Summary Background Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety ...of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. Methods Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1·8 mg once a day (n=233) or exenatide 10 μg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA1c ). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00518882. Findings Mean baseline HbA1c for the study population was 8·2%. Liraglutide reduced mean HbA1c significantly more than did exenatide (−1·12% SE 0·08 vs −0·79% 0·08; estimated treatment difference −0·33; 95% CI −0·47 to −0·18; p<0·0001) and more patients achieved a HbA1c value of less than 7% (54% vs 43%, respectively; odds ratio 2·02; 95% CI 1·31 to 3·11; p=0·0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (−1·61 mmol/L SE 0·20 vs −0·60 mmol/L 0·20; estimated treatment difference −1·01 mmol/L; 95% CI −1·37 to −0·65; p<0·0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide −3·24 kg vs exenatide −2·87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0·448, p<0·0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1·93 vs 2·60 events per patient per year; rate ratio 0·55; 95% CI 0·34 to 0·88; p=0·0131; 25·5% vs 33·6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. Interpretation Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations. Funding Novo Nordisk A/S.
A fixed-ratio combination of the basal insulin analogue insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide has been developed as a once-daily injection for the treatment of ...type 2 diabetes. We aimed to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients.
In this phase 3, 26-week, open-label, randomised trial, adults with type 2 diabetes, HbA1c of 7-10% (inclusive), a BMI of 40 kg/m(2) or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1·8 mg per day). IDegLira and insulin degludec were titrated to achieve a self-measured prebreakfast plasma glucose concentration of 4-5 mmol/L. The primary endpoint was change in HbA1c after 26 weeks of treatment, and the main objective was to assess the non-inferiority of IDegLira to insulin degludec (with an upper 95% CI margin of 0·3%), and the superiority of IDegLira to liraglutide (with a lower 95% CI margin of 0%). This study is registered with ClinicalTrials.gov, number NCT01336023.
1663 adults (mean age 55 years SD 10, HbA1c 8·3% 0·9, and BMI 31·2 kg/m(2) 4·8) were randomly assigned, 834 to IDegLira, 414 to insulin degludec, and 415 to liraglutide. After 26 weeks, mean HbA1c had decreased by 1·9% (SD 1·1) to 6·4% (1·0) with IDegLira, by 1·4% (1·0) to 6·9% (1·1) with insulin degludec, and by 1·3% (1·1) to 7·0% (1·2) with liraglutide. IDegLira was non-inferior to insulin degludec (estimated treatment difference -0·47%, 95% CI -0·58 to -0·36, p<0·0001) and superior to liraglutide (-0·64%, -0·75 to -0·53, p<0·0001). IDegLira was generally well tolerated; fewer participants in the IDegLira group than in the liraglutide group reported gastrointestinal adverse events (nausea 8·8 vs 19·7%), although the insulin degludec group had the fewest participants with gastrointestinal adverse events (nausea 3·6%). We noted no clinically relevant differences between treatments with respect to standard safety assessments, and the safety profile of IDegLira reflected those of its component parts. The number of confirmed hypoglycaemic events per patient year was 1·8 for IDegLira, 0·2 for liraglutide, and 2·6 for insulin degludec. Serious adverse events occurred in 19 (2%) of 825 patients in the IDegLira group, eight (2%) of 412 in the insulin degludec group, and 14 (3%) of 412 in the liraglutide group.
IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycaemic control compared with its components given alone.
Novo Nordisk.
Abstract Exenatide once-weekly is an extended release formulation of exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, which can improve glycemic control, body weight, blood pressure, and ...lipid levels in patients with type 2 diabetes mellitus (T2DM). The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding exenatide once-weekly to usual care with usual care alone on major cardiovascular outcomes. EXSCEL is an academically-led, phase III/IV, double-blind, pragmatic placebo-controlled, global trial conducted in 35 countries aiming to enrol 14,000 patients with T2DM and a broad range of cardiovascular risk over approximately 5 years. Participants will be randomized (1:1) to receive exenatide once-weekly 2 mg or matching placebo by subcutaneous injections. The trial will continue until 1360 confirmed primary composite cardiovascular endpoints, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, have occurred. The primary efficacy hypothesis is that exenatide once-weekly is superior to usual care with respect to the primary composite cardiovascular endpoint. EXSCEL is powered to detect a 15% relative risk reduction in the exenatide once weekly group, with 85% power and a 2-sided 5% alpha. The primary safety hypothesis is that exenatide once-weekly is noninferior to usual care with respect to the primary cardiovascular composite endpoint. Noninferiority will be concluded if the upper limit of the confidence interval is <1.30. EXSCEL will assess whether exenatide once-weekly can reduce cardiovascular events in patients with T2DM with a broad range of cardiovascular risk. It will also provide long-term safety information on exenatide once-weekly in people with T2DM. ClinicalTrials.gov Identifier: NCT01144338
Summary Background Glucagon-like peptide-1 receptor agonists exenatide and liraglutide have been shown to improve glycaemic control and reduce bodyweight in patients with type 2 diabetes. We compared ...the efficacy and safety of exenatide once weekly with liraglutide once daily in patients with type 2 diabetes. Methods We did a 26 week, open-label, randomised, parallel-group study at 105 sites in 19 countries between Jan 11, 2010, and Jan 17, 2011. Patients aged 18 years or older with type 2 diabetes treated with lifestyle modification and oral antihyperglycaemic drugs were randomly assigned (1:1), via a computer-generated randomisation sequence with a voice response system, to receive injections of once-daily liraglutide (1·8 mg) or once-weekly exenatide (2 mg). Participants and investigators were not masked to treatment assignment. The primary endpoint was change in glycated haemoglobin (HbA1c ) from baseline to week 26. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01029886. Findings Of 912 randomised patients, 911 were included in the intention-to-treat analysis (450 liraglutide, 461 exenatide). The least-squares mean change in HbA1c was greater in patients in the liraglutide group (−1·48%, SE 0·05; n=386) than in those in the exenatide group (–1·28%, 0·05; 390) with the treatment difference (0·21%, 95% CI 0·08–0·33) not meeting predefined non-inferiority criteria (upper limit of CI <0·25%). The most common adverse events were nausea (93 21% in the liraglutide group vs 43 9% in the exenatide group), diarrhoea (59 13% vs 28 6%), and vomiting 48 11% vs 17 4%), which occurred less frequently in the exenatide group and with decreasing incidence over time in both groups. 24 (5%) patients allocated to liraglutide and 12 (3%) allocated to exenatide discontinued participation because of adverse events. Interpretation Both once daily liraglutide and once weekly exenatide led to improvements in glycaemic control, with greater reductions noted with liraglutide. These findings, plus differences in injection frequency and tolerability, could inform therapeutic decisions for treatment of patients with type 2 diabetes. Funding Eli Lilly and Company and Amylin Pharmaceuticals LLC.
Summary Background The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We ...aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. Methods We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2–11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov , number NCT02092220. Findings We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7–1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8–1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0–10) was greater during the bionic pancreas period (0·52 SD 0·83) than in the comparator period (0·05 0·17; difference 0·47, 95% CI 0·21–0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. Interpretation Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. Funding National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.
Defeating AIDS—advancing global health Piot, Peter, Prof; Abdool Karim, Salim S, PhD; Hecht, Robert, PhD ...
The Lancet (British edition),
07/2015, Letnik:
386, Številka:
9989
Journal Article
Recenzirano
Thanks to considerable resources, leadership, community mobilisation, and innovation, enormous gains have been made in controlling the HIV epidemic, saving millions of people from infection and ...AIDS-related illness and death.
Summary Background Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. ...Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes. Methods In an open-label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged ≥18 years) with type 1 diabetes (glycated haemoglobin HbA1c ≤10% 86 mmol/mol), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computer-generated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA1c after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov , number NCT00982228. Findings Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA1c had fallen by 0·40% points (SE 0·03) and 0·39% points (0·07), respectively, with insulin degludec and insulin glargine (estimated treatment difference −0·01% points 95% CI −0·14 to 0·11; p<0·0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA1c of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42·54 vs 40·18 episodes per patient-year of exposure; estimated rate ratio degludec to glargine 1·07 0·89 to 1·28; p=0·48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4·41 vs 5·86 episodes per patient-year of exposure; 0·75 0·59 to 0·96; p=0·021). Overall serious adverse event rates (14 vs 16 events per 100 patient-years of exposure) were similar for the insulin degludec and insulin glargine groups. Interpretation Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides effective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy. Funding Novo Nordisk.
Background: Observed activity of metformin in reducing the risk of severe COVID-19 suggests a potential use of the anti-hyperglycemic in the prevention of post-acute sequelae of SARS-CoV-2 infection ...(PASC). We assessed the 3-month and 6-month risk of PASC among patients with type 2 diabetes mellitus (T2DM) comparing metformin users to sulfonylureas (SU) or dipeptidyl peptidase-4 inhibitors (DPP4i) users. Methods: We used de-identified patient level electronic health record data from the National Covid Cohort Collaborative (N3C) between October 2021 and April 2023. Participants were adults greater than or equal to 18 years with T2DM who had at least one outpatient healthcare encounter in health institutions in the United States prior to COVID-19 diagnosis. The outcome of PASC was defined based on the presence of a diagnosis code for the illness or using a predicted probability based on a machine learning algorithm. We estimated the 3-month and 6-month risk of PASC and calculated crude and weighted risk ratios (RR), risk differences (RD), and differences in mean predicted probability. Results: We identified 5596 (mean age: 61.1 years; SD: 12.6) and 1451 (mean age: 64.9 years; SD 12.5) eligible prevalent users of metformin and SU/DPP4i respectively. We did not find a significant difference in risk of PASC at 3 months (RR = 0.86 0.56; 1.32, RD = -3.06 per 1000 -12.14; 6.01), or at 6 months (RR = 0.81 0.55; 1.20, RD = -4.91 per 1000 -14.75, 4.93) comparing prevalent users of metformin to prevalent users of SU/ DPP4i. Similar observations were made for the outcome definition using the ML algorithm. Conclusion: The observed estimates in our study are consistent with a reduced risk of PASC among prevalent users of metformin, however the uncertainty of our confidence intervals warrants cautious interpretations of the results. A standardized clinical definition of PASC is warranted for thorough evaluation of the effectiveness of therapies under assessment for the prevention of PASC. Plain Language Summary: Previous research suggests that metformin, due to its anti-viral, anti-inflammatory, and anti-thrombotic properties may reduce the risk of severe COVID-19. Given the shared etiology of COVID-19 and the post-acute sequelae of SARS-CoV-2 (PASC), and the proposed inflammatory processes of PASC, metformin may also be a beneficial preventive option. We investigated the benefit of metformin for PASC prevention in a population of type 2 diabetes mellitus patients with a COVID-19 diagnosis who were on metformin or two other anti-hyperglycemic medications prior to infection with SARS-CoV-2. Our results were consistent with a reduction in the risk of PASC with the use of metformin, however, the imprecise confidence intervals obtained warrants further investigation of this association of the potential beneficial effect of metformin for preventing PASC in patients with medication-managed diabetes. Keywords: COVID-19, Long COVID, Type 2 diabetes Mellitus, Metformin
We investigated functional outcomes after robot-assisted radical cystectomy in terms of urinary continence and erectile function. We found that in general, patients have relatively good functional ...outcomes at 12 mo after surgery.
Little is known regarding functional outcomes after robot-assisted radical cystectomy (RARC) and intracorporeal neobladder (ICNB) reconstruction.
To report on urinary continence (UC) and erectile function (EF) at 12 mo after RARC and ICNB reconstruction and investigate predictors of these outcomes.
We used data from a multi-institutional database of patients who underwent RARC and ICNB reconstruction for bladder cancer.
The cystoprostatectomy sensu stricto followed the conventional steps. ICNB reconstruction was performed at the physician’s discretion according to the Studer/Wiklund, S pouch, Gaston, vescica ileale Padovana, or Hautmann technique. The techniques are detailed in the video accompanying the article.
The outcomes measured were UC and EF at 12 mo.
A total of 732 male patients were identified with a median age at diagnosis of 64 yr (interquartile range 58–70). The ICNB reconstruction technique was Studer/Wiklund in 74%, S pouch in 1.5%, Gaston in 19%, vescica ileale Padovana in 1.5%, and Hautmann in 4% of cases. The 12-mo UC rate was 86% for daytime and 66% for nighttime continence, including patients who reported the use of a safety pad (20% and 32%, respectively). The 12-mo EF rate was 55%, including men who reported potency with the aid of phosphodiesterase type 5 inhibitors (24%). After adjusting for potential confounders, neobladder type was not associated with UC. Unilateral nerve-sparing (odds ratio OR 3.85, 95% confidence interval CI 1.88–7.85; p < 0.001) and bilateral nerve-sparing (OR 6.25, 95% CI 3.55–11.0; p < 0.001), were positively associated with EF, whereas age (OR 0.93, 95% CI 0.91–0.95; p < 0.001) and an American Society of Anesthesiologists score of 3 (OR 0.46, 95% CI 0.25–0.89; p < 0.02) were inversely associated with EF.
RARC and ICNB reconstruction are generally associated with good functional outcomes in terms of UC. EF is highly affected by the degree of nerve preservation, age, and comorbidities.
We investigated functional outcomes after robot-assisted removal of the bladder in terms of urinary continence and erectile function. We found that, in general, patients have relatively good functional outcomes at 12 months after surgery.
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