Insulin glargine 300 units/mL for the treatment of individuals with type 2 diabetes in the real world: A review of the DELIVER programme

Evidence from randomized controlled trials (RCTs) has shown that second-generation basal insulin (BI) analogues, insulin glargine 300 U/mL (Gla-300) and insulin degludec (IDeg), provide similar glycaemic control, with a lower risk of hypoglycaemia compared with the first-generation BI analogue insulin glargine 100 U/mL (Gla-100) in people with type 2 diabetes (T2D). However, the highly selected participants and frequent follow-up of RCTs may not be truly representative of real-life clinical practice. It is important to assess the safety and effectiveness of these second-generation BI analogues in real-life clinical practice settings. The DELIVER programme utilized electronic healthcare records from the United States to compare clinical outcomes in people with T2D who received either Gla-300 or other BI analogues in real-world clinical practice. This review provides a concise overview of the results of the DELIVER studies. Overall, Gla-300 provided similar antihyperglycaemic effectiveness and a lower risk of hypoglycaemia versus the first-generation BI analogues Gla-100 and insulin detemir in people with T2D who had switched BIs. In those who were insulin-naïve, initiation with Gla-300 versus Gla-100 was associated with significantly better antihyperglycaemic effectiveness and similar or lower hypoglycaemic risk. Both glycaemic control and hypoglycaemia risk were also shown to be similar with Gla-300 and IDeg, in people who had switched BIs and in those who were insulin-naïve. In addition, the DELIVER 2 study reported that people with T2D who switched to Gla-300 had reduced healthcare resource utilization, with an overall saving of US$1439 per person per year compared with those who switched to another BI analogue. Overall, the real-world DELIVER programme showed that the glycaemic control with a low risk of hypoglycaemia observed with Gla-300 in RCTs was also seen in standard clinical practice

A comparison of health-related quality of life (health utility) between insulin degludec and insulin glargine: a meta-analysis of phase 3 trials

Aim: To evaluate health-related quality of life (health utility) scores in patients with diabetes receiving insulin degludec (IDeg) or insulin glargine (IGlar). Methods: Patient-level data from six, randomized, controlled, open-label, multicentre, confirmatory, treat-to-target trials of 26- or 52 weeks' duration were pooled in this analysis. The Short Form 36 (SF-36) version-2 health questionnaire was completed by patients at baseline and end-of-trial. SF-36 scores for 4001 individual patients were then mapped onto the EuroQol-5D health utility scale, which has a range from −0.59 (a state worse than death) to 1.00 (perfect health). Results: IDeg treatment exhibited a significant improvement in health status of 0.005 (CI: 0.0006; 0.009) points compared with IGlar (p < 0.024). Gender, region, trial and age also had a significant influence on estimated utility scores as did baseline utility scores, p < 0.05. Prior to the removal of interaction variables a difference of 0.008 points was observed, p < 0.045. Previous insulin treatment did not have an impact on the final outcome. Conclusion: This study shows that IDeg is associated with a modest, but statistically significant, improvement in health utility compared with IGlar in patients with diabetes

Use of non-selective B-blockers is safe in hospitalised decompensated cirrhosis patients and exerts a potential anti-inflammatory effect: Data from the ATTIRE trial

Background: Nonselective B-blockers (NSBBs) are believed to have pleiotropic effects beyond reducing portal pressure. However, studies also report potential harm in patients hospitalized with cirrhosis and ascites. We therefore investigated whether NSBB use at ATTIRE trial entry (Albumin to prevent infection in chronic liver failure, 2016-19) was associated with increased renal or cardiovascular dysfunction, compared the incidence of infection and plasma markers of systemic inflammation, and examined mortality at 28-days, 3 and 6-months. Methods: In ATTIRE patients grouped by NSBB use at trial entry, we studied infection at baseline, hospital acquired infection and organ dysfunction during trial treatment period and mortality, with propensity score matching to account for differences in disease severity. Findings: There were no differences in renal or cardiovascular dysfunction between patients treated with NSBBs or not, during days 3–15 of hospitalization, despite elevated serum creatinine in NSBB patients at hospitalisation. Use of NSBBs was associated with a significant reduction in infection at hospitalization (p = 0.006), lower white cell counts throughout hospital stay (p < 0.001) and reduced plasma procalcitonin (p = 0.009) and interlukin-8 levels (p = 0.04) at baseline, but markers of bacterial translocation and systemic inflammation were the same in treatment groups. There was no reduction in hospital acquired infections in patients taking NSBBs and no beneficial impact on mortality at 28-days, 3 and 6-months. Interpretations: Our real-world data from a completed randomised trial show that use of NSBBs in decompensated cirrhosis patients is safe during hospitalisation. We also show a potential anti-inflammatory role for NSBBs which may be mediated by a downregulation of IL-8 induced leucocytosis, that was associated with reduced infection at baseline but not a survival benefit. Funding: Wellcome Trust and Department of Health and Social Care

Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial

BACKGROUND: Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. METHODS: In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30 g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. FINDINGS: Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P = 0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. INTERPRETATIONS: Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. FUNDING: Wellcome Trust and Department of Health and Social Care

The effects of aetiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial

Aims: Cardiac dyssynchrony is common in patients with heart failure, whether or not they have ischaemic heart disease (IHD). The effect of the underlying cause of cardiac dysfunction on the response to cardiac resynchronization therapy (CRT) is unknown. This issue was addressed using data from the CARE-HF trial.Methods and resultsPatients (n = 813) were grouped by heart failure aetiology (IHD n = 339 vs. non-IHD n = 473), and the primary composite (all-cause mortality or unplanned hospitalization for a major cardiovascular event) and principal secondary (all-cause mortality) endpoints analysed. Heart failure severity and the degree of dyssynchrony were compared between the groups by analysing baseline clinical and echocardiographic variables. Patients with IHD were more likely to be in NYHA class IV (7.5 vs. 4.0; P = 0.03) and to have higher NT-proBNP levels (2182 vs. 1725 pg/L), indicating more advanced heart failure. The degree of dyssynchrony was more pronounced in patients without IHD (assessed using mean QRS duration, interventricular mechanical delay, and aorta-pulmonary pre-ejection time). Left ventricular ejection fraction and left ventricular end-systolic volume improved to a lesser extent in the IHD group (4.53 vs. 8.50 and -35.68 vs. -58.52 cm 3). Despite these differences, CRT improved all-cause mortality, NYHA class, and hospitalization rates to a similar extent in patients with or without IHD.ConclusionThe benefits of CRT in patients with or without IHD were similar in relative terms in the CARE-HF study but as patients with IHD had a worse prognosis, the benefit in absolute terms may be greater

An Educational Review of the Statistical Issues in Analysing Utility Data for Cost-Utility Analysis

The aim of cost-utility analysis is to support decision making in healthcare by providing a standardised mechanism for comparing resource use and health outcomes across programmes of work. The focus of this paper is the denominator of the cost-utility analysis, specifically the methodology and statistical challenges associated with calculating QALYs from patient-level data collected as part of a trial. We provide a brief description of the most common questionnaire used to calculate patient level utility scores, the EQ-5D, followed by a discussion of other ways to calculate patient level utility scores alongside a trial including other generic measures of health-related quality of life and condition- and population-specific questionnaires. Detail is provided on how to calculate the mean QALYs per patient, including discounting, adjusting for baseline differences in utility scores and a discussion of the implications of different methods for handling missing data. The methods are demonstrated using data from a trial. As the methods chosen can systematically change the results of the analysis, it is important that standardised methods such as patient-level analysis are adhered to as best as possible. Regardless, researchers need to ensure that they are sufficiently transparent about the methods they use so as to provide the best possible information to aid in healthcare decision making