Novel Dual Incretin Receptor Agonists in the Spectrum of Metabolic Diseases with a Focus on Tirzepatide: Real Game-Changers or Great Expectations? A Narrative Review.

The prevalence of metabolic diseases including type 2 diabetes (T2D), obesity and non-alcoholic fatty liver disease (NAFLD) increases globally. This highlights an unmet need for identifying optimal therapies for the management of these conditions. Tirzepatide is a novel dual incretin receptor agonist (twincretin) that activates both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. The aim of this narrative review was to examine the impact of novel twincretins, focusing on tirzepatide, on the management of a wide spectrum of metabolic diseases. Data from preclinical and clinical trials have shown that twincretins significantly reduce blood glucose levels in T2D, and tirzepatide is the first agent of this class that has been approved for the management of T2D. Additionally, the beneficial impact of tirzepatide on weight reduction has been corroborated in several studies, showing that this agent can achieve substantial and sustained weight loss in obese patients with or without T2D. Data also suggest that tirzepatide could be a promising drug for hepatic steatosis reduction in individuals with NAFLD. The remarkable effects of tirzepatide on glycaemic control, weight loss and liver-related outcomes have posed new research questions that are likely to lead to further advancements in the treatment of T2D, obesity and related metabolic disorders.

Impact of Glucagon-like peptide 1 receptor agonists on peripheral arterial disease in people with diabetes mellitus: A narrative review.

Peripheral arterial disease (PAD) is a common macrovascular complication of diabetes mellitus (DM). Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are among the latest class of antidiabetic medications that stimulate insulin synthesis and secretion and have been used for the management of type 2 DM. Apart from the effect on glycaemic control, GLP-1RAs also have a robust impact on weight reduction and have shown favorable effects on cardiovascular morbidity and mortality in cardiovascular outcome trials (CVOTs). The aim of this review was to examine the impact of GLP1-RAs on PAD among people with DM based on CVOTs, randomized controlled trials, observational studies as well as systematic reviews and meta-analyses. Data from retrospective studies and meta-analyses have shown superiority of these agents in comparison with other antidiabetic medications such as sodium-glucose cotransporter type 2 inhibitors and dipeptidyl peptidase-4 inhibitors in terms of PAD-related events. Nevertheless, data from CVOTs regarding the impact of GLP-1RAs on PAD are scarce and hence, safe conclusions regarding their effects cannot be drawn. Further prospective studies are needed to examine the impact of GLP-1RAs on PAD-related incidents including major adverse limb events, lower limb amputations and revascularization procedures.

Real-world evaluation of glucose-lowering therapies and the use of weight-adjusted variable rate intravenous insulin infusion in the management of hyperglycaemia in patients with acute coronary syndrome (REGULATE-ACS).

INTRODUCTION: Admission hyperglycaemia in acute coronary syndromes (ACS) is a strong independent predictor of adverse clinical outcomes post-ACS. We examined the safety, efficacy, and feasibility of a modified, weight-adjusted variable rate intravenous insulin infusion (VRIII) and evaluated current practice of prescribing novel cardio-protective glucose-lowering therapies in patients presenting with acute hyperglycaemia across the ACS spectrum. METHODS: REGULATE-ACS was an observational single-centre study of consecutive patients admitted with acute hyperglycaemia post-ACS between 2020 and 2021. Following updated local guidance on a modified VRIII, we evaluated its safety and efficacy in glycaemic control, cardio-metabolic complications including hypoglycaemia (blood glucose <3 mmol/L) and 30-day mortality. We also determined the prescription of glucose-lowering therapies pre-discharge. RESULTS: Out of 107 patients, mean age was 64.9 ± 12.2 years, 82% had known diabetes, and 15% newly diagnosed diabetes. 86.9% (n = 93) had an admission glucose ≥11 mmol/L. In patients treated with VRIII (n = 63/93, 67.7%), glucose improved from 17.5 to 9.0 mmol/L (IQR 7.1-12.1), which was 3 mmol/L lower (p = 0.03) than in patients not treated with VRIII (n = 30/93, 32.3%) where median glucose reduced from 12.6 to 12 mmol/L (IQR 8.6-13.9). No significant hypoglycaemia, arrhythmia or worsening pulmonary oedema associated with VRIII was found. Novel glucose-lowering therapies were initiated in 20/71 (28.2%) and 3/15 (20.0%) of patients with prior and newly diagnosed diabetes, respectively. CONCLUSION: This real-world analysis provides further support of efficacy, safety, and feasibility of a modified, weight-adjusted VRIII in managing acute hyperglycaemia in ACS. Despite established cardio-protective benefits of novel glucose-lowering therapies, <1/3 of eligible patients received such agents pre-discharge, demanding further research and awareness.

Implementation of a Digital Health Tool for Patients Awaiting Input From a Specialist Weight Management Team: Observational Study.

BACKGROUND: Digital tools are increasingly used on a population level as a weight loss strategy for people living with overweight and obesity. Evidence supports the feasibility of digital tools for the management of obesity in a community setting, but there is only emerging evidence for the feasibility of such tools in specialist weight management services. No study has assessed the uptake of digital tools among patients awaiting their first appointment with a specialist weight management service. OBJECTIVE: The objective of this study was to understand interest, acceptance, and engagement with a digital behavioral change platform to support specialist weight management. METHODS: This was an observational study registered as a service innovation. All patients on the waiting list for a first appointment in the tier 3 weight management service at University Hospitals Coventry and Warwickshire National Health Service (NHS) Trust were eligible to access the NHS-approved digital tool. Data on interest and engagement with the digital tool were collected. Routine clinical data were used to describe patient demographics. Focus groups were held to explore patients' views on the use of digital tools as part of a specialist weight management service. RESULTS: A total of 199 patients on the waiting list were informed about the available digital tool. Just over a half (n=102, 51.3%) of patients were interested in using the app, with over one-third (n=68, 34%) of all patients engaging with the app. Overall, a third of patients on the waiting list (n=63, 32%) did not respond to the invite and 34 (17%) of patients expressed no interest in the app. Emotional eating and higher BMI was associated with interest in the Gro Health app. Male gender was associated with reduced engagement with the app. There were no differences in interest in the Gro Health app according to age, ethnicity, metabolic measures of glycemia, and lipid profile. CONCLUSIONS: It is feasible to offer digital tools such as Gro Health to patients awaiting their first appointment with specialist weight management services. Future research should explore barriers and facilitators of engagement with digital tools. Additionally, there is a need to further evaluate the effectiveness of such tools in specialist weight management services.

Delayed onset of neurogenic pulmonary oedema following an evolving ischaemic stroke.

Any insult to the central nervous system can lead to the rare occurrence of neurogenic pulmonary oedema (NPO). It is usually associated with significant neurological injury (eg, subarachnoid haemorrhage or traumatic brain injury) with a relatively rapid onset. As an exception to this observation, we report a middle-aged woman who developed NPO 72 hours after the onset of a subtle but evolving right middle cerebral artery infarction confirmed on CT. Aggressive use of diuretics and vasodilators, as is normally the case for cardiogenic pulmonary oedema, can compromise cerebral blood flow and the ischaemic penumbra. This case illustrates how the diagnostic and therapeutic challenges were successfully addressed with the aid of bedside ultrasonography and close haemodynamic monitoring to reverse the respiratory failure while protecting the brain.

Late maternal diagnosis of DiGeorge syndrome with congenital hypoparathyroidism following antenatal detection of the same 22q11.2 microdeletion syndrome in the fetus.

Genetic causes of hypocalcaemia can be overlooked in patients who present without apparent syndromic features. One relatively common but under-recognised genetic disorder is DiGeorge syndrome, which is often diagnosed in childhood but rarely in adulthood. Its enigmatic diagnosis can be attributed to its broad heterogeneous clinical presentation, such as the absence of cardiac abnormalities with only subtly abnormal facies. The presence of hypoparathyroidism-related hypocalcaemia may be the first early sign. We describe a young female adult with childhood-onset hypocalcaemia who was diagnosed with DiGeorge syndrome during her pregnancy when the fetus was found to have the same condition on antenatal screening and autopsy. This case reminds clinicians to consider the genetic causes of hypoparathyroidism-induced hypocalcaemia early on in childhood, while acknowledging the possibility of a late diagnosis in adulthood. We also highlight the risks of severe hypocalcaemia in pregnancy and outline a systematic approach to the evaluation of chronic hypocalcaemia.

Linezolid: a Promising Agent for the Treatment of Multiple and Extensively Drug-Resistant Tuberculosis.

Tuberculosis is a severe, infectious disease caused by Mycobacterium tuberculosis. The aim of this review was to present the efficacy of linezolid as an agent against multidrug and extensively drug-resistant tuberculosis as gathered from many recent research studies. Linezolid seems to have strongly the potential of being used as an anti-tuberculosis agent because it blocks bacterial ribosomal protein synthesis. Nevertheless caution is required because of the adverse effects it causes, especially when the linezolid daily dosage exceeds 600 mg. The most severe adverse effects include anemia, peripheral neuropathy, optic neuropathy and thrombocytopenia. Still, more trials and research need to be done in order to gather more information and value the cost-benefit dosage of the treatment.