazones. On the other hand, GLP-1 analogs, DPP-4 inhibitors and acarbose are generally less critical and can be used in the majority of patients. We identified the following gaps with respect to the selection of antidiabetic drug treatment in patients with co-morbid disease conditions: 1) Guidelines fail to give advice on the use of specific antidiabetic drugs in patients with co-morbidity. 2) The literature is deficient in studies documenting antidiabetic drug use in patients with severely impaired renal function, diabetic retinopathy, cerebrovascular disease and systolic heart failure. 3) Further there are no specific data on patients with multiple of these co-morbid disease conditions. We postulate that differential use of antidiabetic drugs in patients with co-morbid disease constellations will help to reduce treatment related complications and might improve prognosis.
Volatile anaesthetics exert protective effects on the heart against perioperative ischaemic injury. However, there is growing evidence that these cardioprotective properties are reduced in case of type 2 diabetes mellitus. A strong predictor of postoperative cardiac function is myocardial substrate metabolism. In the type 2 diabetic heart, substrate metabolism is shifted from glucose utilisation to fatty acid oxidation, resulting in metabolic inflexibility and cardiac dysfunction. The ischaemic heart also loses its metabolic flexibility and can switch to glucose or fatty acid oxidation as its preferential state, which may deteriorate cardiac function even further in case of type 2 diabetes mellitus.
Recent experimental studies suggest that the cardioprotective properties of volatile anaesthetics partly rely on changing myocardial substrate metabolism. Interventions that target at restoration of metabolic derangements, like lifestyle and pharmacological interventions, may therefore be an interesting candidate to reduce perioperative complications. This review will focus on the current knowledge regarding myocardial substrate metabolism during volatile anaesthesia in the obese and type 2 diabetic heart during perioperative ischaemia.
Volatile anaesthetics; Substrate metabolism; Ischaemia; Diabetes; Heart
All fibrates are peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C). However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones) are used to treat type 2 diabetes mellitus (T2DM). They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates). Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants, induced atherosclerotic plaque regression in thoracic and abdominal aorta and improved endothelial function. In addition, bezafibrate has important fibrinogen-related properties and anti-inflammatory effects. In clinical trials bezafibrate was highly effective for cardiovascular risk reduction in patients with metabolic syndrome and atherogenic dyslipidemia. The principal differences between bezafibrate and other fibrates are related to effects on glucose level and insulin resistance. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Currently statins are the cornerstone of the treatment and prevention of cardiovascular diseases related to atherosclerosis. However, despite the increasing use of statins as monotherapy for low density lipoprotein- cholesterol (LDL-C) reduction, a significant residual cardiovascular risk is still presented in patients with atherogenic dyslipidemia and insulin resistance, which is typical for T2DM and metabolic syndrome. Recently, concerns were raised regarding the development of diabetes in statin-treated patients. Combined bezafibrate/statin therapy is more effective in achieving a comprehensive lipid control and residual cardiovascular risk reduction. Based on the beneficial effects of pan-PPAR agonist bezafibrate on glucose metabolism and prevention of new-onset diabetes, one could expect a neutralization of the adverse pro-diabetic effect of statins using the strategy of a combined statin/fibrate therapy.
Atherogenic dyslipidemia; Bezafibrate; Combined fibrate/statin therapy; Metabolic syndrome; PPAR; Prevention; Residual cardiovascular risk; Type 2 diabetes
Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus are common and underdiagnosed medical conditions. It was predicted that chronic obstructive pulmonary disease will be the third leading cause of death worldwide by 2020. The healthcare burden of this disease is even greater if we consider the significant impact of chronic obstructive pulmonary disease on the cardiovascular morbidity and mortality.
Chronic obstructive pulmonary disease may be considered as a novel risk factor for new onset type 2 diabetes mellitus via multiple pathophysiological alterations such as: inflammation and oxidative stress, insulin resistance, weight gain and alterations in metabolism of adipokines.
On the other hand, diabetes may act as an independent factor, negatively affecting pulmonary structure and function. Diabetes is associated with an increased risk of pulmonary infections, disease exacerbations and worsened COPD outcomes. On the top of that, coexistent OSA may increase the risk for type 2 DM in some individuals.
The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and chronic obstructive pulmonary disease may be viewed as a risk factor for the new onset type 2 diabetes mellitus. Conversely, both types of diabetes mellitus should be viewed as strong contributing factors for the development of obstructive lung disease. Such approach can potentially improve the outcomes and medical control for both conditions, and, thus, decrease the healthcare burden of these major medical problems.
COPD; Dysglycemia; Insulin resistance; Obesity; Metabolic syndrome; Diabetes mellitus endothelial dysfunction; Vasculopathy
Currently the world faces epidemic of several closely related conditions: obesity, metabolic syndrome and type 2 diabetes (T2DM). The lipid profile of these patients and those with metabolic syndrome is characterized by the concurrent presence of qualitative as well as quantitative lipoprotein abnormalities: low levels of HDL, increased triglycerides, and prevalence of LDL particles that are smaller and denser than normal. This lipid phenotype has been defined as atherogenic dyslipidemia. Overwhelming evidences demonstrate that all components of the atherogenic dyslipidemia are important risk-factors for cardiovascular diseases. Optimal reduction of cardiovascular risk through comprehensive management of atherogenic dyslipidemias basically depends of the presence of efficacious lipid-modulating agents (beyond statin-based reduction of LDL-C). The most important class of medications which can be effectively used nowadays to combat atherogenic dyslipidemias is the fibrates. From a clinical point of view, in all available 5 randomized control trials beneficial effects of major fibrates (gemfibrozil, fenofibrate, bezafibrate) were clearly demonstrated and were highly significant in patients with atherogenic dyslipidemia. In these circumstances, the main determinant of the overall results of the trial is mainly dependent of the number of the included appropriate patients with atherogenic dyslipidemia. In a meta-analysis of dyslipidemic subgroups totaling 4726 patients a significant 35% relative risk reduction in cardiovascular events was observed compared with a non significant 6% reduction in those without dyslipidemia. However, different fibrates may have a somewhat different spectrum of effects. Currently only fenofibrate was investigated and proved to be effective in reducing microvascular complications of diabetes. Bezafibrate reduced the severity of intermittent claudication. Cardinal differences between bezafibrate and other fibrates are related to the effects on glucose metabolism and insulin resistance. Bezafibrate is the only clinically available pan - (alpha, beta, gamma) PPAR balanced activator. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Among major fibrates, bezafibrate appears to have the strongest and fenofibrate the weakest effect on HDL-C. Current therapeutic use of statins as monotherapy is still leaving many patients with atherogenic dyslipidemia at high risk for coronary events because even intensive statin therapy does not eliminate the residual cardiovascular risk associated with low HDL and/or high triglycerides. As compared with statin monotherapy (effective mainly on LDL-C levels and plaque stabilization), the association of a statin with a fibrate will also have a major impact on triglycerides, HDL and LDL particle size. Moreover, in the specific case of bezafibrate one could expect neutralizing of the adverse pro-diabetic effect of statins. Though muscle pain and myositis is an issue in statin/fibrate treatment, adverse interaction appears to occur to a significantly greater extent when gemfibrozil is administered. However, bezafibrate and fenofibrate seems to be safer and better tolerated. Combined fibrate/statin therapy is more effective in achieving a comprehensive lipid control and may lead to additional cardiovascular risk reduction, as could be suggested for fenofibrate following ACCORD Lipid study subgroup analysis and for bezafibrate on the basis of one small randomized study and multiple observational data. Therefore, in appropriate patients with atherogenic dyslipidemia fibrates- either as monotherapy or combined with statins – are consistently associated with reduced risk of cardiovascular events. Fibrates currently constitute an indispensable part of the modern anti-dyslipidemic arsenal for patients with atherogenic dyslipidemia.
Atherogenic dyslipidemia; Bezafibrate; Combined fibrate/statin therapy; Fenofibrate; Metabolic syndrome; Residual cardiovascular risk; Type 2 diabetes
Diabetes mellitus currently affects more than 170 million individuals worldwide and is expected to afflict another 200 million individuals in the next 30 years. Complications of diabetes as a result of oxidant stress affect multiple systems throughout the body, but involvement of the cardiovascular system may be one of the most severe in light of the impact upon cardiac and vascular function that can result in rapid morbidity and mortality for individuals. Given these concerns, the signaling pathways of the mammalian target of rapamycin (mTOR) offer exciting prospects for the development of novel therapies for the cardiovascular complications of diabetes. In the cardiovascular and metabolic systems, mTOR and its multi-protein complexes of TORC1 and TORC2 regulate insulin release and signaling, endothelial cell survival and growth, cardiomyocyte proliferation, resistance to β-cell injury, and cell longevity. Yet, mTOR can, at times, alter insulin signaling and lead to insulin resistance in the cardiovascular system during diabetes mellitus. It is therefore vital to understand the complex relationship mTOR and its downstream pathways hold during metabolic disease in order to develop novel strategies for the complications of diabetes mellitus in the cardiovascular system.
Akt; AMPK; Cardiac; Diabetes Mellitus; Endothelial; Insulin Receptor Substrate 1; Sirtuin; SIRT1; TORC1; TORC2
Based on the results of recent randomized, controlled clinical trials and analyses of their follow-up periods the concept of metabolic memory cannot be restricted to antihyperglycaemic treatment only, rather it can be extended to lipid-lowering and antihypertensive treatment and even life-style modification. This broadened concept can be designated as vascular memory. According to this new concept, not only immediate and short-term but long-term effects of the metabolic and cardiovascular risk milieu are of great importance. Consequently, early and intensive lifestyle interventions, treatment of hyperglycaemia, lipid abnormalities and hypertension can result in beneficial effects on cardiovascular outcomes even in the long run. On the contrary, failing in target-oriented treatment from early detection of abnormalities can be associated with life-threatening cardiovascular events subsequently. Additional experimental studies are needed to characterize the exact pathomechanism of vascular memory and further clinical trials are also essential to explore its real clinical significance.
Metabolic memory; Metabolic legacy; Vascular memory; Cardiovascular diseases
The risk of cardiovascular complication in a diabetes patient is similar to that in a nondiabetic patient with a history of myocardial infarction. Although intensive control of glycemia achieved by conventional antidiabetic agents decreases microvascular complications such as retinopathy and nephropathy, no marked effect has been reported on macrovascular complications or all-cause mortality. Evidence from VADT, ACCORD, and ADVANCE would suggest that glycemic control has little effect on macrovascular outcomes. Moreover, in the case of ACCORD, intensive glycemic control may be associated with an increased risk of mortality. There is sufficient evidence that suggests that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease in diabetes patients. However, there are no prospective clinical trials supporting the recommendation that lowering postprandial blood glucose leads to lower risk of cardiovascular outcomes. Mitiglinide is a short-acting insulinotropic agent used in type 2 diabetes treatment. It has a rapid stimulatory effect on insulin secretion and reduces postprandial plasma glucose level in patients with type 2 diabetes. Because of its short action time, it is unlikely to exert adverse effects related to hypoglycemia early in the morning and between meals. Mitiglinide reduces excess oxidative stress and inflammation, plays a cardioprotective role, and improves postprandial metabolic disorders. Moreover, mitiglinide add-on therapy with pioglitazone favorably affects the vascular endothelial function in type 2 diabetes patients. These data suggest that mitiglinide plays a potentially beneficial role in the improvement of postprandial hyperglycemia in type 2 diabetes patients and can be used to prevent cardiovascular diseases. Although the results of long-term, randomized, placebo-controlled trials for determining the cardiovascular effects of mitiglinide on clinical outcomes are awaited, this review is aimed at summarizing substantial insights into this topic.
Atherosclerosis; Endothelial function; Cardiovascular disease prevention
Type 2 diabetes (2DM), obesity, and coronary artery disease (CAD) are frequently coexisted being as key components of metabolic syndrome. Whether there is shared genetic background underlying these diseases remained unclear. We performed a meta-analysis of 35 genome screens for 2DM, 36 for obesity or body mass index (BMI)-defined obesity, and 21 for CAD using genome search meta-analysis (GSMA), which combines linkage results to identify regions with only weak evidence and provide genetic interactions among different diseases. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to the best linkage evidence within each bin. For each disease, bin 6.2 achieved genomic significanct evidence, and bin 9.3, 10.5, 16.3 reached suggestive level for 2DM. Bin 11.2 and 16.3, and bin 10.5 and 9.3, reached suggestive evidence for obesity and CAD respectively. In pooled all three diseases, bin 9.3 and 6.5 reached genomic significant and suggestive evidence respectively, being relatively much weaker for 2DM/CAD or 2DM/obesity or CAD/obesity. Further, genomewide significant evidence was observed of bin 16.3 and 4.5 for 2DM/obesity, which is decreased when CAD was added. These findings indicated that bin 9.3 and 6.5 are most likely to be shared by 2DM, obesity and CAD. And bin 16.3 and 4.5 are potentially common regions to 2DM and obesity only. The observed shared susceptibility regions imply a partly overlapping genetic aspects of disease development. Fine scanning of these regions will definitely identify more susceptibility genes and causal variants.
Meta-analysis; Type 2 diabetes; Obesity; Coronary artery disease; Genome-wide association study
In spite of the current optimal therapy, the mortality of patients with ischemic heart disease (IHD) remains high, particularly in cases with diabetes mellitus (DM) as a co-morbidity. Myocardial infarct size is a major determinant of prognosis in IHD patients, and development of a novel strategy to limit infarction is of great clinical importance. Ischemic preconditioning (PC), postconditioning (PostC) and their mimetic agents have been shown to reduce infarct size in experiments using healthy animals. However, a variety of pharmacological agents have failed to demonstrate infarct size limitation in clinical trials. One of the possible reasons for the discrepancy between the results of animal experiments and clinical trials is that co-morbidities, including DM, modified myocardial responses to ischemia/reperfusion and to cardioprotective agents. Here we summarize observations of the effects of DM on myocardial infarct size and ischemic PC and PostC and discuss perspectives for protection of DM hearts.
Diabetes mellitus; Infarct size; Preconditioning; Postconditioning
Long standing diabetes leads to structural and functional alterations in both the micro- and the macro-vasculature. Vascular endothelial cells (ECs) are the primary target of the hyperglycemia-induced adverse effects. Vascular stem cells that give rise to endothelial progenitor cells (EPCs) and mesenchymal progenitor cells (MPCs) represent an attractive target for cell therapy for diabetic patients. A number of studies have reported EPC dysfunction as a novel participant in the culmination of the diabetic complications. The controversy behind the identity of EPCs and the similarity between these progenitor cells to hematopoietic cells has led to conflicting results. MPCs, on the other hand, have not been examined for a potential role in the pathogenesis of the complications. These multipotent cells, however, do show a therapeutic role. In this article, we summarize the vascular changes that occur in diabetic complications highlighting some of the common features, the key findings that illustrate an important role of vascular stem cells (VSCs) in the pathogenesis of chronic diabetic complications, and provide mechanisms by which these cells can be used for therapy.
Diabetes; Diabetic complications; Angiopathy; Endothelial cells; Vasculogenesis; Angiogenesis; Stem cells; Progenitors; Perivascular cells
Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminura and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the only ARB with an indication for the prevention of CV disease progression, is available in two SPC formulations, telmisartan/HCTZ and telmisartan/amlodipine. Clinical studies suggest that in CV high-risk patients and those with evidence of renal disease, the use of an ARB/CCB combination may be preferred to ARB/HCTZ combinations due to superior renoprotective and CV benefits and reduced metabolic side effects in patients with concomitant metabolic disorders. However, selection of the most appropriate antihypertensive combination should be dependent on careful review of the individual patient and appropriate consideration of drug pharmacology.
Amlodipine; Angiotensin receptor II blocker; Diabetes mellitus; Hydrochlorothiazide; Hypertension; Renal impairment; Single-pill combination; Telmisartan
Diabetes mellitus is a potentially morbid condition with high prevalence worldwide thus being a major medical concern. Experimental induction of diabetes mellitus in animal models is essential for the advancement of our knowledge and understanding of the various aspects of its pathogenesis and ultimately finding new therapies and cure. Experimental diabetes mellitus is generally induced in laboratory animals by several methods that include: chemical, surgical and genetic (immunological) manipulations. Most of the experiments in diabetes are carried out in rodents, although some studies are still performed in larger animals. The present review highlights the various methods of inducing diabetes in experimental animals in order to test the newer drugs for their anti-diabetic potential.
Streptozotocin; alloxan; diabetic rats; animal models; diabetes
Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM.
DPP-4 inhibitors; saxagliptin; type 2 diabetes mellitus; cardiovascular safety
The growing prevalence rate of pediatric obesity, which is frequently accompanied by several cardiometabolic risk factors, has become a serious global health issue. To date, little is known regarding differences for cardiometabolic risk factors (prevalence and means) in children from different countries. In the present review, we aimed to provide a review for the available evidence regarding cardiometabolic risk factors in overweight pediatric populations. We therefore provided information with respect to the prevalence of impaired fasting glucose/impaired glucose tolerance, high triglycerides, low HDL-cholesterol and hypertension (components of the metabolic syndrome) among cohorts from different countries. Moreover, we aimed to compare the means of glucose and lipid levels (triglycerides and HDL-cholesterol) and systolic/diastolic blood pressure values. After careful selection of articles describing cohorts with comparable age and sex, it was shown that both prevalence rates and mean values of cardiometabolic risk factors varied largely among cohorts of overweight children. After ranking for high/low means for each cardiometabolic risk parameter, Dutch-Turkish children and children from Turkey, Hungary, Greece, Germany and Poland were in the tertile with the most unfavorable risk factor profile overall. In contrast, cohorts from Norway, Japan, Belgium, France and the Dominican Republic were in the tertile with most favorable risk profile. These results should be taken with caution, given the heterogeneity of the relatively small, mostly clinical cohorts and the lack of information concerning the influence of the values of risk parameters on true cardiometabolic outcome measures in comparable cohorts. The results of our review present a fair estimation of the true differences between cardiometabolic risk profiles among pediatric cohorts worldwide, based on available literature.
Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk.
Aspirin has been recommended for the prevention of major adverse cardiovascular events (MACE, composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in diabetic patients without previous cardiovascular disease. However, recent meta-analyses have prompted re-evaluation of this practice. The study objective was to evaluate the relative and absolute benefits and harms of aspirin for the prevention of incident MACE in patients with diabetes.
We performed a systematic review and meta-analysis on seven studies (N = 11,618) reporting on the use of aspirin for the primary prevention of MACE in patients with diabetes. Two reviewers conducted a systematic search of electronic databases (MEDLINE, EMBASE, the Cochrane Library, and BIOSIS) and hand searched bibliographies and clinical trial registries. Reviewers extracted data in duplicate, evaluated the quality of the trials, and calculated pooled estimates.
A total of 11,618 participants were included in the analysis. The overall risk ratio (RR) for MACE was 0.91 (95% confidence intervals, CI, 0.82-1.00) with little heterogeneity among trials (I2 0.0%). Secondary outcomes of interest included myocardial infarction (RR, 0.85; 95% CI, 0.66-1.10), stroke (RR, 0.84; 95% CI, 0.64-1.11), cardiovascular death (RR, 0.95; 95% CI, 0.71-1.27), and all-cause mortality (RR, 0.95; 95% CI, 0.85-1.06). There were higher rates of hemorrhagic and gastrointestinal events. In absolute terms, these relative risks indicate that for every 10,000 diabetic patients treated with aspirin, 109 MACE may be prevented at the expense of 19 major bleeding events (with the caveat that the relative risk for the latter is not statistically significant).
The studies reviewed suggest that aspirin reduces the risk of MACE in patients with diabetes without cardiovascular disease, while also causing a trend toward higher rates of bleeding and gastrointestinal complications. These findings and our absolute benefit and risk calculations suggest that those with diabetes but without cardiovascular disease lie somewhere between primary and secondary prevention patients on the spectrum of benefit and risk. This underscores the importance of considering individual risk in clinical decision making regarding aspirin in those with diabetes.
Obesity is associated with metabolic derangements such as insulin resistance, inflammation and hypercoagulobility which can all be understood as consequences of adipose tissue dysfunction. The potential role for adipose tissue derived cytokines and adipokines in the development of vascular disease and diabetes may produce a clinical need to influence adipose tissue function. Various pharmacological and non-pharmacological interventions affect plasma cytokine and adipokine levels. The effects of these interventions depend on weight loss per se, changes in fat distribution without weight loss and/or direct effects on adipose tissue inflammation.
Weight loss, as a result of diet, pharmacology and surgery, positively influences plasma adipokines and systemic inflammation. Several classes of drugs influence systemic inflammation directly through their anti-inflammatory actions. PPAR-γ agonism positively influences adipose tissue inflammation in several classes of intervention such as the thiazolidinediones and perhaps salicylates, CB1-antagonists and angiotensin II receptor blockers. Furthermore, within drug classes there are differential effects of individual pharmacologic agents on adipose tissue function.
It can be concluded that several commonly used pharmacological and non-pharmacological interventions have unintended influences on adipose tissue function. Improving adipose tissue function may contribute to reducing the risk of vascular diseases and the development of type 2 diabetes.
Diabetes mellitus has emerged as one of the main alarms to human health in the 21st century. Pronounced changes in the human environment, behavior and lifestyle have accompanied globalization, which resulted in escalating rates of both obesity and diabetes, already described as diabesity. This pandemic causes deterioration of life quality with high socio-economic costs, particularly due to premature morbidity and mortality. To avoid late complications of type 2 diabetes and related costs, primary prevention and early treatment are therefore necessary. In this context, effective non-pharmacological measures, such as regular physical activity, are imperative to avoid complications, as well as polymedication, which is associated with serious side-effects and drug-to-drug interactions.
Our previous work showed, in an animal model of obese type 2 diabetes, the Zucker Diabetic Fatty (ZDF) rat, that regular and moderate intensity physical exercise (training) is able, per se, to attenuate insulin resistance and control glycaemia, dyslipidaemia and blood pressure, thus reducing cardiovascular risk, by interfering with the pathophysiological mechanisms at different levels, including oxidative stress and low-grade inflammation, which are key features of diabesity.
This paper briefly reviews the wide pathophysiological pathways associated with Type 2 diabetes and then discusses in detail the benefits of training therapy on glycaemic control and on cardiovascular risk profile in Type 2 diabetes, focusing particularly on antioxidant and anti-inflammatory properties. Based on the current knowledge, including our own findings using an animal model, it is concluded that regular and moderate intensity physical exercise (training), due to its pleiotropic effects, could replace, or at least reduce, the use of anti-diabetic drugs, as well as of other drugs given for the control of cardiovascular risk factors in obese type 2 diabetic patients, working as a physiological "polypill".