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1.
Clinical Considerations When Initiating and Titrating Insulin Degludec/Liraglutide (IDegLira) in People with Type 2 Diabetes.
Harris, S, Abrahamson, MJ, Ceriello, A, Charpentier, G, Evans, M, Lehmann, R, Liebl, A, Linjawi, S, Holt, RIG, Hosszúfalusi, N, et al
Drugs. 2020;(2):147-165
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Abstract
Therapeutic inertia is a substantial obstacle to the initiation of insulin therapy in people with uncontrolled type 2 diabetes (T2D). This effect has in part been perpetuated by concerns over the impact of a burdensome regimen and the increased risk of hypoglycemia and body weight gain often associated with insulin use. An effective, yet simple, less burdensome regimen with a lower risk of body weight gain and hypoglycemia compared with an insulin-only regimen, may help to address these concerns more effectively. We review the available clinical and real-world data on IDegLira, a once-daily, injectable, fixed-ratio combination of insulin degludec (degludec) and the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide, in people with T2D. Evidence from the comprehensive DUAL clinical trial program suggests an advantage of IDegLira over traditional insulin therapies in a number of clinical outcomes, including maintenance of glycemic control, achievement of glycemic targets, reducing the risk of hypoglycemia, and body weight loss. These findings were demonstrated in participants with T2D irrespective of prior GLP-1RA and insulin use. Furthermore, the individual components of IDegLira have confirmed safety (degludec) or significant benefit in terms of improvement of cardiovascular risk (liraglutide). As an injectable therapy that is simple to titrate, IDegLira has the potential to optimize the ability to achieve relevant glycemic targets, and offers a suitable treatment option for people with T2D requiring insulin therapy who are at risk of hypoglycemia or weight gain.
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2.
Natural history and risk factors for diabetic kidney disease in patients with T2D: lessons from the AMD-annals.
Viazzi, F, Russo, GT, Ceriello, A, Fioretto, P, Giorda, C, De Cosmo, S, Pontremoli, R
Journal of nephrology. 2019;(4):517-525
Abstract
The Associazione Medici Diabetologi (AMD) annals initiative is an ongoing observational survey promoted by AMD. It is based on a public network of about 700 Italian diabetes clinics, run by specialists who provide diagnostic confirmation and prevention and treatment of diabetes and its complications. Over the last few years, analysis of the AMD annals dataset has contributed several important insights on the clinical features of type-2 diabetes kidney disease and their prognostic and therapeutic implications. First, non-albuminuric renal impairment is the predominant clinical phenotype. Even though associated to a lower risk of progression compared to overt albuminuria, it contributes significantly to the burden of end-stage renal disease morbidity. Second, optimal blood pressure control provides significant but incomplete renal protection. It reduces albuminuria but there may be a J curve phenomenon with eGFR at very low blood pressure values. Third, hyperuricemia and diabetic hyperlipidemia, namely elevated triglycerides and low HDL cholesterol, are strong independent predictors of chronic kidney disease (CKD) onset in diabetes, although the pathogenetic mechanisms underlying these associations remain uncertain. Fourth, the long-term intra-individual variability in HbA1c, lipid parameters, uric acid and blood pressure plays a greater role in the appearance and progression of CKD than the absolute value of each single variable. These data help clarify the natural history of CKD in patients with type 2 diabetes and provide important clues for designing future interventional studies.
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3.
The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin: Implications for Clinical Practice.
Ceriello, A, De Nigris, V, Iijima, H, Matsui, T, Gouda, M
Drugs. 2019;(7):733-750
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Abstract
Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan and Korea and is being researched in several countries. Teneligliptin is a potent, selective, and long-lasting DPP-4 inhibitor with a t½ of approximately 24 h and unique pharmacokinetic properties: it is metabolized by cytochrome P450 (CYP) 3A4 and flavin-containing monooxygenase 3 (FMO3), or excreted from the kidney in an unchanged form. Because of its multiple elimination pathways, dose adjustment is not needed in patients with hepatic or renal impairment, and it is considered to have a low potential for drug-drug interactions. Clinical studies and postmarketing surveillance show that teneligliptin, administered as monotherapy and/or in combination with antihyperglycemic agents, is effective and well tolerated in T2DM patients, including in elderly patients and those with renal impairment. Furthermore, teneligliptin has antioxidative properties, which induce the antioxidant cascade, as well as ·OH scavenging properties. In addition, it has shown endothelial protective effects in several non-clinical and clinical studies. From its unique profile and clinical data, teneligliptin represents a potential therapeutic option in a wide variety of patients, including elderly diabetic patients and those with renal impairment. The fixed-dose combination (FDC) tablet of teneligliptin and canagliflozin has been approved in Japan; this is the first FDC tablet of a DPP-4 inhibitor and sodium glucose co-transporter 2 inhibitor in Japan, and the third globally. The FDC tablet may also provide additional prescribing and adherence benefits.
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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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5.
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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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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A unique plasma microRNA profile defines type 2 diabetes progression.
de Candia, P, Spinetti, G, Specchia, C, Sangalli, E, La Sala, L, Uccellatore, A, Lupini, S, Genovese, S, Matarese, G, Ceriello, A
PloS one. 2017;(12):e0188980
Abstract
A major unmet medical need to better manage Type 2 Diabetes (T2D) is the accurate disease prediction in subjects who show glucose dysmetabolism, but are not yet diagnosed as diabetic. We investigated the possibility to predict/monitor the progression to T2D in these subjects by retrospectively quantifying blood circulating microRNAs in plasma of subjects with i) normal glucose tolerance (NGT, n = 9); ii) impaired glucose tolerance (IGT, n = 9), divided into non-progressors (NP, n = 5) and progressors (P, n = 4) based on subsequent diabetes occurrence, and iii) newly diagnosed T2D (n = 9). We found that impaired glucose tolerance associated with a global increase of plasma circulating microRNAs. While miR-148 and miR-222 were specifically modulated in diabetic subjects and correlated with parameters of glucose tolerance, the most accentuated microRNA dysregulation was found in NP IGT subjects, with increased level of miR-122, miR-99 and decreased level of let-7d, miR-18a, miR-18b, miR-23a, miR-27a, miR-28 and miR-30d in comparison with either NGT or T2D. Interestingly, several of these microRNAs significantly correlated with parameters of cholesterol metabolism. In conclusion, we observed the major perturbation of plasma circulating microRNA in NP pre-diabetic subjects and identified a unique microRNA profile that may become helpful in predicting diabetic development.
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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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Clinical use of the co-formulation of insulin degludec and insulin aspart.
Kumar, A, Awata, T, Bain, SC, Ceriello, A, Fulcher, GR, Unnikrishnan, AG, Arechavaleta, R, Gonzalez-Gálvez, G, Hirose, T, Home, PD, et al
International journal of clinical practice. 2016;(8):657-67
Abstract
AIMS: To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. METHODS Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. RESULTS In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. CONCLUSIONS IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.
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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.