Hypoglycemia represents a dark and tormented side of diabetes mellitus therapy. Patients treated with insulin or drug inducing hypoglycemia, consider hypoglycemia as a harmful element, which leads to their resistance and lack of acceptance of the pathology and relative therapies. Severe hypoglycemia, in itself, is a risk for patients and relatives. The possibility to have novel strategies and scientific knowledge concerning hypoglycemia could represent an enormous benefit. Novel available glucagon formulations, even now, allow clinicians to deal with hypoglycemia differently with respect to past years. Novel scientific evidence leads to advances concerning physiopathological mechanisms that regulated glycemic homeostasis. In this review, we will try to show some of the important aspects of this field.

In Hashimoto’s thyroiditis (HT), the genetic bases play a central role in determining development of the disease. In particular, the most frequent genes involved in the onset of HT are the Human Leukocyte Antigen (HLA). However, there are other genes and transcription factors in the autoimmune background of HT, both isolated and as part of autoimmune polyendocrine syndromes (APS). Recently more interest is being fueled toward BACH2 (BTB Domain and CNC Homolog 2), that promotes Tregs (T regulators lymphocytes) differentiation and enhances Treg-mediated immunity. The synergistic interaction between environmental agents and the aforementioned genes leads to the onset of autoimmunity and ultimately to damage of the thyroid gland. In this scenario, the role of Th17 (T helper-17 lymphocytes) and Treg cells is still less defined as compared to action of Th1 cells (T helper-1 lymphocytes) and cytotoxic lymphocytes (CD8 + T lymphocytes). Evidences show that an imbalance of Th17/Treg ratio represents a prognostic factor with respect to the gland damage. Moreover, the deficient ability of Treg to inhibit the proliferation of T cells against the self can break the immune balance. In light of these considerations, the use of genetic panels and the progress of immunotherapy could allow for better targeting treatment and preventive interventions in subjects with potential or early stage of HT.

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This is an interim evaluation of the STOP study, a proof-of-concept observation, whose aim is to test effectiveness and safety of IDegLira in deintensifying diabetes therapy in insulin-treated persons with T2DM aged >65 years. The study, retrospective observational, gathered so far data related to 93 consecutive persons with T2 DM, in whom IDegLira was introduced in therapy, and for whom clinical data were available for at least 6 months after the switch. The 93 persons (42 F, age 76±8 yrs, diabetes duration 20±10 yrs, duration of insulin treatment 13±12 yrs, BMI 28.6±4.9 kg/m2, A1C 7.4±0.9), were for the 75% in basal/bolus insulin therapy. Sixteen % of them, needed caregiver, whereas 53% were in follow up at the Geriatric Clinic for mild/severe cognitive impairment. After 3 months, fasting plasma glucose (PG) decreased (from 138±38 to 117±24 mg/dl, p=0.000036 vs baseline), similarly A1C (from 7.4±0.9 to 7.0±0.6%, p=0.000126). All results showed additional improvement at 6 month (p< 0.005 vs baseline). Rates of hypoglycemia at any time of day (PG <70 mg/dl) were lower after 3 months (0.35±0.94 vs 1.15±2.61, episodes/pt/month, p=0.0057). Episodes with PG <54 mg/dl decreased from 0.56±1.71 to 0.03±0.25, p=0.0093). Accordingly, the proportion of patients with at least one episode of PG <70 mg and 54 mg/dl, felt down from baseline to 3 month (23.7 to 14%;16.1 to 11%, respectively), being zero at 6 months. Rapid acting insulin dose decreased by 80 % at 3, up to 95% at 6 months (from 0.18±0.13 to 0.04±0.06 at 3, and 0.01±0.04 U/kg at 6 months, p< 0.0001). Nearly all patients interrupted it. IDegLira was initiated at a mean dose of 17±5.4 U/die to further increase to 23±9.6 after 6 months. BMI did not change significantly (p=ns). According to our preliminary results, IDegLira seems to offer a relevant option, to more complex insulin regimens, in terms of effectiveness and safety, in a population in whom preventing hypoglycemia and improving quality of life are mandatory and clinical inertia is often present. Disclosure A. Mazzieri: None. M. De fano: None. F. Mancinetti: None. D. Xenos: None. V. Boccardi: None. C. G. Fanelli: None. F. Porcellati: Board Member; Lilly Diabetes, Sanofi, Consultant; Novo Nordisk.