Drug-resistant tuberculosis: a persistent global health concern.

Drug-resistant tuberculosis (TB) is estimated to cause 13% of all antimicrobial resistance-attributable deaths worldwide and is driven by both ongoing resistance acquisition and person-to-person transmission. Poor outcomes are exacerbated by late diagnosis and inadequate access to effective treatment. Advances in rapid molecular testing have recently improved the diagnosis of TB and drug resistance. Next-generation sequencing of Mycobacterium tuberculosis has increased our understanding of genetic resistance mechanisms and can now detect mutations associated with resistance phenotypes. All-oral, shorter drug regimens that can achieve high cure rates of drug-resistant TB within 6-9 months are now available and recommended but have yet to be scaled to global clinical use. Promising regimens for the prevention of drug-resistant TB among high-risk contacts are supported by early clinical trial data but final results are pending. A person-centred approach is crucial in managing drug-resistant TB to reduce the risk of poor treatment outcomes, side effects, stigma and mental health burden associated with the diagnosis. In this Review, we describe current surveillance of drug-resistant TB and the causes, risk factors and determinants of drug resistance as well as the stigma and mental health considerations associated with it. We discuss recent advances in diagnostics and drug-susceptibility testing and outline the progress in developing better treatment and preventive therapies.

Impact of concomitant oral glucose-lowering medications on the success of basal insulin titration in insulin-naïve patients with type 2 diabetes: a systematic analysis.

Basal insulin treatment for type 2 diabetes is usually initiated on a background of oral glucose-lowering medications (OGLM). We wanted to examine the influence of various OGLMs on fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) values achieved after titration. A PubMed literature search retrieved 42 publications (clinical trials introducing basal insulin in 17 433 insulin-naïve patients with type 2 diabetes on a defined background of OGLM) and reporting FPG, HbA1c, target achievement, hypoglycemic events, and insulin doses. 60 individual study arms were grouped by OGLM (combinations) allowed during the titration process: (a) metformin only; (b) sulfonylureas only; (c) metformin and sulfonylureas; or (d) metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors. For all OGLM categories, weighted means and SD were calculated for baseline and end-of-treatment FPG, HbA1c, target achievement, incidence of hypoglycemic events, and insulin doses. Primary end point was a difference in FPG after titration between OGLM categories. Statistics: analysis of variance and post hoc comparisons. Sulfonylureas, alone or in combination with metformin, impair the titration of basal insulin (insulin doses 30%-40% lower, more hypoglycemic episodes), thus leading to poorer final glycemic control (p<0.05 for FPG and HbA1c after titration). Conversely, adding a DPP-4 inhibitor to metformin is superior to metformin alone (p<0.05 for FPG and HbA1c achieved) in patients with type 2 diabetes initiating basal insulin therapy. In conclusion, OGLM are a major determinant of the success of basal insulin therapy. Sulfonylureas impair, while DPP-4 inhibitors (added to metformin) may facilitate the achievement of ambitious fasting glucose targets. PROSPERO registration number CRD42019134821.

Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials.

Some epidemiological data have suggested an elevated risk of acute pancreatitis and pancreatic cancer after exposure to glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors. Recently, such outcomes have been assessed and adjudicated as adverse events of special interest in cardiovascular outcomes studies. We performed a meta-analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in cardiovascular outcomes trials (CVOTs) with GLP-1 receptor agonists and DPP-4 inhibitors. The numbers of cases observed with active drug or placebo (both on a background of standard care) were related to patient-years of observation. Rate ratios and their confidence intervals were calculated for the individual agents as well as for the classes of GLP-1 receptor agonists and DPP-4 inhibitors. Neither data on individual CVOTs of GLP-1 receptor agonists nor their meta-analysis [rate ratio: 1.05 (0.78-1.41)] indicated a significantly elevated risk of acute pancreatitis. All individual DPP-4 inhibitors displayed a non-significant trend towards an increased risk of acute pancreatitis, which was significant in the meta-analysis [1.75 (1.14-2.70); P = 0.01]. Neither GLP-1 receptor agonists nor DPP-4 inhibitors were associated with a significantly elevated or reduced risk of pancreatic cancer or for the totality of all malignant neoplasms. Based on a large database of randomized, placebo-controlled, prospective cardiovascular outcomes studies with GLP-1 receptor agonists and DPP-4 inhibitors, no signal for pancreatic cancer or any malignant neoplasms were detected. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta-analysis of DPP-4 inhibitor CVOTs.

Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors.

Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease.

A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients.

AIMS: To study differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose-lowering medications (OGLM). METHODS: Prospective, randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared. RESULTS: Of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively (Δ -.12%, P < .0001). Basal insulin was more effective in reducing fasting plasma glucose (Δ -1.8 mmol/L, P < .0001). GLP-1 RAs reduced bodyweight more effectively (Δ -3.71 kg; P < .0001). The proportion of patients experiencing hypoglycaemic episodes was 34% lower with GLP-1 RAs ( P < .0001), with a similar trend for severe hypoglycaemia. Systolic blood pressure was lower and heartrate was higher with GLP-1 RAs ( P < .0001). Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better than short-acting GLP-1 RAs in reducing HbA1c and fasting glucose, but were similar regarding bodyweight. CONCLUSIONS: Slightly better glycaemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP-1 RAs.

Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials.

AIM: GLP-1 receptor agonists (RAs) may cause nausea, vomiting or diarrhoea. The aim of this study was to assess the risk of adverse events (AEs) with GLP-1 RAs and their relation to dose, background medication and duration of action. RESEARCH DESIGN AND METHODS: The PubMed database was searched and 32 clinical trials with GLP-1 RAs (phase 3) were selected. We performed a systematic analysis and compared the proportion of patients reporting nausea, vomiting or diarrhoea, for different doses and glucose-lowering background medications, and relative to a reference compound within the subclasses of short- (exenatide b.i.d.) and long-acting (liraglutide) GLP-1 RAs, calculating the relative risks ± 95% confidence intervals. RESULTS: The risk of nausea was dose-dependent for long-acting (P = .0063) and across all GLP-1 RAs (P = .0017), and a similar trend was observed for vomiting (P = .23). Diarrhoea was dose-dependent (P = .031). Background treatment with metformin was associated with more nausea (P = .04) and vomiting (P = .0009). Compared to exenatide b.i.d., there was less nausea and diarrhoea with lixisenatide. Compared to liraglutide, there was a similar risk associated with dulaglutide, and less with exenatide q.w. and albiglutide. Long-acting GLP-1 RAs were associated with less nausea and vomiting, but with more diarrhoea than short-acting agents. CONCLUSIONS: GLP-1 RAs are associated with gastrointestinal AEs that are related to dose and background medications (especially metformin) and may vary in a compound-specific manner. Long-acting agents are associated with less nausea and vomiting but with more diarrhoea.