Comparing the effectiveness and cost-effectiveness of sulfonylureas and newer diabetes drugs as second-line therapy for patients with type 2 diabetes.

INTRODUCTION: We aimed to compare the effectiveness and cost-effectiveness profiles of glucagon-like peptide-1 receptor agonist (GLP-1-RA), sodium-glucose cotransporter 2 inhibitor (SGLT2i), and dipeptidyl peptidase-4 inhibitor (DPP-4i) compared with sulfonylureas and glinides (SU). RESEARCH DESIGN AND METHODS: Population-based retrospective cohort study based on linked regional healthcare utilization databases. The cohort included all residents in Lombardy aged ≥40 years, treated with metformin in 2014, who started a second-line treatment between 2015 and 2018 with SU, GLP-1-RA, SGLT2i, or DPP-4i. For each cohort member who started SU, one patient who began other second-line treatments was randomly selected and matched for sex, age, Multisource Comorbidity Score, and previous duration of metformin treatment. Cohort members were followed up until December 31, 2022. The association between second-line treatment and clinical outcomes was assessed using Cox proportional hazards models. The incremental cost-effectiveness ratios (ICERs) were calculated and compared between newer diabetes drugs and SU. RESULTS: Overall, 22 867 patients with diabetes were included in the cohort, among which 10 577, 8125, 2893 and 1272 started a second-line treatment with SU, DPP-4i, SGLT2i and GLP-1-RA, respectively. Among these, 1208 patients for each group were included in the matched cohort. As compared with SU, those treated with DPP-4i, SGLT2i and GLP-1-RA were associated to a risk reduction for hospitalization for major adverse cardiovascular events (MACE) of 22% (95% CI 3% to 37%), 29% (95% CI 12% to 44%) and 41% (95% CI 26% to 53%), respectively. The ICER values indicated an average gain of €96.2 and €75.7 each month free from MACE for patients on DPP-4i and SGLT2i, respectively. CONCLUSIONS: Newer diabetes drugs are more effective and cost-effective second-line options for the treatment of type 2 diabetes than SUs.

Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group.

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

Assessment of Glucose Lowering Medications' Effectiveness for Cardiovascular Clinical Risk Management of Real-World Patients with Type 2 Diabetes: Targeted Maximum Likelihood Estimation under Model Misspecification and Missing Outcomes.

The results from many cardiovascular (CV) outcome trials suggest that glucose lowering medications (GLMs) are effective for the CV clinical risk management of type 2 diabetes (T2D) patients. The aim of this study is to compare the effectiveness of two GLMs (SGLT2i and GLP-1RA) for the CV clinical risk management of T2D patients in a real-world setting, by simultaneously reducing glycated hemoglobin, body weight, and systolic blood pressure. Data from the real-world Italian multicenter retrospective study Dapagliflozin Real World evideNce in Type 2 Diabetes (DARWINT 2D) are analyzed. Different statistical approaches are compared to deal with the real-world-associated issues, which can arise from model misspecification, nonrandomized treatment assignment, and a high percentage of missingness in the outcome, and can potentially bias the marginal treatment effect (MTE) estimate and thus have an influence on the clinical risk management of patients. We compare the logistic regression (LR), propensity score (PS)-based methods, and the targeted maximum likelihood estimator (TMLE), which allows for the use of machine learning (ML) models. Furthermore, a simulation study is performed, resembling the structure of the conditional dependencies among the main variables in DARWIN-T2D. LR and PS methods do not underline any difference in the effectiveness regarding the attainment of combined CV risk factor goals between the two treatments. TMLE suggests instead that dapagliflozin is significantly more effective than GLP-1RA for the CV risk management of T2D patients. The results from the simulation study suggest that TMLE has the lowest bias and SE for the estimate of the MTE.

Performance assessment across different care settings of a heart failure hospitalisation risk-score for type 2 diabetes using administrative claims.

Predicting the risk of cardiovascular complications, in particular heart failure hospitalisation (HHF), can improve the management of type 2 diabetes (T2D). Most predictive models proposed so far rely on clinical data not available at the higher Institutional level. Therefore, it is of interest to assess the risk of HHF in people with T2D using administrative claims data only, which are more easily obtainable and could allow public health systems to identify high-risk individuals. In this paper, the administrative claims of > 175,000 patients with T2D were used to develop a new risk score for HHF based on Cox regression. Internal validation on the administrative data cohort yielded satisfactory results in terms of discrimination (max AUROC = 0.792, C-index = 0.786) and calibration (Hosmer-Lemeshow test p value < 0.05). The risk score was then tested on data gathered from two independent centers (one diabetes outpatient clinic and one primary care network) to demonstrate its applicability to different care settings in the medium-long term. Thanks to the large size and broad demographics of the administrative dataset used for training, the proposed model was able to predict HHF without significant performance loss concerning bespoke models developed within each setting using more informative, but harder-to-acquire clinical variables.

Glycated Albumin for Glycemic Control in T2DM Population: A Multi-Dimensional Evaluation.

PURPOSE: To investigate the glycated albumin (GA) introduction implications, as an add-on strategy to traditional glycemic control (Hb1Ac and fasting plasma glucose - FPG) instruments, considering insulin-naïve individuals with type 2 diabetes mellitus (T2DM), treated with oral therapies. METHODS: A Health Technology Assessment was conducted in Italy, as a multi-dimensional approach useful to validate any innovative technology. The HTA dimensions, derived from the EUnetHTA Core Model, were deployed by means of literature evidence, health economics tools and qualitative questionnaires, filled-in by 15 professionals. RESULTS: Literature stated that the GA introduction could lead to a higher number of individuals achieving therapeutic success after 3 months of therapy (97.0% vs 71.6% without GA). From an economic point of view, considering a projection of 1,955,447 T2DM insulin-naïve individuals, potentially treated with oral therapy, GA introduction would imply fewer individuals requiring a therapy switch (-89.44%), with a 1.06% in costs reduction, on annual basis, thus being also the preferable solution from a cost-effectiveness perspective (cost-effectiveness value: 237.74 vs 325.53). According to experts opinions, lower perceptions on GA emerged with regard to equity aspects (0.13 vs 0.72, p-value>0.05), whereas it would improve both individuals (2.17 vs 1.33, p-value=0.000) and caregivers quality of life (1.50 vs 0.83, p-value=0.000). Even if in the short term, GA required additional investments in training courses (-0.80 vs 0.10, p-value = 0.036), in the long run, GA could become the preferable technology (0.30 vs 0.01, p-value=0.018) from an organisational perspective. CONCLUSION: Adding GA to traditional glycaemic control instruments could improve the clinical pathway of individuals with T2DM, leading to economic and organisational advantages for both hospitals and National Healthcare Systems.

Pharmacovigilance assessment of the association between Fournier's gangrene and other severe genital adverse events with SGLT-2 inhibitors.

Objective: Sodium glucose cotransporter-2 inhibitors (SGLT2i) exert cardiorenal protection in people with diabetes. By inducing glycosuria, SGLT2i predispose to genital infections. In addition, rare occurrence of Fournier's gangrene (FG) has been reported. We aimed to investigate such association through the U.S. Food and Drug Administration (FDA) adverse event (AE) reporting system (FAERS). Research design and methods: We mined the FAERS up to 2018q3 (before FDA warning about SGLT2i-associated FG) to retrieve reports including FG as an AE and SGLT2i as suspect or concomitant drugs, and calculated proportional reporting ratios (PRR). Results: We retrieved 47 cases of FG and 17 cases of other severe AEs of the genital area associated with SGLT2i. Patients with FG were ~10 years older than those with other severe genital AEs. Overall, 77% occurred in men. Three patients were concomitantly treated with systemic immunosuppressive drugs. Increased reporting frequency emerged for SGLT2i compared with other drugs, with a PRR ranging from 5 to 10. The disproportional reporting of FG with SGLT2i remained robust and consistently significant when restricting to the period when SGLT2i were available, to reports filed for glucose-lowering medications or for drugs with the diabetes indication, and after refining the definition of FG. FG was disproportionally associated with psoriasis and with the combination of immunosuppressants and SGLT2i. Conclusions: Although causality cannot be demonstrated, SGLT2i may predispose to FG and other severe genital AEs. Since the use of SGLT2i is expected to increase significantly, clinicians should be aware of these severe, although rare, AEs and their predisposing factors.

Synergistic interactions among metabolic syndrome components and homeostasis model assessment of insulin resistance in a middle-aged general population over time.

BACKGROUND: Insulin resistance is considered a hallmark feature of the metabolic syndrome, but how metabolic syndrome components and insulin resistance measures interact over time is unclear. The homeostasis model assessment of insulin resistance (HOMA-IR) is a static index of insulin resistance typically used in epidemiological studies. We explored how HOMA-IR is affected by clustering metabolic syndrome components over time in a population of middle-aged, healthy subjects. METHODS: A total of 1757 subjects aged 41.3±7.5 years (39% males) free from diabetes at baseline were followed-up for a median of 5.7 years. At baseline and at the end of observation, we determined metabolic syndrome components and HOMA-IR. RESULTS: Cross-sectionally, HOMA-IR was synergistically increased by clustering of at least two to three metabolic syndrome components as determined at baseline and at study end by departure from additivity. Some combinations of metabolic syndrome components were associated with a significant synergic increase in HOMA-IR, and some combinations of two components entailed a synergistic risk of developing metabolic syndrome. Over time, the average change in HOMA-IR was more than additively affected by change in the number of metabolic syndrome components. Baseline HOMA-IR values were predictive of incident metabolic syndrome independent from age, sex, and each metabolic syndrome component. CONCLUSIONS: We show synergistic interaction between clustering metabolic syndrome components and insulin resistance, estimated by HOMA-IR, cross-sectionally and over time. This more than additive effect explains the incremental value of HOMA-IR in predicting metabolic risk.

Continuous glucose monitoring accuracy results vary between assessment at home and assessment at the clinical research center.

BACKGROUND: Continuous glucose monitoring system (CGMS) accuracy is of critical importance both in delivering therapeutic value and as a component of a closed-loop system. This study aims at assessing the differences between accuracy assessments of CGMS at home and at the clinical research center (CRC). METHODS: Twelve patients with type 1 diabetes used the Dexcom® SEVEN® PLUS (DexCom, Inc.) CGMS for 7 days. Patients performed ≥6 finger pricks [self-measurement of blood glucose (SMBG)] per day while at home. Reference blood glucose measurements were taken during a 24 h CRC admission (YSI 2300 STAT Plus™). Continuous glucose monitoring system data were compared with YSI and SMBG values. Outcome measures included mean absolute relative difference (MARD) and Clarke error grid analysis (CEGA). RESULTS: During CRC admission, the MARD of CGMS vs YSI glucose values was 19.2% (n = 509)--significantly higher than 16.8% at home (n = 611) (p = .004). In the hypoglycemic range, MARD was 23.9% at CRC (n = 26)--not significantly different from 41.6% at home (n = 39) (p = .269). In the hyperglycemic range, CRC MARD at 20.3% (n = 115) was significantly higher than home MARD at 11.2% (n = 118) (p = .001). Clarke error grid analysis showed no significant difference in distribution of data pairs (overall p = .317). CONCLUSIONS: This study illustrates the importance of the setting used when assessing CGMS accuracy. Continuous glucose monitoring system accuracy at home appeared better than at the CRC. This is probably due to the higher sampling rate of reference measurements, feasible only in the CRC. Testing CGMS accuracy in the CRC provides valuable information over and above home testing.