As far as concern research activities, the Unit performs both spontaneous and sponsored clinical trials, in collaboration with the Trial Office and the main five clinical areas of the Institute. The Unit has also activated collaborations with the Research Units of CCM to carry on studies managed by nurses and psychologists on the psycho-social aspects of diabetes.
An important collaboration has been started with the Department of Cardiovascular, Dysmetabolic and Aging Diseases of the Istituto Superiore di Sanità (ISS) focused on the study of diabetes, cardiovascular diseases and related risk factors. ISS and CCM will share the data collected by the Institutes on these topics, in particular the data from the CUORE Project, and carry out detailed statistical analyses for:
- evaluation of lifestyles aspects in diabetic patients, and association with other clinical and socio-economic risk conditions;
- assessment of the role of fasting glucose for the prediction of cardiovascular risk in the general population;
- implementation of nested case-control studies, using biological data and samples available from both parties for project proposals in public health setting;
- realization of common projects for the implementation of strategies to prevent diabetes and its complications, and more generally chronic diseases at the population level;
- activation of initiative services of primary prevention aiming to slow, and/or avoid, and/or postpone the disease in people with dysglycemia and pre-hypertension, improving lifestyles and in particular physical activity;
- dissemination of information on dysglycemia and diabetes and on the promotion of prevention through healthy lifestyles, indicated in the mission of the Department of Cardiovascular, Dysmetabolic and Aging Diseases of ISS.
Effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on left ventricular myocardial dysfunction in patients with type 2 diabetes mellitus and concentric left ventricular geometry (DYDA2-trial)
The glucagon-like peptide-1 receptors (glucagon-like peptide-1, GLP-1) have been identified in the myocardium and in the endothelium and the hypothesis that they carry out anti-apoptotic protective effects has been advanced. Experimental data suggest that GLP-1, besides exercising the classic glucoregulatory actions, has direct effects on the cardiovascular system. These direct effects have characteristics of cardioprotection and vasodilation. Some preliminary human clinical studies seem to support an improvement in mechanical function following GLP-1 administration to patients with dysfunctional left ventricle. GLP-1 receptor agonists such as exenatide have been shown to reduce necrotic damage to post-ischemic reperfused myocardium.
To date, the information available on the effect of dipeptidyl peptidase-4 inhibitors (DPP-4) is poor, on the other hand the unexpected and unclearly increase in hospitalizations for heart failure in patients DDP-4 inhibitor saxagliptin, recently reported as part of the SAVOR TIMI study, requires extensive assessments in this field. In animal experiments (rat), a cardioprotective function of linagliptin has been demonstrated in the setting of acute myocardial infarction and uremic cardiomyopathy. Based on these observations, we propose the evaluation of the addition of linagliptin on left ventricular function in patients with type 2 diabetes mellitus (DMT2) adequately controlled with the usual therapy, as part of a randomized study, placebo-controlled, on subjects with concentric LV geometry, defined by a prior basic echocardiographic evaluation.
The aim of the study is to gather information on the efficacy and safety of linagliptin administered as adjunctive therapy to patients with DMT2 with asymptomatic LV systolic dysfunction.
Selection of people at low cardiovascular risk: development of an inexpensive pre-screening algorithm using only non-laboratory measures. The SKIM risk study
Early identification of individuals at high risk remains the cornerstone of primary cardiovascular prevention (CV). However, cardiovascular screening including people at low CV diseases (CVD) risk are too costly, time consuming and poorly effective in reducing incident CV events to be proposed at population level. Thus, innovative tools excluding low risk subjects for primary prevention are needed. In this study, we will assess whether a new low-cost strategy for CV risk stratification, based on non-laboratory measures, will allow to identify low risk subjects not needing further and expensive measures. To this end, we will take advantage of a General Practitioners national network that will allow to act in the natural contest of primary prevention. If successful, the project will provide the basis for future, cost-effective prevention programs to be performed at national level.
Impact of therapy on hospital outcomes in diabetic patients admitted for acute myocardial infarction
Sulphonylureas are known to exert harmful effects on the heart (interference with ischemic preconditioning, negative inotropic effect, reduction of coronary flow, pro-arrhythmic effect); on the contrary, these unfavorable effects have been documented with other drugs used to treat diabetes mellitus, such as metformin. Indeed, recent trials have shown that SGLT2 inhibitors and GLP-1 receptor agonists reduce major cardiovascular events (MACE) and mortality. It is not known whether the different effects on the heart of the various antidiabetic treatments have a possible relevance on the clinical hospital course during the acute phase of acute myocardial infarction (AMI). The objective of the study is to evaluate the possible association between various types of hypoglycemic drugs, short-term clinical outcome and extension of the infarct area in a cohort of diabetic patients with AMI. Demographic, clinical, biochemical and angiographic data will be collected from about 600 diabetic patients admitted with AMI. In all patients, home hypoglycemic therapy taken before admission will be evaluated.
Effects of incretin analogues on the function of diabetic patients’ CD34 stem cells
Recently a new class of antidiabetic drugs, agonists of glucagon-like peptide 1 receptor (GLP-1R), displayed pleiotropic cardiovascular effects in type 2 diabetes (T2D) patients. In particular, besides its glucose-lowering action, liraglutide reduced the risk of death from cardiovascular disease as well as progression of kidney disease in T2D patients at high risk for cardiovascular disease. Since these patients already experienced high risk of cardiovascular disease, these clinical outcomes raise the possibility that liraglutide treatment can reverse hyperglycemic memory. At a cellular and molecular level liraglutide inhibited atherogenesis by reducing high glucose-induced oxidative stress and inflammation in human endothelial cells. Whereas in the heart liraglutide improved experimental myocardial infarction outcomes by activating cytoprotective pathways in mice and attenuated angiotensin II-induced cardiac fibrosis in rats. The overall effects were mediated by GLP-1 receptors which are present in most tissues of human body. To date, studies in humans describing the effects of liraglutide on the biological processes of dysfunctional CD34+ stem cells and underlying mechanisms are lacking. New understanding derived from this study will raise the possibility to identify new pharmacological interventions that, by reverting metabolic memory, will be able to reduce the development of cardiovascular disease complications or to improve the efficiency of autologous stem cells therapies following delivery. The aim of this study is to evaluate the effects of liraglutide on dysfunctional CD34+ stem cells and detail the mechanisms underlying the ability to restore or improve their regenerative potential.
The role of PCSK9 in the modulation of platelet function
The primary objective of the project is to investigate the role of PCSK9 in platelet function by defining the mechanisms underlying the enhancement of platelet reactivity observed in healthy subjects and evaluating whether PCSK9 can contribute to the known diabetic patient's hyperreactivity. Secondary objectives of the study are 1) the identification of the molecular mechanisms responsible for the presence of PCSK9 in platelets; 2) the characterization of the platelet subpopulation that expresses PCSK9; 3) the definition of platelet agonists that better "collaborate" with PCSK9 in modulating platelet function; 4) analysis of polymorphisms in genes associated with platelet function and/or those associated with antithrombotic drug response.
- Marzona I, Avanzini F, Tettamanti M, Vannini T, Fortino I, Bortolotti A, Merlino L, Genovese S, Roncaglioni MC. Prevalence and management of diabetes in immigrants resident in the Lombardy Region: the importance of ethnicity and duration of stay. Acta Diabetol. 2018 Jan 22. [Epub ahead of print]
- Pagani L, Diekmann Y, Sazzini M, De Fanti S, Rondinelli M, Farnetti E, Casali B, Caretto A, Novara F, Zuffardi O, Garagnani P, Mantero F, Thomas MG, Luiselli D, Rossi E. Three Reportedly Unrelated Families With Liddle Syndrome Inherited From a Common Ancestor. Hypertension. 2018 ;71(2):273-279.
- Lapolla A, Berra C, Boemi M, Bossi AC, Candido R, Di Cianni G, Frontoni S, Genovese S, Ponzani P, Provenzano V, Russo GT, Sciangula L, Simioni N, Bette C, Nicolucci A; NN2211-4118 Study Group. Long-Term Effectiveness of Liraglutide for Treatment of Type 2 Diabetes in a Real-Life Setting: A 24-Month, Multicenter, Non-interventional, Retrospective Study. Adv Ther. 2017 Dec 21. [Epub ahead of print]
- Cattaneo M, La Sala L, Rondinelli M, Errichiello E, Zuffardi O, Puca AA, Genovese S, Ceriello A. A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients. BMC Med Genet. 2017;18(1):147
- Scavini M, Rossi MC, Scardapane M, Nicolucci A, Manicardi V, Russo G, Di Bartolo P, Giorda CB, Musacchio N, Ceriello A, Genovese S, Molinari C, Dozio N; AMD-Annals Study Group. Portrait of women with type 1 or type 2 diabetes of childbearing age attending diabetes clinics in Italy: the AMD-Annals initiative. Acta Diabetol. 2017 Dec 5. [Epub ahead of print]
Maurizio Rondinelli, MD
Roberto Manfrini, MD
Catia Trudu, Nurse
Carmen Cinieri, Nurse