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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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Dietary Glycemic Index and Load and the Risk of Type 2 Diabetes: A Systematic Review and Updated Meta-Analyses of Prospective Cohort Studies.
Livesey, G, Taylor, R, Livesey, HF, Buyken, AE, Jenkins, DJA, Augustin, LSA, Sievenpiper, JL, Barclay, AW, Liu, S, Wolever, TMS, et al
Nutrients. 2019;(6)
Abstract
Published meta-analyses indicate significant but inconsistent incident type-2 diabetes(T2D)-dietary glycemic index (GI) and glycemic load (GL) risk ratios or risk relations (RR). It is nowover a decade ago that a published meta-analysis used a predefined standard to identify validstudies. Considering valid studies only, and using random effects dose-response meta-analysis(DRM) while withdrawing spurious results (p < 0.05), we ascertained whether these relationswould support nutrition guidance, specifically for an RR > 1.20 with a lower 95% confidence limit>1.10 across typical intakes (approximately 10th to 90th percentiles of population intakes). Thecombined T2D-GI RR was 1.27 (1.15-1.40) (p < 0.001, n = 10 studies) per 10 units GI, while that forthe T2D-GL RR was 1.26 (1.15-1.37) (p < 0.001, n = 15) per 80 g/d GL in a 2000 kcal (8400 kJ) diet.The corresponding global DRM using restricted cubic splines were 1.87 (1.56-2.25) (p < 0.001, n =10) and 1.89 (1.66-2.16) (p < 0.001, n = 15) from 47.6 to 76.1 units GI and 73 to 257 g/d GL in a 2000kcal diet, respectively. In conclusion, among adults initially in good health, diets higher in GI or GLwere robustly associated with incident T2D. Together with mechanistic and other data, thissupports that consideration should be given to these dietary risk factors in nutrition advice.Concerning the public health relevance at the global level, our evidence indicates that GI and GLare substantial food markers predicting the development of T2D worldwide, for persons ofEuropean ancestry and of East Asian ancestry.
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Achievement of guideline targets for blood pressure, lipid, and glycaemic control in type 2 diabetes: A meta-analysis.
Khunti, K, Ceriello, A, Cos, X, De Block, C
Diabetes research and clinical practice. 2018;:137-148
Abstract
We assessed global achievement of targets recommended by the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), and National Institute of Health and Care Excellence (NICE) for type 2 diabetes. We searched Medline, Embase, and The Cochrane Library for observational studies reporting target attainment (2006 to 2017 inclusive) for HbA1c, blood pressure, or lipids (low density lipoprotein cholesterol [LDL-C], high density lipoprotein cholesterol [HDL-C], or triglycerides). Rates were pooled using a random-effects meta-analysis. Study quality and risk of small study of bias was assessed. From 2491 screened records, 24 studies were included reporting on 369,251 people from 20 countries. The pooled target achievement rates were; 42.8% (95% CI 38.1-47.5%) for glycaemic control, 29.0% (22.9-35.9%) for blood pressure, 49.2% (39.0-59.4%) for LDL-C, 58.2% (51.7-64.4%) for HDL-C, and 61.9% (55.2-68.2%) for triglyceride control. A higher proportion of people achieved HbA1c targets within Europe and North America than the rest of the world. A higher proportion of people achieved blood pressure targets in North America than Europe or the rest of the world. Meta regression showed no significant improvement in rates by year for any target. The achievement of evidence-based targets is markedly suboptimal globally and not improving.
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Improved Glucose Profile in Patients With Type 2 Diabetes With a New, High-Protein, Diabetes-Specific Tube Feed During 4 Hours of Continuous Feeding.
Lansink, M, Hofman, Z, Genovese, S, Rouws, CHFC, Ceriello, A
JPEN. Journal of parenteral and enteral nutrition. 2017;(6):968-975
Abstract
BACKGROUND Hyperglycemia frequently occurs in hospitalized patients receiving nutrition support. In this study, the effects of a new diabetes-specific formula (DSF) on glucose profile during 4 hours of continuous feeding and 4 hours after stopping feeding were compared with a standard formula (SF). MATERIALS AND METHODS In this randomized, controlled, double-blind, crossover study, ambulant, nonhospitalized patients with type 2 diabetes received the DSF or an isocaloric, fiber-containing SF via a nasogastric tube. After overnight fasting, the formula was continuously administered to the patients during 4 hours. Plasma glucose and insulin concentrations were determined during the 4-hour period and in the subsequent 4 hours during which no formula was provided. RESULTS During the 4-hour feeding period, DSF compared with SF resulted in a lower mean delta glucose concentration in the 3- to 4-hour period (0.3 ± 1.0 and 2.4 ± 1.5 mmol/L; P < .001). Also, the (delta) peak concentrations, (delta) mean concentrations, and incremental area under the curve (iAUC) for glucose and insulin were significantly lower during DSF compared with SF feeding (all comparisons: P < .001). Furthermore, fewer patients experienced hyperglycemia (>10 mmol/L) on DSF compared with SF (2 vs 11, P = .003, respectively). No differences in number of patients with hypoglycemia (<3.9 mmol/L) were observed. No significant differences in tolerance were observed. CONCLUSION Administration of a new, high-protein DSF during 4 hours of continuous feeding resulted in lower glucose and insulin levels compared with a fiber-containing SF in ambulant, nonhospitalized patients with type 2 diabetes. These data suggest that a DSF may contribute to lower glucose levels in these patients.
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Lispro insulin in people with non-alcoholic liver cirrhosis and type 2 diabetes mellitus.
Gentile, S, Guarino, G, Strollo, F, Romano, M, Genovese, S, Masarone, M, Ceriello, A
Diabetes research and clinical practice. 2016;:179-86
Abstract
AIMS: To compare metabolic control under lispro and recombinant regular human insulin (RHI) in people with diet-unresponsive type 2 diabetes mellitus (T2DM) and compensated non-alcoholic liver disease (CLD).
METHODS 108 people with T2DM and CLD were randomly allocated to RHI or lispro according to a 12+12 week cross-over protocol. A 1-week continuous glucose monitoring (CGM) session was performed at the end of each treatment period followed by a standard meal test with a 12IU lispro or RHI shot ahead.
RESULTS CGM showed higher glycemic excursions under RHI than under lispro (p<0.01) with lower glucose levels in the late post-absorption phase (p<0.05) and even more during the night (p<0.01). Post-challenge incremental areas under the curve (ΔAUC) were undistinguishable for insulin but lower for glucose, while insulin peaked higher and earlier and glycemic excursions were lower with lispro than with RHI (0.05
CONCLUSIONS Lispro granted lower early postprandial glucose levels and late postprandial hypoglycemic rates and therefore might represent the treatment of choice for people with T2DM and compensated CLD. This might depend on its faster/shorter-living effects, as well as, on the lower liver glucose output expected from its earlier hepatic distribution.
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Achievement of therapeutic targets in patients with diabetes and chronic kidney disease: insights from the Associazione Medici Diabetologi Annals initiative.
De Cosmo, S, Viazzi, F, Pacilli, A, Giorda, C, Ceriello, A, Gentile, S, Russo, G, Rossi, MC, Nicolucci, A, Guida, P, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2015;(9):1526-33
Abstract
BACKGROUND Chronic kidney disease (CKD) entails a worse cardiovascular outcome. The aim of our work was to study the relationship between CKD and the achievement of recommended targets for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) in a real-life sample of patients with type 2 diabetes mellitus (T2DM). METHODS We analysed a sample of 116 777 outpatients from the Network of the Italian Association of Clinical Diabetologists; all patients had T2DM and at least one measurement of HbA1c, LDL-c, BP, serum creatinine and albuminuria in the year 2010. The outcome was the achievement of HbA1c, LDL-c and BP values as recommended by International Guidelines. RESULTS In the entire sample, the mean value of HbA1c was 7.2 ± 1.2%, of LDL-c was 102 ± 33 mg/dL and of BP was 138/78 ± 19/9 mmHg. CKD and its components were associated with poor glycaemic and BP control, notwithstanding greater use of glucose and BP-lowering drugs, while no association was found with LDL-c values. Factors independently related to unsatisfactory glycaemic control included female gender, body mass index, duration of disease and high albuminuria. Men, older people and those taking statins were more likely to reach LDL-c target levels. Male gender, age and high albuminuria strongly affected the achievement of BP targets. CONCLUSIONS CKD or its components, mainly high albuminuria, are associated with failure to reach therapeutic targets, especially for HbA1c and BP, despite a greater use of drugs in patients with T2DM.
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Prospective, randomized trial on intensive SMBG management added value in non-insulin-treated T2DM patients (PRISMA): a study to determine the effect of a structured SMBG intervention.
Scavini, M, Bosi, E, Ceriello, A, Giorgino, F, Porta, M, Tiengo, A, Vespasiani, G, Bottalico, D, Marino, R, Parkin, C, et al
Acta diabetologica. 2013;(5):663-72
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Abstract
Self-monitoring of blood glucose (SMBG) is a core component of diabetes management. However, the International Diabetes Federation recommends that SMBG be performed in a structured manner and that the data are accurately interpreted and used to take appropriate therapeutic actions. We designed a study to evaluate the impact of structured SMBG on glycemic control in non-insulin-treated type 2 diabetes (T2DM) patients. The Prospective, Randomized Trial on Intensive SMBG Management Added Value in Non-insulin-Treated T2DM Patients (PRISMA) is a 12-month, prospective, multicenter, open, parallel group, randomized, and controlled trial to evaluate the added value of an intensive, structured SMBG regimen in T2DM patients treated with oral agents and/or diet. One thousand patients (500 per arm) will be enrolled at 39 clinical sites in Italy. Eligible patients will be randomized to the intensive structured monitoring (ISM) group or the active control (AC) group, with a glycosylated hemoglobin (HbA1c) target of <7.0%. Intervention will comprise (1) structured SMBG (4-point daily glucose profiles on 3 days per week [ISM]; discretionary, unstructured SMBG [AC]); (2) comprehensive patient education (both groups); and (3) clinician's adjustment of diabetes medications using an algorithm targeting SMBG levels, HbA1c and hypoglycemia (ISM) or HbA1c and hypoglycemia (AC). The intervention and trial design build upon previous research by emphasizing appropriate and collaborative use of SMBG by both patients and physicians. Utilization of per protocol and intent-to-treat analyses facilitates assessment of the intervention. Inclusion of multiple dependent variables allows us to assess the broader impact of the intervention, including changes in patient and physician attitudes and behaviors.
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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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The glucose triad and its role in comprehensive glycaemic control: current status, future management.
Ceriello, A
International journal of clinical practice. 2010;(12):1705-11
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Abstract
The prevalence of type 2 diabetes across the world has been described as a global pandemic. Despite significant efforts to limit both the increase in the number of cases and the long-term impact on morbidity and mortality, the total number of people with diabetes is projected to continue to rise and most patients still fail to achieve adequate glycaemic control. Optimal management of type 2 diabetes requires an understanding of the relationships between glycosylated haemoglobin (HbA(1c)), fasting plasma glucose and postprandial glucose (the glucose triad), and how these change during development and progression of the disease. Early and sustained control of glycaemia remains important in the management of type 2 diabetes. The contribution of postprandial glucose levels to overall glycaemic control and the role of postprandial glucose targets in disease management are currently debated. However, many patients do not reach HbA(1C) targets set according to published guidelines. As recent data suggest, if driving HbA(1C) down to lower target levels is not the answer, what other factors involved in glucose homeostasis can or should be targeted? Has the time come to change the treatment paradigm to include awareness of the components of the glucose triad, the existence of glucose variability and their potential influence on the choice of pharmacological treatment? It is becomingly increasingly clear that physicians are likely to have to consider plasma glucose levels both after the overnight fast and after meals as well as the variability of glucose levels, in order to achieve optimal glycaemic control for each patient. When antidiabetic therapy is initiated, physicians may need to consider selection of agents that target both fasting and postprandial hyperglycaemia.
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Lowering glucose to prevent adverse cardiovascular outcomes in a critical care setting.
Ceriello, A, Zarich, SW, Testa, R
Journal of the American College of Cardiology. 2009;(5 Suppl):S9-13
Abstract
High admission blood glucose levels after acute myocardial infarction are common and associated with an increased risk of death in patients with or without diabetes. Hyperglycemia is associated with altered myocardial blood flow and energetics and can lead to a pro-oxidative/proinflammatory state. The use of intensive insulin treatment has shown superior benefits in the treatment of hyperglycemia versus glucose-insulin-potassium infusion, particularly in critical care settings.