Use of Tirzepatide in Adults with Type 2 Diabetes Mellitus: Scientific Evidence and Practical Aspects.

Tirzepatide is a novel antidiabetic medication a single-molecule, agonist to the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors. It is approved in the USA and EU for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Due to the potential novelty represented by incorporating tirzepatide to clinical practice, we aim to review practical aspects of tirzepatide use in T2DM and the supporting scientific evidence. A group of ten endocrinologists involved as investigators in the phase 3 SURPASS clinical trial program followed a nominal group technique, a qualitative research methodology designed as a semi-structured group discussion to reach a consensus on the selection of a set of practical aspects. The scientific evidence for tirzepatide has been reviewed with respect to a number of patients' clinical profiles and care goals. Information of interest related to adverse events, special warnings and precautions, and other considerations for tirzepatide use has been included. Finally, information provided to the patients has been summarized. The practical aspects reported herein may be helpful in guiding physicians in the use of tirzepatide and contribute to optimizing the management of T2DM.

Calcifediol in the management of vitamin D deficiency-related skeletal and extraskeletal diseases: overview and clinical cases.

As well as being essential for musculoskeletal health, vitamin D is involved in numerous other physiological processes. Poor vitamin D status is linked to a wide range of diseases, including cardiovascular disease, autoimmune conditions, pulmonary disorders and upper respiratory tract infections. While optimal target concentrations of serum 25-hydroxyvitamin D (25(OH)D) for health maintenance or therapeutic purposes are still the subject of debate, there is reasonable agreement that serum 25(OH)D levels <50 nmol/L (20 ng/mL) constitute vitamin D deficiency and that severe deficiency states (serum 25(OH)D levels <25-30 nmol/L ≈ 10-12 ng/mL) should be avoided. Main strategies to maintain or improve vitamin D status are food supplementation and therapeutic use of medicinal forms of vitamin D. In this review, we examine evidence that implicates vitamin D deficiency in diverse conditions in the clinical settings of endocrinology, rheumatology, pneumology and reproductive health. Cholecalciferol (vitamin D3) is the most frequently used vitamin D supplement worldwide, though calcifediol (25-hydroxyvitamin D3) has recently become more widely available. Calcifediol is one step closer than cholecalciferol in the metabolic pathway to biologically active vitamin D. Pharmacokinetic differences between these vitamin D metabolites confer putative advantages for calcifediol in certain clinical situations. The clinical use of calcifediol is explored more closely through case studies, which illustrate its adjunctive role in the treatment of several vitamin D deficiency-related skeletal and extraskeletal diseases.

Comprehensive approach to people with type 2 diabetes. Diabetes Knowledge Area of the Spanish Society of Endocrinology and Nutrition.

OBJECTIVE: To provide practical recommendations for the comprehensive approach of people with type 2 diabetes according to evidence-based medicine. PARTICIPANTS: Members of the Diabetes Knowledge Area of the Spanish Society of Endocrinology and Nutrition. METHODS: The recommendations were formulated according to the degrees of evidence of the Standards of Medical Care in Diabetes-2022. After reviewing the available evidence and formulating recommendations by the authors of each section, several rounds of comments were developed incorporating the contributions and voting on controversial points. Finally, the final document was sent to the rest of the members of the area for review and incorporation of contributions, to finally carry out the same process with the members of the Spanish Society of Endocrinology and Nutrition Board of Directors. CONCLUSIONS: The document establishes practical recommendations based on the latest available evidence for the management of people with type 2 diabetes.

[Evaluation of improved nutritional status in patients over 60 years with 6-month follow-up by a nutritionist in a hospital setting in Almería. The MOR-NUT study]. / Evaluación de la mejora del estado nutricional en pacientes mayores de 60 años con seguimiento de 6 meses por un nutricionista en el ámbito hospitalario de Almería. El estudio MOR-NUT.

Introduction: Background: non-institutionalized elderly patients who are prescribed an oral nutritional supplement (ONS) often have difficulties with compliance, which leads to physical deterioration and increases the risk of malnutrition. Objective: to assess improvement in the nutritional status of patients over 60 years of age, using the Mini Nutritional Assessment (MNA) score after the intervention of a nutritionist during a 6-month follow-up of malnourished patients with an indication for ONS. To demonstrate that the intervention of a nutritionist provides long-term improvements in the nutritional status of malnourished patients who are taking an ONS. Results: the nutritional intervention significantly improved BMI (from 22.9 ± 4.5 to 24.0 ± 4.1; p = 0.001) and the MNA score (from 14.7 ± 4.4 to 20.4 ± 5.8; p < 0.001) of the patients, as well as their perception of health (measured by VAS). Conclusions: the nutritional advice provided by a nutritionist to patients who were taking an ONS provided a high rate of adherence to treatment, which resulted in improvement in the nutritional status of patients.

Introducción: Antecedentes: los pacientes mayores no institucionalizados a los que se les prescribe un suplemento nutricional oral (SNO) suelen tener dificultades con el cumplimiento, lo que origina deterioro físico e incrementa el riesgo de desnutrición. Objetivo: evaluar la proporción de pacientes mayores de 60 años que mejoran su categorización de la versión completa del Mini Nutritional Assessment (MNA) desde el inicio hasta la visita final tras la intervención de un nutricionista en el seguimiento de pacientes desnutridos y con indicación de SNO a lo largo de 6 meses. Demostrar que la intervención de un nutricionista aporta mejoras a largo plazo en el estado nutricional de los pacientes desnutridos que están tomando un SNO. Resultados: la intervención nutricional mejoró significativamente el IMC (de 22,9 ± 4,5 a 24,0 ± 4,1; p = 0,001), y la puntuación MNA (de 14,7 ± 4,4 a 20,4 ± 5,8 p < 0,001) de los pacientes, así como su percepción de la salud (medida mediante una EVA). Conclusiones: el consejo nutricional proporcionado por un nutricionista en los pacientes que están tomando un SNO, consiguió una elevada adherencia al tratamiento, lo que produjo una mejora en el estado nutricional de los pacientes.

Benefits of SGLT2i for the Treatment of Heart Failure Irrespective of Diabetes Diagnosis: A State-of-the-Art Review.

Morbidity and mortality associated with heart failure (HF) has remained high despite advances in therapy. Furthermore, HF-associated risk in patients with type 2 diabetes mellitus (T2D) is even higher than in patients without T2D owing to the strong reciprocal relationship between conditions. However, until recently, no therapy to treat patients with diabetes also reduced cardiovascular risks related to HF. Recent clinical studies (DAPA-HF, EMPEROR-Reduced and EMPEROR-Preserved, SOLOIST-WHF trial) and meta-analysis have demonstrated that sodium-glucose cotransporter-2 inhibitors (SGLT2i) are among the first antidiabetic drugs capable of reducing cardiovascular risks related to HF and improving the prognosis of patients with and without diabetes. Their pleiotropic mechanisms of action place them at the intersection of hemodynamic, metabolic, and neurohumoral pathways, with clear advantages for treating these patients independent of its glucose-lowering effect. Moreover, the benefits of SGLT2i were consistent across the cardiorenal continuum in different populations and clinical settings, which has led to different guidelines introducing SGLT2i as a first-line treatment for HF.

Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are indicated in type 2 diabetes and obesity for their high efficacy in controlling glycaemia and inducing body weight loss, respectively. Patients may develop gastrointestinal adverse events (GI AEs), namely nausea, vomiting, diarrhoea and/or constipation. To minimize their severity and duration, healthcare providers (HCPs) and patients must be aware of appropriate measures to follow while undergoing treatment. An expert panel comprising endocrinologists, nephrologists, primary care physicians, cardiologists, internists and diabetes nurse educators convened across virtual meetings to reach a consensus regarding these compelling recommendations. Firstly, specific guidelines are provided about how to reach the maintenance dose and how to proceed if GI AEs develop during dose-escalation. Secondly, specific directions are set about how to avoid/minimize nausea, vomiting, diarrhoea and constipation symptoms. Clinical scenarios representing common situations in daily practice, and infographics useful to guide both HCPs and patients, are included. These recommendations may prevent people with T2D and/or obesity from withdrawing from GLP-1 RAs treatment, thus benefitting from their superior effect on glycaemic control and weight loss.

Executive summary: Position document: Evaluation and management of hypoglycemia in the patient with diabetes mellitus 2020. Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition.

OBJECTIVE: To provide practical recommendations for the evaluation and management of hypoglycemia in patients with diabetes mellitus. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN). METHODS: The recommendations were made based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to establish both the strength of the recommendations and the level of evidence. A systematic search was made in MEDLINE (PubMed) for the available evidence on each subject, and articles written in English and Spanish with an inclusion date up to 30 November 2019 were reviewed. This executive summary takes account of the evidence incorporated since 2013. CONCLUSIONS: The document establishes practical evidence-based recommendations regarding the evaluation and management of hypoglycemia in patients with diabetes mellitus.

Executive summary: Position document: Evaluation and management of hypoglycemia in the patient with diabetes mellitus 2020. Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition. / Resumen ejecutivo: Documento de posicionamiento: evaluación y manejo de la hipoglucemia en el paciente con diabetes mellitus 2020. Grupo de Trabajo de Diabetes Mellitus de la Sociedad Española de Endocrinología y Nutrición.

OBJECTIVE: To provide practical recommendations for the evaluation and management of hypoglycemia in patients with diabetes mellitus. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN). METHODS: The recommendations were made based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to establish both the strength of the recommendations and the level of evidence. A systematic search was made in MEDLINE (PubMed) for the available evidence on each subject, and articles written in English and Spanish with an inclusion date up to 28 February 2020 were reviewed. This executive summary takes account of the evidence incorporated since 2013. CONCLUSIONS: The document establishes practical evidence-based recommendations regarding the evaluation and management of hypoglycemia in patients with diabetes mellitus.

Clinical Approach to Flash Glucose Monitoring: An Expert Recommendation.

The flash glucose monitoring (FGM) system FreeStyle Libre® is a device that measures interstitial glucose in a very simple way and indicates direction and speed of glucose change. This allows persons with diabetes to prevent hypoglycemic and hyperglycemic events. Scientific evidence indicates that the system can improve glycemic control and quality of life. To obtain the maximum benefit, it is necessary to properly handle glucose values and trends. Due to the generalization of the system use, the purpose of the document is to provide recommendations for the optimal use of the device, not only in the management of glucose values and trends but also in the prevention of hypoglycemia, actuation in exercise, special situations, and retrospective analysis of the glucose data, among others.

Document on a comprehensive approach to type 2 diabetes mellitus. / Documento de abordaje integral de la diabetes tipo 2.

OBJECTIVE: Treatment of type 2 diabetes mellitus (T2DM) is complex and is intended to decrease morbidity and mortality. Management should therefore include adequate diabetes education, lifestyle changes, drug treatment to achieve early blood glucose control and reduction of cardiovascular (CV) risk factors, early detection and treatment of complications, and assessment of associated comorbidities. The objective was to prepare a document including all aspects required for a comprehensive approach to T2DM. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology. METHODS: The available evidence regarding each aspect of diabetes management (blood glucose control goals, diet and exercise, drug treatment, risk factor management and control, detection of complications, and management of frail patients) was reviewed. Recommendations were formulated based on the grades of evidence stated in the 2018 Standards of Medical Care in Diabetes. Recommendations were discussed and agreed by the working group members. CONCLUSIONS: This document is intended to provide evidence-based practical recommendations for comprehensive management of T2DM by clinical endocrinologists.

Electrical changes during hypoglycaemia in patients with type 1 and type 2 diabetes and high cardiovascular risk.

The relationship between glycaemia, arrhythmia and changes in electrocardiogram (ECG) has been addressed showing mixed results. The objective of this study was to evaluate the changes in ECG, evaluated by Holter monitoring, induced by clinical hypoglycaemia in patients with type 1 diabetes (T1DM) and type 2 diabetes (T2DM), aged 50 or older, with high cardiovascular risk. Five-lead Holter monitoring (BL-900 Braemar, Inc, Norav Medical NH301-2.4.5 software), and blinded interstitial continuous glucose monitoring (CGM) (Dexcom G4-Platinum, range 40-400 mg/dl) was performed with time synchronization. In the Holter registry, in patients with hypoglycemic episodes, mean QTc during hypoglycaemia was longer compared to mean QTc in total group (+4.6 ms, p = 0.037) and T1DM patients (+5.5 ms, p = 0.048) but not in T2DM patients (+3 ms, p = 0.459). During hypoglycaemia, non-clinical significant disturbances in heart rhythm were observed. In conclusion, we observed a prolongation in QTc during hypoglycemia, mainly in T1DM. However, our study does not show a relationship between episodes of hypoglycaemia and clinical arrhythmias, at least in T1DM and T2DM patients with high cardiovascular risk.

Cost-effectiveness analysis of insulin degludec compared with insulin glargine u100 for the management of type 1 and type 2 diabetes mellitus - from the Spanish National Health System perspective.

BACKGROUND: The objective of this study was to assess the cost-effectiveness of insulin degludec versus insulin glargine, from the Spanish NHS in three groups of patients. METHODS: A short-term cost utility model was developed to estimate effectiveness results in terms of the total number of hypoglycaemic events and their disutility impact throughout the year on the initial level of quality of life for patients in each treatment. RESULTS: Degludec was the dominant strategy for T2DM BOT and exhibited an incremental cost-effectiveness ratio of 52.70€/QALY and 11,240.88€/QALY for T1DM B/B and T2DM B/B, respectively. Lower costs are primarily driven by lower nocturnal and severe hypoglycaemic events, which were reduced versus IGlar. Improvements in clinical outcomes in all three patient groups are result of the reduced number of hypoglycaemic events showing 0.0211, 0.0328 and 0.0248 QALYs gained when compared to IGlar for T1DM B/B, T2DM BOT and T2DM B/B, respectively. Different scenario analyses showed that the ICERS were stable to plausible variations in the analysed parameters, except when the same number of SMBG for both treatments is used, with T2DM B/B showing an ICER over the accepted threshold. CONCLUSION: This analysis demonstrates that degludec is a cost-effective option in the Spanish NHS, when used in patients currently treated with long-acting insulin.

The Economic Burden of Insulin-Related Hypoglycemia in Spain.

INTRODUCTION: An analysis was conducted to estimate the economic burden of insulin-related hypoglycemia in adults in Spain, derived from a novel concept developed for the UK known as the Local Impact of Hypoglycemia Tool. METHODS: Costs per severe and non-severe hypoglycemic episode were calculated for patients with type 1 diabetes (T1DM) and type 2 diabetes (T2DM). The costs per episode were applied to the population of adults with T1DM and T2DM using insulin in Spain according to the number of severe and non-severe episodes experienced per year. Costs were calculated using Spanish-specific resource costs and published values for resource utilization, including ambulance, accident and emergency (A&E) department, hospitalization, healthcare professional visits, and extra self-monitoring of blood glucose (SMBG) tests used in the week following the episode. A one-way sensitivity analysis on all model inputs was then performed. RESULTS: The cost of insulin-related hypoglycemia in Spain is estimated as €662.0 m per year, €292.6 m of which is due to severe episodes and €369.4 m to non-severe episodes. The cost per episode varies from €1.25 for patients with T1DM and €1.48 for patients with T2DM for a non-severe episode where extra SMBG testing after the episode is the only action taken, to €4378.22 for T1DM and €3005.74 for T2DM for a severe episode that was treated in hospital and requires an ambulance, A&E visit, hospitalization, and a diabetes specialist visit. A reduction in severe and non-severe hypoglycemia rates of just 20% could lead to considerable cost savings of €284,925 per 100,000 general population. CONCLUSION: This analysis highlights the substantial economic burden of hypoglycemia in Spain, and gives budget holders the ability to assess the costs of new treatments or patient education programs in relation to the potential cost savings due to lower hypoglycemia rates.

Liraglutide Versus Lixisenatide: Long-Term Cost-Effectiveness of GLP-1 Receptor Agonist Therapy for the Treatment of Type 2 Diabetes in Spain.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists are used successfully in the treatment of patients with type 2 diabetes as they are associated with low hypoglycemia rates, weight loss and improved glycemic control. This study compared, in the Spanish setting, the cost-effectiveness of liraglutide 1.8 mg versus lixisenatide 20 µg, both GLP-1 receptor agonists, for patients with type 2 diabetes who had not achieved glycemic control targets on metformin monotherapy. METHODS: The IMS CORE Diabetes Model was used to project clinical outcomes and costs, expressed in 2015 Euros, over patient lifetimes. Baseline cohort data and treatment effects were taken from the 26-week, open-label LIRA-LIXI™ trial (NCT01973231). Treatment and management costs of diabetes-related complications were retrieved from published sources and databases. Future benefits and costs were discounted by 3% annually. Sensitivity analyses were conducted. RESULTS: Compared with lixisenatide 20 µg, liraglutide 1.8 mg was associated with higher life expectancy (14.42 vs. 14.29 years), higher quality-adjusted life expectancy [9.40 versus 9.26 quality-adjusted life years (QALYs)] and a reduced incidence of diabetes-related complications. Higher acquisition costs resulted in higher total costs for liraglutide 1.8 mg (EUR 42,689) than for lixisenatide 20 µg (EUR 42,143), but these were partly offset by reduced costs of treating diabetes-related complications (EUR 29,613 vs. EUR 30,636). Projected clinical outcomes and costs resulted in an incremental cost-effectiveness ratio of EUR 4113 per QALY gained for liraglutide 1.8 mg versus lixisenatide 20 µg. CONCLUSIONS: Long-term projections in the Spanish setting suggest that liraglutide 1.8 mg is likely to be cost-effective compared with lixisenatide 20 µg in type 2 diabetes patients who have not achieved glycemic control targets on metformin monotherapy. Liraglutide 1.8 mg presents a clinically and economically attractive treatment option in the Spanish setting.

Clinical Effects of Liraglutide in a Real-World Setting in Spain: eDiabetes-Monitor SEEN Diabetes Mellitus Working Group Study.

INTRODUCTION: A limitation with randomized controlled trials is that, while they provide unbiased evidence of the efficacy of interventions, they do so under unreal conditions and in a very limited and highly selected patient population. Our aim was to provide data about the effectiveness of liraglutide treatment in a real-world and clinical practice setting. METHODS: In a retrospective and observational study, data from 753 patients with type 2 diabetes were recorded through an online tool (eDiabetes-Monitor). RESULTS: Mean baseline glycated hemoglobin (HbA1c) was 8.4 ± 1.4% and mean body mass index (BMI) was 38.6 ± 5.4 kg/m(2). After 3-6 months of treatment with liraglutide, we observed a change in HbA1c of -1.1 ± 1.2%, -4.6 ± 5.3 kg in weight and -1.7 ± 2.0 kg/m(2) in BMI (p < 0.001 for all). Compared to baseline, there was a significant reduction in systolic blood pressure (-5.9 mmHg, p < 0.001), diastolic blood pressure (-3.2 mmHg, p < 0.001), LDL cholesterol (-0.189 mmol/l, p < 0.001) and triglycerides (-0.09 mmol/l, p = 0.021). In patients switched from DPP-4 inhibitors, liraglutide induced a decrease of -1.0% in HbA1c (p < 0.001) and a reduction in weight (-4.5 kg, p < 0.001). In patients treated with liraglutide as an add-on therapy to insulin a decrease of -1.08% in HbA1c (p < 0.001) and a weight reduction of -4.15 kg (p < 0.001) were observed. CONCLUSION: Our study confirms the effectiveness of liraglutide in a real-life and clinical practice setting. FUNDING: Spanish Society of Endocrinology and Nutrition.

Cost-Effectiveness Analysis of Incretin Therapy for Type 2 Diabetes in Spain: 1.8 mg Liraglutide Versus Sitagliptin.

OBJECTIVES: Metformin is the first-line therapy for most patients with type 2 diabetes, but the majority require treatment intensification at some stage due to the progressive nature of the disease. The 1860-LIRA-DPP-4 trial showed that liraglutide exhibited greater improvements compared with sitagliptin in glycated hemoglobin and body mass index in patients with type 2 diabetes inadequately controlled on metformin monotherapy. As a follow-up to a previously published cost-effectiveness analysis of 1.2 mg liraglutide versus sitagliptin in Spain, the aim of this analysis was to compare long-term projections of the clinical and cost implications associated with 1.8 mg liraglutide and sitagliptin. METHODS: For the modeling analysis, 52-week treatment effect data (as opposed to 26-week data in the previous analysis) were taken from the 1860-LIRA-DPP-4 trial, for adults with type 2 diabetes receiving 1.8 mg liraglutide or 100 mg sitagliptin daily in addition to metformin. Long-term (patient lifetime) projections of clinical outcomes and direct costs (2012 EUR) were made using a published and validated model of type 2 diabetes, with modeling assumptions as per the 1.2 mg liraglutide analysis. RESULTS: Liraglutide was associated with increased life expectancy (14.24 versus 13.87 years) and quality-adjusted life expectancy [9.24 versus 8.84 quality-adjusted life years (QALYs)] over sitagliptin. Improved clinical outcomes were attributable to the improvement in glycemic control, leading to a reduced incidence of diabetes-related complications, including renal disease, cardiovascular disease, ophthalmic and diabetic foot complications. Liraglutide was associated with increased direct costs (EUR 56,628 versus EUR 52,450), driven by increased pharmacy costs. Based on these estimates, liraglutide was associated with an incremental cost-effectiveness ratio of EUR 10,436 per QALY gained versus sitagliptin. CONCLUSIONS: A previous analysis has suggested that 1.2 mg liraglutide is cost-effective from a healthcare payer perspective in Spain, and the present analysis suggests that the 1.8 mg dose is also likely to be cost-effective.

Self-reported frequency and impact of hypoglycemic events in Spain.

INTRODUCTION: Hypoglycemia is a common side effect of insulin therapy and has negative implications for quality of life and healthcare resources. The authors investigated the self-reported frequency of non-severe and severe hypoglycemic events (NSHEs and SHEs), hypoglycemia awareness, patient-physician communication, health-related effects and economic impact on people with insulin-treated diabetes (Type-1 and Type-2) in Spain. METHODS: People with Type-1 (T1DM) or insulin-treated Type-2 (T2DM) diabetes older than 15 years of age completed up to 4 questionnaires at weekly intervals. NSHE was an event which respondents could manage without assistance. SHE needed help from a third party to manage. RESULTS: In total, 630 respondents completed questionnaires covering 2,235 weeks. Mean self-reported NSHEs per respondent-week were 1.7 (T1DM) and 0.4-0.8 (T2DM). Impaired hypoglycemia awareness or unawareness was reported by 55% of T1DM and 39% of T2DM respondents. Overall, 31% of T1DM and 20% of T2DM respondents rarely/never informed their physician about NSHEs. Respondents reported feeling tired/fatigued after 67% of NSHE and less alert after 45% of NSHE. Over the week following an NSHE, blood glucose measurement test-strip use increased by 5.3 (mean). In employed respondents (43%), 18% of NSHEs were reported to lead to lost work time (mean 1.5 h per event). After an SHE, 49% of respondents required emergency visits and/or hospital admission. CONCLUSION: NSHE are a common occurrence with T1DM and insulin-treated T2DM in Spain and are associated with a cost burden and negative impact on well-being. Patient-physician communication is higher in Spain than Europe overall; however, many patients expressed reluctance to discuss their hypoglycemia.