Context Pembrolizumab (Keytruda) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAE) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases. Evidence Acquisition Systematic search of 4 databases (Medline, Embase, Web of Science and Cochrane Library) using the search terms “diabetes” or “ketoacidosis” and “pembrolizumab”, “nivolumab”, “PD-1 inhibitor” or “immunotherapy. Included were articles published in English between January 1, 2012 and January 1, 2018. The search was supplemented by bibliographic searches of the complete reference lists of all included papers. Evidence synthesis We provide an overview of all published cases (n=42) of programmed cell death-1 (PD-1) inhibitor induced type 1 diabetes mellitus to date, including a well-characterized novel case of islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA) positive diabetes mellitus, in a patient with a diabetes prone HLA genotype. She presented with diabetic ketoacidosis (DKA) during pembrolizumab therapy for a metastatic uveal melanoma. Furthermore, we discuss potential pathogenic mechanisms, clinical presentation, prognostic markers (beta-cell antibodies, HLA type), a treatment and a screening protocol. Conclusions Since the use of immunotherapy will increase, it is essential that all clinicians are aware of diabetic ketoacidosis as a rare and life-threatening side effect of immunotherapy. Blood glucose monitoring during anti-PD-1 therapy is necessary.

OBJECTIVE In 2016, nationwide reimbursement of intermittently scanned continuous glucose monitoring (isCGM) for people living with type 1 diabetes treated in specialist diabetes centers was introduced in Belgium. We undertook a 12-month prospective observational multicenter real-world study to investigate impact of isCGM on quality of life and glycemic control. RESEARCH DESIGN AND METHODS Between July 2016 and July 2018, 1,913 adults with type 1 diabetes were consecutively recruited in three specialist diabetes centers. Demographic, metabolic, and quality of life data were collected at baseline, 6 months, and 12 months of standardized clinical follow-up. The primary end point was evolution of quality of life from baseline to 12 months. Secondary outcome measures were, among others, change in HbA_1c, time spent in different glycemic ranges, occurrence of acute diabetes complications, and work absenteeism. RESULTS General and diabetes-specific quality of life was high at baseline and remained stable, whereas treatment satisfaction improved (P < 0.0001). Admissions for severe hypoglycemia and/or ketoacidosis were rare in the year before study (n = 63 out of 1,913; 3.3%), but decreased further to 2.2% (n = 37 out of 1,711; P = 0.031). During the study, fewer people reported severe hypoglycemic events (n = 280 out of 1,913 [14.6%] vs. n = 134 out of 1,711 [7.8%]; P < 0.0001) or hypoglycemic comas (n = 52 out of 1,913 [2.7%] vs. n = 18 out of 1,711 [1.1%]; P = 0.001) while maintaining HbA_1c levels. Fewer people were absent from work (n = 111 out of 1,913 [5.8%] vs. n = 49 out of 1,711 [2.9%]; P < 0.0001). Time spent in hypoglycemia significantly decreased in parallel with less time in range and more time in hyperglycemia. Eleven percent (n = 210) of participants experienced skin reactions, leading to stopping of isCGM in 22 participants (1%). CONCLUSIONS Nationwide unrestricted reimbursement of isCGM in people with type 1 diabetes treated in specialist diabetes centers results in higher treatment satisfaction, less severe hypoglycemia, and less work absenteeism, while maintaining quality of life and HbA_1c.

Context: Autoimmune gastritis and pernicious anemia are common autoimmune disorders, being present in up to 2% of the general population. In patients with type 1 diabetes or autoimmune thyroid disease, the prevalence is 3- to 5-fold increased. This review addresses the epidemiology, pathogenesis, diagnosis, clinical consequences, and management of autoimmune gastritis in type 1 diabetic patients. Synthesis: Autoimmune gastritis is characterized by: 1) atrophy of the corpus and fundus; 2) autoantibodies to the parietal cell and to intrinsic factor; 3) achlorhydria; 4) iron deficiency anemia; 5) hypergastrinemia; 6) pernicious anemia may result from vitamin B12 deficiency; and 7) in up to 10% of patients, autoimmune gastritis may predispose to gastric carcinoid tumors or adenocarcinomas. This provides a strong rationale for screening, early diagnosis, and treatment. The management of patients with autoimmune gastritis implies yearly determination of gastrin, iron, vitamin B12 levels, and a complete blood count. Iron or vitamin B12 should be supplemented in patients with iron deficiency or pernicious anemia. Whether regular gastroscopic surveillance, including biopsies, is needed in patients with autoimmune gastritis/pernicious anemia is controversial. The gastric carcinoids that occur in these patients generally do not pose a great threat to life, whereas the danger of developing carcinoma is controversial. Nevertheless, awaiting a consensus statement, we suggest performing gastroscopy and biopsy at least once in patients with autoantibodies to the parietal cell, iron-, or vitamin B12-deficiency anemia, or high gastrin levels. Conclusion: The high prevalence of autoimmune gastritis in type 1 diabetic patients and its possible adverse impact on the health of the patient provide a strong rationale for screening, early diagnosis, periodic surveillance by gastroscopy, and treatment.

Glucose management in intensive care unit (ICU) patients has been a matter of debate for almost two decades. Compared to intermittent monitoring systems, continuous glucose monitoring (CGM) can offer benefit in the prevention of severe hyperglycemia and hypoglycemia by enabling insulin infusions to be adjusted more rapidly and potentially more accurately because trends in glucose concentrations can be more readily identified. Increasingly, it is apparent that a single glucose target/range may not be optimal for all patients at all times and, as with many other aspects of critical care patient management, a personalized approach to glucose control may be more appropriate. Here we consider some of the evidence supporting different glucose targets in various groups of patients, focusing on those with and without diabetes and neurological ICU patients. We also discuss some of the reasons why, despite evidence of benefit, CGM devices are still not widely employed in the ICU and propose areas of research needed to help move CGM from the research arena to routine clinical use.

There is an unmet need for non-invasive tests to improve case-finding and aid primary care professionals in referring patients at high risk of liver disease. A metabolic dysfunction-associated fibrosis (MAF-5) score was developed and externally validated in a total of 21,797 individuals with metabolic dysfunction, in population-based (NHANES2017-2020, NHANESIII, Rotterdam Study) as well as hospital-based cohorts (from Antwerp and Bogota). Fibrosis was defined as liver stiffness (LSM)≥8.0kPa. Diagnostic accuracy was compared to FIB-4, NFS and SAFE. MAF-5 was externally validated with LSM≥8.0kPa, with shear-wave elastography (SWE≥7.5 kPa) and biopsy-proven steatotic liver disease according to METAVIR and NASH-CRN scores, and was tested for prognostic performance (all-cause mortality). The MAF-5 score comprised waist circumference, BMI, diabetes, AST and platelets. With this score, 60.9% was predicted at low, 14.1% at intermediate and 24.9% at high risk of fibrosis. The observed prevalence was 3.3%, 7.9% and 28.1%, respectively. The AUROC of MAF-5 (0.81) was significantly higher than FIB-4 (0.61), and outperformed the FIB-4 among the young (NPV 99% [AUC 0.86] versus 94% [AUC 0.51]) and elderly (NPV 94% [AUC 0.75] versus 88% [AUC 0.55]). MAF-5 showed excellent performance to detect LSM≥12kPa (AUC 0.86 training, AUC 0.85 validation) and good performance in detecting liver stiffness and biopsy-proven liver fibrosis among the external validation cohorts. MAF-5 score>1 was associated with increased risk of all-cause mortality in (un)adjusted models (aHR:1.59, 95%CI:1.47-1.73). The MAF-5 score is a validated, age-independent, inexpensive referral tool to identify individuals at high risk of liver fibrosis and all-cause mortality in primary care populations, using simple variables.

Tirzepatide is a novel glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide 1 (GLP‐1) receptor agonist approved in the United States as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes and under investigation for use in chronic weight management, major adverse cardiovascular events and the management of other conditions, including heart failure with preserved ejection fraction and obesity and non‐cirrhotic non‐alcoholic steatohepatitis. The Phase 3 SURPASS 1‐5 clinical trial programme was designed to assess efficacy and safety of once‐weekly subcutaneously injected tirzepatide (5, 10 and 15 mg), as monotherapy or combination therapy, across a broad spectrum of people with type 2 diabetes. Use of tirzepatide in clinical studies was associated with marked reductions of glycated haemoglobin (−1.87 to −2.59%, −20 to −28 mmol/mol) and body weight (−6.2 to −12.9 kg), as well as reductions in parameters commonly associated with heightened cardiometabolic risk such as blood pressure, visceral adiposity and circulating triglycerides. In SUPRASS‐2, these reductions were greater than with the GLP‐1 receptor agonist semaglutide 1 mg. Tirzepatide was well tolerated, with a low risk of hypoglycaemia when used without insulin or insulin secretagogues and showed a generally similar safety profile to the GLP‐1 receptor agonist class. Accordingly, evidence from these clinical trials suggests that tirzepatide offers a new opportunity for the effective lowering of glycated haemoglobin and body weight in adults with type 2 diabetes.