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Diabetes as a cardiovascular risk factor: An overview of global trends of macro and micro vascular complications.
Dal Canto, E, Ceriello, A, Rydén, L, Ferrini, M, Hansen, TB, Schnell, O, Standl, E, Beulens, JW
European journal of preventive cardiology. 2019;(2_suppl):25-32
Abstract
The global prevalence of diabetes is predicted to increase dramatically in the coming decades as the population grows and ages, in parallel with the rising burden of overweight and obesity, in both developed and developing countries. Cardiovascular disease represents the principal cause of death and morbidity among people with diabetes, especially in those with type 2 diabetes mellitus. Adults with diabetes have 2-4 times increased cardiovascular risk compared with adults without diabetes, and the risk rises with worsening glycaemic control. Diabetes has been associated with 75% increase in mortality rate in adults, and cardiovascular disease accounts for a large part of the excess mortality. Diabetes-related macrovascular and microvascular complications, including coronary heart disease, cerebrovascular disease, heart failure, peripheral vascular disease, chronic renal disease, diabetic retinopathy and cardiovascular autonomic neuropathy are responsible for the impaired quality of life, disability and premature death associated with diabetes. Given the substantial clinical impact of diabetes as a cardiovascular risk factor, there has been a growing focus on diabetes-related complications. While some population-based studies suggest that the epidemiology of such complications is changing and that rates of all-cause and cardiovascular mortality among individuals with diabetes are decreasing in high-income countries, the economic and social burden of diabetes is expected to rise due to changing demographics and lifestyle especially in middle- and low-income countries. In this review we outline data from population-based studies on recent and long-term trends in diabetes-related complications.
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Targets for blood glucose: What have the trials told us.
Valensi, P, Prévost, G, Schnell, O, Standl, E, Ceriello, A
European journal of preventive cardiology. 2019;(2_suppl):64-72
Abstract
The challenges of diabetes treatment are to prevent or delay microangiopathic complications and macrovascular disease. Early, effective and sustained glycaemic control is advocated by all diabetes guidelines to mitigate the risks of prolonged hyperglycaemia. The post-hoc analyses of the large randomised glucose intervention trials and the long-term results of these trials have shown clearly that intensive glycaemic control may have more favourable cardiovascular effects when initiated earlier in the course of diabetes, particularly among in patients without cardiovascular disease. Based on the intervention trials a haemoglobin A1c level of less than 7.0% (<53 mmol/mol) is a generally accepted target to reduce microvascular disease and should be initiated early in the course of the diabetes. However, haemoglobin A1c targets should be individualised. Achieving a good glycaemic control without detrimental effect and preferably with benefit to the cardiovascular system and to renal function is an important challenge. When targeting a tight glycaemic control, avoidance of hypoglycaemia is crucial particularly in patients with coronary artery disease and in patients with heart failure. The cardiovascular outcomes trials performed to test the cardiovascular safety of the new glucose-lowering therapies offer compelling evidence in favour of the role of these drugs for cardiovascular prevention. Thus, both the glycaemic target and the choice of therapies should now be defined on an individual basis.
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Glucose-lowering therapies in patients with type 2 diabetes and cardiovascular diseases.
Prattichizzo, F, La Sala, L, Rydén, L, Marx, N, Ferrini, M, Valensi, P, Ceriello, A
European journal of preventive cardiology. 2019;(2_suppl):73-80
Abstract
Type 2 diabetes mellitus is a major risk factor for developing cardiovascular disease, and many patients with diabetes have prevalent cardiovascular complications. Recent cardiovascular outcome clinical trials suggest that certain new glucose-lowering drugs are accompanied by additional cardioprotective properties. Indeed, selected glucagon-like peptide-1 receptor agonists have a proved cardiovascular benefit in terms of a reduced incidence of ischaemic events, while sodium/glucose co-transporter-2 inhibitors have also shown significant protection, with a striking effect on heart failure and renal endpoints. These findings have been integrated in recent guidelines which now recommend prescribing (when initial metformin monotherapy fails) a glucagon-like peptide-1 receptor agonist or a sodium/glucose co-transporter-2 inhibitor with clinical trial-confirmed benefit in patients with diabetes and atherosclerotic cardiovascular disease, and a sodium/glucose co-transporter-2 inhibitor in such patients with heart failure or chronic kidney disease at initial stages. Furthermore, the new 2019 European Society of Cardiology guidelines in collaboration with the European Association for the Study of Diabetes recommend a glucagon-like peptide-1 receptor agonist or a sodium/glucose co-transporter-2 inhibitor in treatment-naive patients with type 2 diabetes mellitus with pre-existing cardiovascular disease or at high cardiovascular risk. Future research will disentangle the mechanisms underpinning these beneficial effects and will also establish to what extent these results are generalisable to the whole diabetes population. In the meantime, available evidence should prompt a wide diffusion of these two classes of drugs among patients with diabetes and cardiovascular disease. Here, we briefly summarise recent findings emerging from cardiovascular outcome clinical trials, discuss their impact on treatment algorithms and propose new possible approaches to improve our knowledge further regarding the cardiovascular effect of glucose-lowering medications.
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Atherogenicity of postprandial hyperglycemia and lipotoxicity.
Ceriello, A, Genovese, S
Reviews in endocrine & metabolic disorders. 2016;(1):111-6
Abstract
Type 2 diabetes is characterized by a gradual decline in insulin secretion in response to nutrient loads; hence, it is primarily a disorder of postprandial glucose regulation. However, physicians continue to rely on fasting plasma glucose and glycated hemoglobin to guide management. There is a linear relationship between the risk of cardiovascular death and the 2-h oral glucose tolerance test, while a study confirms postprandial hyperglycemia as independent risk factor for cardiovascular disease in type 2 diabetes. At the same time, several studies show that postprandial hypertriglyceridemia may also be a cardiovascular risk factor. Interestingly, the simultaneous presence of postprandial hyperglycemia and postprandial hypertriglyceridemia has an additive effect in worsening endothelial function and inflammation. Evidence supports the hypothesis glucose postprandial hyperglycemia and hypertriglyceridemia may favor the appearance of the cardiovascular disease through the generation of an oxidative stress. Furthermore, clinical data suggest that postprandial hyperglycemia is a common phenomenon even in patients who may be considered in "good metabolic control". Therefore, physicians should consider monitoring and targeting postprandial plasma glucose, as well as glycated hemoglobin and fasting plasma glucose, in patients with type 2 diabetes.
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The protective effect of the Mediterranean diet on endothelial resistance to GLP-1 in type 2 diabetes: a preliminary report.
Ceriello, A, Esposito, K, La Sala, L, Pujadas, G, De Nigris, V, Testa, R, Bucciarelli, L, Rondinelli, M, Genovese, S
Cardiovascular diabetology. 2014;:140
Abstract
BACKGROUND In type 2 diabetes, acute hyperglycemia worsens endothelial function and inflammation,while resistance to GLP-1 action occurs. All these phenomena seem to be related to the generation of oxidative stress. A Mediterranean diet, supplemented with olive oil, increases plasma antioxidant capacity, suggesting that its implementation can have a favorable effect on the aforementioned phenomena. In the present study, we test the hypothesis that a Mediterranean diet using olive oil can counteract the effects of acute hyperglycemia and can improve the resistance of the endothelium to GLP-1 action. METHODS Two groups of type 2 diabetic patients, each consisting of twelve subjects, participated in a randomized trial for three months, following a Mediterranean diet using olive oil or a control low-fat diet. Plasma antioxidant capacity, endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels were evaluated at baseline and at the end of the study. The effect of GLP-1 during a hyperglycemic clamp, was also studied at baseline and at the end of the study. RESULTS Compared to the control diet, the Mediterranean diet increased plasma antioxidant capacity and improved basal endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels. The Mediterranean diet also reduced the negative effects of acute hyperglycemia, induced by a hyperglycemic clamp, on endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels. Furthermore, the Mediterranean diet improved the protective action of GLP-1 on endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels, also increasing GLP-1-induced insulin secretion. CONCLUSIONS These data suggest that the Mediterranean diet, using olive oil, prevents the acute hyperglycemia effect on endothelial function, inflammation and oxidative stress, and improves the action of GLP-1, which may have a favorable effect on the management of type 2 diabetes, particularly for the prevention of cardiovascular disease.
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Post hoc subgroup analysis of the HEART2D trial demonstrates lower cardiovascular risk in older patients targeting postprandial versus fasting/premeal glycemia.
Raz, I, Ceriello, A, Wilson, PW, Battioui, C, Su, EW, Kerr, L, Jones, CA, Milicevic, Z, Jacober, SJ
Diabetes care. 2011;(7):1511-3
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Abstract
OBJECTIVE To identify the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) trial subgroups with treatment difference. RESEARCH DESIGN AND METHODS In 1,115 type 2 diabetic patients who had suffered from an acute myocardial infarction (AMI), the HEART2D trial compared two insulin strategies targeting postprandial or fasting/premeal glycemia on time until first cardiovascular event (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome). The HEART2D trial ended prematurely for futility. We used the classification and regression tree (CART) to identify baseline subgroups with potential treatment differences. RESULTS CART estimated the age of >65.7 years to best predict the difference in time to first event. In the subgroup aged>65.7 years (prandial, n=189; basal, n=210), prandial patients had a significantly longer time to first event and a lower proportion experienced a first event (n=56 [29.6%] vs. n=85 [40.5%]; hazard ratio 0.69 [95% CI 0.49-0.96]; P=0.029), despite similar A1C levels. CONCLUSIONS Older type 2 diabetic AMI survivors may have a lower risk for a subsequent cardiovascular event with insulin targeting postprandial versus fasting/premeal glycemia.
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Premeal insulin lispro plus bedtime NPH or twice-daily NPH in patients with type 2 diabetes: acute postprandial and chronic effects on glycemic control and cardiovascular risk factors.
Ceriello, A, Del Prato, S, Bue-Valleskey, J, Beattie, S, Gates, J, de la Peña, A, Malone, J
Journal of diabetes and its complications. 2007;(1):20-7
Abstract
OBJECTIVE Two insulin regimens were used to explore acute and chronic postprandial changes in glycemia, lipemia, and metabolic markers associated with increased risk of cardiovascular disease. METHODS An open-label, randomized, two-period crossover study (12 weeks/period) compared a prandial regimen [premeal insulin lispro+bedtime neutral protamine Hagedorn (NPH)] with a basal regimen (twice-daily NPH). There were 30 patients (12 women and 18 men; mean age=61 years) with type 2 diabetes mellitus (mean duration=16 years) who were randomized after a 2-month lead-in with twice-daily NPH treatment. A standard lunch test meal developed according to each patient's caloric needs was administered at the end of each treatment period. RESULTS Insulin lispro was associated with significantly lower postprandial glucose (area under the curve0-5 h=43.54 vs. 57.65 mM/h; P<.001), elevated insulin concentrations, and acutely altered lipid fractions that included an early decrease followed by an increase in free fatty acids, lower triglycerides, elevated total cholesterol, elevated low-density lipoprotein cholesterol (LDL), and elevated high-density lipoprotein cholesterol. After 12 weeks of treatment, insulin lispro+bedtime NPH reduced hemoglobin A1c (HbA1c; mean+/-SE=7.6+/-0.2 vs. 8.2+/-0.2%; P<.001) without increasing hypoglycemia or insulin dose as compared with twice-daily NPH. Furthermore, treatment with the prandial insulin regimen resulted in lower total cholesterol, lower LDL cholesterol, and lower oxidized LDL. CONCLUSION Improved postprandial glycemic control, as observed in a regimen containing both prandial insulin lispro and NPH as the basal insulin, is associated with significantly lower HbA1c and acute modulation of lipid fractions after a test meal. These biochemical modifications may potentially have a favorable impact on cardiovascular risk in patients with type 2 diabetes mellitus.