Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial.

BACKGROUND: This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes. METHODS: This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated haemoglobin 7-10% (53-86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants. FINDINGS: From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was -9·6% (SE 0·4) with semaglutide 2·4 mg vs -3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was -6·2 percentage points (95% CI -7·3 to -5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo. INTERPRETATION: In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo. FUNDING: Novo Nordisk.

An indirect treatment comparison of the efficacy of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg.

AIM: To compare the effects of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg on HbA1c and body weight in patients with type 2 diabetes. MATERIALS AND METHODS: A Bucher indirect comparison was conducted to compare efficacy outcomes of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg using published results from the SUSTAIN 7 and AWARD-11 trials. Sensitivity analyses using individual patient data from SUSTAIN 7 and aggregate data from AWARD-11 were conducted to explore the impact of adjustment for cross-trial imbalances in baseline characteristics. RESULTS: Semaglutide 1.0 mg significantly reduced HbA1c versus dulaglutide 3.0 mg, with an estimated treatment difference (ETD) of -0.24%-points (95% confidence interval [CI] -0.43, -0.05), with comparable reductions in HbA1c versus dulaglutide 4.5 mg with an ETD of -0.07%-points (95% CI -0.26, 0.12). Semaglutide 1.0 mg significantly reduced body weight versus dulaglutide 3.0 and 4.5 mg with an ETD of -2.65 kg (95% CI -3.57, -1.73) and -1.95 kg (95% CI -2.87, -1.03), respectively. Sensitivity analyses supported the primary analysis findings. CONCLUSIONS: This indirect comparison showed significantly greater reductions in HbA1c with semaglutide 1.0 mg versus dulaglutide 3.0 mg and comparable HbA1c reductions versus dulaglutide 4.5 mg. Semaglutide 1.0 mg significantly reduced body weight versus both dulaglutide 3.0 and 4.5 mg. With several glucagon-like peptide-1 receptor agonists available, information regarding their comparative efficacy can be valuable to clinicians.

Low cholesterol syndrome and drug development.

PURPOSE OF REVIEW: Low cholesterol syndromes were considered curiosities. The present article reviews some hypolipidaemic disorders and the drugs developed from the insights they provided. RECENT FINDINGS: Abetalipopoproteinaemia and hypobetalipoproteinaemia are associated with low cholesterol concentrations and caused by mutations in apolipoprotein (apo) B or microsomal transfer protein. This led to the development of mipomersen and lomitapide which are used to treat homozygous familial hypercholesterolaemia. Mutations in proprotein convertase subtilisin kexin-9 (PCSK9) can cause either high or low cholesterol. Loss of function PCSK9 mutations prompted the development of antibody therapies to PCSK9 which are now widely used to treat hypercholesterolaemia. Mutations in apolipoprotein C-3 and angiopoietin-like protein 3 (ANGPTL3) cause hypolipoproteinaemia and reduced triglycerides. Antisense therapies to apolipoprotein C-3 and antibodies to ANGPTL3 are in development to treat familial chylomicronaemia syndrome. Activating mutations in apoA-1 result in hyper-functioning high-density lipoprotein (HDL) and suggest that modifying HDL turnover may reduce cardiovascular disease (CVD) risk. SUMMARY: Orphan lipid disorders have provided insights into mechanisms involved in lowering cholesterol levels and the potential safety and efficacy of interventional processes. They have been not only enabled development of drugs to treat rare lipid disorders but also those finding wider use in general lowering of CVD risk.

Evaluation of the long-term cost-effectiveness of once-weekly semaglutide versus dulaglutide for treatment of type 2 diabetes mellitus in the UK.

AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists are appealing as glucose-lowering therapy for individuals with type 2 diabetes mellitus (T2DM) as they also reduce body weight and are associated with low rates of hypoglycaemia. This analysis assessed the long-term cost-effectiveness of semaglutide 0.5 and 1 mg vs dulaglutide 1.5 mg (two once-weekly GLP-1 receptor agonists) from a UK healthcare payer perspective, based on the head-to-head SUSTAIN 7 trial, to inform healthcare decision making. MATERIALS AND METHODS: Long-term outcomes were projected using the IQVIA CORE Diabetes Model (version 9.0). Baseline cohort characteristics, changes in physiological parameters and adverse event rates were derived from the 40-week SUSTAIN 7 trial. Costs to a healthcare payer were assessed, and these captured pharmacy costs and costs of complications. Utilities were taken from published sources. RESULTS: Once-weekly semaglutide 0.5 and 1 mg were associated with improvements in quality-adjusted life expectancy of 0.04 and 0.10 quality-adjusted life years, respectively, compared with dulaglutide 1.5 mg. Clinical benefits were achieved at reduced costs, with lifetime cost savings of GBP 35 with once-weekly semaglutide 0.5 mg and GBP 106 with the once-weekly semaglutide 1 mg, resulting from fewer diabetes-related complications due to better glycaemic control. Therefore, both doses of once-weekly semaglutide were considered dominant vs dulaglutide 1.5 mg (improving outcomes and reducing costs). CONCLUSIONS: Compared with treatment with dulaglutide, once-weekly semaglutide represents a cost-effective option for treating individuals in the UK with T2DM who are not achieving glycaemic control with metformin, projected to both improve clinical outcomes and reduce costs.

IDegLira improves patient-reported outcomes while using a simple regimen with fewer injections and dose adjustments compared with basal-bolus therapy.

AIMS: Basal-bolus therapy is associated with greater treatment burden and lower adherence compared with more simplified regimens. This post hoc analysis studied the difference between insulin degludec/liraglutide (IDegLira) and basal-bolus therapy on number of injections, dose adjustments and patient outcomes in the DUAL VII trial. MATERIALS AND METHODS: DUAL VII was a 26-week, open-label trial in which patients with uncontrolled type 2 diabetes who were using metformin and insulin glargine 100 units/mL (20-50 U) were randomized 1:1 to IDegLira (N = 252) or basal-bolus (insulin glargine U100 + insulin aspart ≤4 times/day) (N = 254). This post hoc analysis reports the observed mean number of injections and cumulative dose adjustments during 26 weeks of treatment. Patient-reported outcomes (Treatment-Related Impact Measure - Diabetes [TRIM-D] and Short Form-36 Health Survey version 2 [SF-36v2]) were collected at scheduled visits and change from baseline scores calculated. RESULTS: The clinical benefits (non-inferior HbA1c reductions, weight benefit, less hypoglycaemia) of IDegLira vs basal-bolus therapy were achieved with fewer cumulative dose adjustments (16.6 vs 217.2, respectively) and fewer injections (1 vs ≥3 per day, respectively). Patients treated with IDegLira experienced significant improvements across all TRIM-D domains compared with those undergoing basal-bolus therapy. The SF-36v2 showed improvements in both treatment arms with no significant difference between arms in the physical component summary, but there was a significant improvement in patients treated with IDegLira in the mental component summary (P = .0228). CONCLUSIONS: These findings, combined with the DUAL VII results, suggest that IDegLira, through a more simplified regimen versus basal-bolus therapy, may help improve patient adherence and improve patient outcomes related to diabetes management, treatment burden and mental health, which in turn may assist in the timely achievement of glycaemic control in clinical practice.

An update on trials of novel lipid-lowering drugs.

PURPOSE OF REVIEW: A number of novel trials have assessed the efficacy of new lipid-lowering therapies in cardiovascular disease (CVD). RECENT FINDINGS: Proprotein convertase subtilisin kexin-9 inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 50-55%. A CVD outcome trial in patients with acute coronary syndromes with evolocumab achieved a LDL-C of 0.8 mmol/l (31 mg/dl) and a 20% relative risk reduction in CVD events in 2.2 years. Cholesterol ester transfer protein inhibitors raise high-density lipoprotein cholesterol and can lower LDL-C. Anacetrapib reduced coronary artery disease events by 7%, but not wider composite CVD outcomes, in a population with chronic CVD with pretreatment LDL-C of 1.6 mmol/l (62 mg/dl). The conflicting outcomes of cholesterol ester transfer protein inhibitor trials means these compounds are not being developed further. Trials using lipid drugs targeting inflammation have previously been generally unsuccessful, but recent data on the interleukin-1B receptor antagonist canakinumab has proven the concept of intervention on inflammation in atherosclerosis by showing a reduction in acute coronary interventions, but at the predictable cost of increased infections. SUMMARY: Despite the success of proprotein convertase subtilisin kexin-9 inhibition, the ability to achieve low LDL-C with off-patent medications and the costs of novel therapies will limit their use even in high-risk patients and confine them to the highest-risk sub-groups of patients.

Review of referral criteria to lipid clinics and outcomes of treatment in four UK centres.

BACKGROUND: Little data exist on the referral patterns and effectiveness of lipid clinics. METHODS: An audit was conducted in four clinics of 100 consecutive referrals each. Data were recorded on referral criteria, cardiovascular disease (CVD) risk factors, drug history, investigations, diagnoses, therapies, results and referrals. RESULTS: Patients were aged 56 ± 14 years, 47% were male and 87% were primary prevention. Risk factors included smoking (16%), type 2 diabetes (13%) and hypertension (13%). Referrals were made for hypercholesterolaemia (68%), diagnosis of FH (31%), statin intolerance (23%) and hypertriglyceridaemia (23%). Initial total cholesterol (TC) was 7.65 ± 2.64 mmol/L, triglycerides (TG) 2.17 (0.41-76.9 mmol/L) mmol/L, HDL-C 1.53 ± 0.71 mmol/L, LDL-C 4.57 ± 1.66 mmol/L with non-HDL-C 5.90 ± 2.09 mmol/L. Criteria for FH were met in 21% with genetic testing in 13% and lipid cascade testing in 30% of index cases. Triglycerides >20 mmol/L were present in 4%. The diagnosis was changed in 21%: hypercholesterolaemia (7%), mixed hyperlipidaemia (7%) and hypertriglyceridaemia (7%). Hepatic steatosis was identified in 14.5%. Lipoprotein(a) levels >125 nmol/L occurred in 41% in one clinic. Therapy changes included altered statins (40%), addition of a fibrate (11%) or ezetimibe (8%). These reduced TC by 1.92 mmol/L (19%; P = 0.0001), LDL-C 1.07 mmol/L (15%; P = 0.02), non-HDL-C 1.50 mmol/L (16%; P < 0.001), and TG 2.3 (-4 to 38) mmol/L (16%; P < 0.001) with 11% extra achieving TG <5 mmol/L while HDL-C increased by 7% (P = 0.37). CONCLUSIONS: Lipid clinics have diverse functions including diagnosis of FH, managing severe hypercholesterolaemia, mixed hyperlipidaemia and statin intolerance. Effectiveness criteria of average reductions of 1.5 mmol/L in TC or non-HDL-C, 1 mmol/L in LDL-C and 2 mmol/L in TG would be reasonable for newly referred patients.

Predicting residual kidney function in hemodialysis patients using serum ß-trace protein and ß2-microglobulin.

Residual kidney function (RKF) contributes significant solute clearance in hemodialysis patients. Kidney Diseases Outcomes Quality Initiative (KDOQI) guidelines suggest that hemodialysis dose can be safely reduced in those with residual urea clearance (KRU) of 2 ml/min/1.73 m(2) or more. However, serial measurement of RKF is cumbersome and requires regular interdialytic urine collections. Simpler methods for assessing RKF are needed. ß-trace protein (ßTP) and ß2-microglobulin (ß2M) have been proposed as alternative markers of RKF. We derived predictive equations to estimate glomerular filtration rate (GFR) and KRU based on serum ßTP and ß2M from 191 hemodialysis patients based on standard measurements of KRU and GFR (mean of urea and creatinine clearances) using interdialytic urine collections. These modeled equations were tested in a separate validation cohort of 40 patients. A prediction equation for GFR that includes both ßTP and ß2M provided a better estimate than either alone and contained the terms 1/ßTP, 1/ß2M, 1/serum creatinine, and a factor for gender. The equation for KRU contained the terms 1/ßTP, 1/ß2M, and a factor for ethnicity. Mean bias between predicted and measured GFR was 0.63 ml/min and 0.50 ml/min for KRU. There was substantial agreement between predicted and measured KRU at a cut-off level of 2 ml/min/1.73 m(2). Thus, equations involving ßTP and ß2M provide reasonable estimates of RKF and could potentially be used to identify those with KRU of 2 ml/min/1.73 m(2) or more to follow the KDOQI incremental hemodialysis algorithm.

Hb Kalavasos [HBA2: c.275T > A; p.Leu92His]: a Novel α Chain Hemoglobin Variant.

We present a case of a novel pathogenic variant, Hb Kalavasos [α91(FG3)Leu→His (α2); HBA2: c.275T > A; p.Leu92His (NM_000517.4)]; this codon was previously numbered 91 on the α2-globin gene that was discovered following routine Hb A1c testing on a 65-year-old female of Cypriot origin. The band, seen by high performance liquid chromatography (HPLC) but not capillary zone electrophoresis (CZE), was confirmed as a hitherto undescribed a chain variant, that we have named Hb Kalavasos for the Cypriot village of family origin of the proband.

Renal biomarkers for the prediction of cardiovascular disease.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is a well-known risk factor for cardiovascular disease (CVD). Renal biomarkers might be valuable in predicting CVD. Investigation of these biomarkers may uncover some of the poorly understood mechanisms that link renal and CVD as well as aid in the modification of disease and serve as a useful tool in diagnosing early disease and monitoring therapeutic responses. In this review we discuss the clinical utility of emerging and known renal biomarkers in predicting CVD. RECENT FINDINGS: Prior to adopting a biomarker into routine clinical practice, evidence-based laboratory medicine requires optimal technical and analytical performance, which is a prerequisite to have confidence in the result. Furthermore, an ideal biomarker should have evidence of its utility in predicting clinical, therapeutic and other health outcomes as well as proving its organizational impact and cost-effectiveness. The renal biomarkers that have been associated with CVD include cystatin C as a better marker of glomerular filtration than creatinine, albuminuria, neutrophil gelatinase associated lipocalin, a marker of acute kidney injury, fibroblast growth factor-23 and parathyroid hormone. Only urine albumin has been adopted into routine clinical practice. SUMMARY: Of all the renal biomarkers, only albumin is clearly associated with CVD. The other biomarkers are earlier in clinical development and the evidence base for their clinical utility needs to be expanded substantially before they can be adopted into routine practice.

The Road towards Triple Agonists: Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide and Glucagon Receptor - An Update.

Obesity is the fifth leading risk factor for global deaths with numbers continuing to increase worldwide. In the last 20 years, the emergence of pharmacological treatments for obesity based on gastrointestinal hormones has transformed the therapeutic landscape. The successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, followed by the synergistic combined effect of glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists achieved remarkable weight loss and glycemic control in those with the diseases of obesity and type 2 diabetes. The multiple cardiometabolic benefits include improving glycemic control, lipid profiles, blood pressure, inflammation, and hepatic steatosis. The 2023 phase 2 double-blind, randomized controlled trial evaluating a GLP-1/GIP/glucagon receptor triagonist (retatrutide) in patients with the disease of obesity reported 24.2% weight loss at 48 weeks with 12 mg retatrutide. This review evaluates the current available evidence for GLP-1 receptor agonists, dual GLP-1/GIP receptor co-agonists with a focus on GLP-1/GIP/glucagon receptor triagonists and discusses the potential future benefits and research directions.

Lipid clinic experience with bempedoic acid in three UK centres.

OBJECTIVE: Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. METHODS: This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres - a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. RESULTS: The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 = .33) was predicted by baseline LDL-C (ß = .54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (ß = 1.60; p = .009) was a contributing factor to discontinuation. CONCLUSION: This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals.

SGLT2 Inhibitors - The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review.

A substantial evidence base supports the use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in the treatment of type 2 diabetes mellitus (T2DM). This class of medicines has demonstrated important benefits that extend beyond glucose-lowering efficacy to protective mechanisms capable of slowing or preventing the onset of long-term cardiovascular, renal and metabolic (CVRM) complications, making their use highly applicable for organ protection and the maintenance of long-term health outcomes. SGLT2is have shown cost-effectiveness in T2DM management and economic savings over other glucose-lowering therapies due to reduced incidence of cardiovascular and renal events. National and international guidelines advocate SGLT2i use early in the T2DM management pathway, based upon a plethora of supporting data from large-scale cardiovascular outcome trials, renal outcomes trials and real-world studies. While most people with T2DM would benefit from CVRM protection through SGLT2i use, prescribing hesitancy remains, potentially due to confusion concerning their place in the complex therapeutic paradigm, variation in licensed indications or safety perceptions/misunderstandings associated with historical data that have since been superseded by robust clinical evidence and long-term pharmacovigilance reporting. This latest narrative review developed by the Improving Diabetes Steering Committee (IDSC) outlines the place of SGLT2is within current evidence-informed guidelines, examines their potential as the standard of care for the majority of newly diagnosed people with T2DM and sets into context the perceived risks and proven advantages of SGLT2is in terms of sustained health outcomes. The authors discuss the cost-effectiveness case for SGLT2is and provide user-friendly tools to support healthcare professionals in the correct application of these medicines in T2DM management. The previously published IDSC SGLT2i Prescribing Tool for T2DM Management has undergone updates and reformatting and is now available as a Decision Tool in an interactive pdf format as well as an abbreviated printable A4 poster/wall chart.

New therapies to reduce low-density lipoprotein cholesterol.

PURPOSE OF REVIEW: Lipid-lowering is an intervention that reduces atherosclerosis and its complications. Statins currently form the standard of care but are not able to reduce low-density lipoprotein cholesterol (LDL-C) adequately in all patients - particularly those with familial hypercholesterolaemia and those with statin intolerance. RECENT FINDINGS: Combination therapy with statins is well established and ezetimibe is often used as an additional LDL-C-lowering agent reducing LDL-C by 20%. However, its clinical efficacy still remains controversial. Newer, more potent methods of LDL-C reduction are in development. Both lomitapide, a microsomal transfer protein inhibitor (MTPI), and mipomersen, an antisense oligonucleotide (ASO), have been shown to improve LDL-C levels by 25-50% in patients with homozygous familial hypercholesterolaemia. In patients with heterozygous familial hypercholesterolaemia or statin intolerance antibody-based inhibitors of preprotein convertase subtilisin/kexin 9 (PCSK9) produce reductions in LDL-C of 30-65%. Cholesterol ester transfer protein inhibitors (CETPIs) reduce LDL-C by 30-40% as well as raising levels of high-density lipoprotein cholesterol (HDL-C) and may also have a role as additional LDL-C-reducing drugs. SUMMARY: Surrogate outcome trials will be required with lomitapide or mipomersen to confirm their effects in homozygous familial hypercholesterolaemia and clinical endpoint trials will be needed for PCSK9 and CETPIs if these are to be used widely.

Vitamin D and cardiovascular disease - dilemma, delight or 'dont know?'.

The current lack of sufficient evidence of vitamin D's role in CVD calls for perspective and caution to avoid that health claims, vitamin D testing and supplementations' sales will continue to run well ahead of the scientific evidence.

The need for combination drug therapies in patients with complex dyslipidemia.

Statins are first line therapy for the prevention of cardiovascular disease (CVD). Only 30 %-70 % of high risk patients will attain standard low-density lipoprotein cholesterol targets. Patients with familial hypercholesterolemia and genetic mixed hyperlipidemias do not meet goals with standard therapy. Patients with mixed hyperlipidemia secondary to the metabolic syndrome, diabetes, renal, or HIV infection are at high residual risk due to low HDL-cholesterol or high triglycerides. Newer therapies can be added to statins. The use of ezetimibe has CVD outcomes evidence in chronic renal disease. Adding omega-3 fatty acids, fibrates, or niacin to statins has failed to show any benefit except possibly with fibrates in patients with diabetes and low HDL-C/high triglycerides. Additional benefits on lipid profiles have been shown with pro-protein convertase subtilisin/kexin-9 (PCSK9), mipomersen, lomitapide, and cholesterol ester transfer protein inhibitors (CETPIs). Two CETPIs have failed to show benefit in hard outcomes trials but others remain under investigation. It remains unclear whether additional therapies add to statins for the prevention of CVD in most patients. They may have some added benefit in patients with complex dyslipidemias.

Glucagon-Like Peptide 1 Therapy: From Discovery to Type 2 Diabetes and Beyond.

The therapeutic benefits of the incretin hormone, glucagon-like peptide 1 (GLP1), for people with type 2 diabetes and/or obesity, are now firmly established. The evidence-base arising from head-to-head comparative effectiveness studies in people with type 2 diabetes, as well as the recommendations by professional guidelines suggest that GLP1 receptor agonists should replace more traditional treatment options such as sulfonylureas and dipeptidyl-peptidase 4 (DPP4) inhibitors. Furthermore, their benefits in reducing cardiovascular events in people with type 2 diabetes beyond improvements in glycaemic control has led to numerous clinical trials seeking to translate this benefit beyond type 2 diabetes. Following early trial results their therapeutic benefit is currently being tested in other conditions including fatty liver disease, kidney disease, and Alzheimer's disease.

The long-term cost-effectiveness of once-weekly semaglutide 1 mg vs. dulaglutide 3 mg and 4.5 mg in the UK.

AIMS: Once-weekly semaglutide and dulaglutide represent two highly efficacious treatment options for type 2 diabetes. A recent indirect treatment comparison (ITC) has associated semaglutide 1 mg with similar and greater improvements in glycated haemoglobin (HbA1c) and body weight, respectively, vs. dulaglutide 3 mg and 4.5 mg. The present study aimed to evaluate the long-term cost-effectiveness of semaglutide 1 mg vs. dulaglutide 3 mg and 4.5 mg in the UK. MATERIALS AND METHODS: The IQVIA CORE Diabetes Model (v9.0) was used to project outcomes over patients' lifetimes. Baseline cohort characteristics were sourced from SUSTAIN 7, with changes in HbA1c and body mass index applied as per the ITC. Modelled patients received semaglutide or dulaglutide for 3 years, after which treatment was intensified to basal insulin. Costs (expressed in 2020 pounds sterling [GBP]) were accounted from a healthcare payer perspective. RESULTS: Semaglutide 1 mg was associated with improvements in quality-adjusted life expectancy of 0.05 and 0.04 quality-adjusted life years (QALYs) vs. dulaglutide 3 mg and 4.5 mg, respectively, due to a reduced incidence of diabetes-related complications with semaglutide. Direct costs were estimated to be GBP 76 lower and GBP 8 higher in the comparisons with dulaglutide 3 mg and 4.5 mg, respectively. Overall outcomes were similar, but favoured semaglutide, and based on modelled mean outcomes it was considered dominant vs. dulaglutide 3 mg and associated with an incremental cost-effectiveness ratio of GBP 228 per QALY gained vs. dulaglutide 4.5 mg. CONCLUSIONS: Semaglutide 1 mg represents a cost-effective treatment vs. dulaglutide 3 mg and 4.5 mg for type 2 diabetes from a healthcare payer perspective in the UK.

Time to Reach Glycaemic and Body Weight Loss Thresholds with Tirzepatide in Patients with Type 2 Diabetes: A Pre-planned Exploratory Analysis of SURPASS-2 and SURPASS-3.

INTRODUCTION: Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, provides clinically meaningful improvements in glycaemic control and body weight loss in people with type 2 diabetes. The early efficacy profile of tirzepatide after treatment initiation is of interest. In this exploratory pre-planned analysis, we evaluated the time to achieve glycaemic control and body weight loss thresholds with tirzepatide. METHODS: In two randomised studies, we compared time to achieve HbA1c (< 7.0% and ≤ 6.5%) and weight loss (≥ 5%, SURPASS-2 only) thresholds among people treated with tirzepatide (5, 10, and 15 mg), semaglutide 1 mg in SURPASS-2, and titrated insulin degludec in SURPASS-3. Longitudinal logistic regression models were used to explore the proportion of participants achieving HbA1c and body weight loss thresholds at 4, 12, and 24 weeks. The time to achieve these thresholds was analysed and compared between groups using the Cox proportional-hazards model. RESULTS: Overall, greater proportions of participants achieved the HbA1c and body weight loss thresholds at 4, 12, and 24 weeks with tirzepatide compared with semaglutide 1 mg and insulin degludec. The median time to achieve HbA1c < 7.0% (8.1 weeks with each tirzepatide dose, 12.0 weeks with semaglutide 1 mg, and 12.1 weeks with insulin degludec) and ≤ 6.5% (12.1, 15.7, and 24.1 weeks, respectively) was faster with tirzepatide than semaglutide 1 mg and insulin degludec. In SURPASS-2, the median time to first achieve a body weight loss of ≥ 5% was faster with tirzepatide 5 mg (16.0 weeks) and 10 and 15 mg (12.4 weeks) than with semaglutide 1 mg (24.0 weeks). CONCLUSION: Analyses of data from SURPASS-2 and -3 revealed that tirzepatide treatment enabled more people with type 2 diabetes to achieve glycaemic thresholds and these were achieved faster than with semaglutide 1 mg or insulin degludec. Tirzepatide-treated participants also achieved a body weight loss of ≥ 5% significantly faster with tirzepatide than with semaglutide 1 mg. TRIAL REGISTRATION NUMBERS: NCT03987919; NCT03882970.

Triglycerides: a case for treatment?

PURPOSE OF REVIEW: To discuss the relevance of triglycerides to cardiovascular disease (CVD) risk. RECENT FINDINGS: Triglycerides are a commonly measured component of lipid profiles. Raised triglycerides are a component of the metabolic syndrome and are strongly associated with future risk of diabetes as well as cardiovascular disease. Triglyceride-rich particles form a component of cardiovascular risk above that delineated by low density lipoprotein (LDL) cholesterol. Elevated triglycerides are a marker of atherogenic small dense LDL, excess baseline and residual CVD risk even after statin therapy. Additional methods to lower triglycerides include niacin, fibrates and omega-3 fatty acids. Trials in monotherapy with both niacin and fibrates suggest some benefit in reducing CVD events based on evidence mostly derived from older studies. However, endpoint trials of adding either niacin or fenofibrate to statins have not shown any benefit, except possibly in patients with an increased atherogenic index (triglyceride : HDL-C ratio), or have been underpowered. Trials of omega-3 fatty acids have been performed at doses insufficient to affect lipid profiles in populations with inadequate control of LDL-C but did reduce CVD events. SUMMARY: Further trials of lipid-lowering agents beyond statins will be required in patients with LDL-C adequately controlled on statin therapy.