Effects of liraglutide compared with placebo on events of acute gallbladder or biliary disease in patients with type 2 diabetes at high risk for cardiovascular events in the LEADER randomized trial. Diabetes Care 2019;42:1912-1920

Skelin et al. have raised an important issue about competing risk in time-to-event analyses of acute gallbladder or biliary disease in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. We thank them for the opportunity to discuss the data in the light of competing risk from a lower frequency of all-cause death with liraglutide compared with placebo in LEADER

Comparison of genotyping using pooled DNA samples (allelotyping) and individual genotyping using the affymetrix genome-wide human SNP array 6.0

Background: Genome-wide association studies (GWAS) using array-based genotyping technology are widely used to identify genetic loci associated with complex diseases or other phenotypes. The costs of GWAS projects based on individual genotyping are still comparatively high and increase with the size of study populations. Genotyping using pooled DNA samples, as also being referred as to allelotyping approach, offers an alternative at affordable costs. In the

Emerging role of insulin with incretin therapies for management of type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a progressive disease warranting intensification of treatment, as beta-cell function declines over time. Current treatment algorithms recommend metformin as the first-line agent, while advocating the addition of either basal-bolus or premixed insulin as the final level of intervention. Incretin therapy, including incretin mimetics or enhancers, are the latest group of drugs available for treatment of T2DM. These agents act through the incretin axis, are currently recommended as add-on agents either as second-or third-line treatment, without concurrent use of insulin. Given the novel role of incretin therapy in terms of reducing postprandial hyperglycemia, and favorable effects on weight with reduced incidence of hypoglycemia, we explore alternative options for incretin therapy in T2DM management. Furthermore, as some evidence alludes to incretins potentially increasing betacell mass and altering disease progression, we propose introducing these agents earlier in the treatment algorithm. In addition, we suggest the concurrent use of incretins with insulin, given the favorable effects especially in relation to weight gain

Occurence of First and Recurrent Major Adverse Cardiovascular Events with Liraglutide Treatment among Patients with Type 2 Diabetes and High Risk of Cardiovascular Events: A Post Hoc Analysis of a Randomized Clinical Trial

Importance: After the occurrence of nonfatal cardiovascular events, recurrent events are highly likely. Most cardiovascular outcomes trials analyze first events only; extending analyses to first and recurrent (total) events can provide clinically meaningful information. Objective: To investigate whether liraglutide is associated with reduced first and recurrent total major adverse cardiovascular events (MACE) compared with placebo among patients with type 2 diabetes and high risk of cardiovascular events. Design, Setting, and Participants: This post hoc analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) randomized, double-blind, clinical trial included data from patients with type 2 diabetes who had established or were at high risk for cardiovascular disease at 410 sites in 32 countries from August 2010, to December 2015. Data analysis was performed from August 15, 2016, to July 5, 2019. Interventions: Patients were randomized 1:1 to receive liraglutide (up to 1.8 mg per day) or placebo, both with standard care, for 3.5 to 5.0 years. Main Outcomes and Measures: Assessed outcomes were MACE (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), expanded MACE (primary MACE plus coronary revascularization and hospitalization for heart failure or unstable angina pectoris), and the individual end points. Results: The 9340 LEADER trial participants (6003 [64.3%] male; mean [SD] age, 64.3 [7.2] years) experienced 1605 total MACE (1302 first and 303 recurrent events; median follow-up, 3.8 years [range, 0-5.2 years]). Patients who experienced any MACE were older (1 MACE: mean [SD] age, 65.6 [8.0] years; >1 MACE: 65.7 [7.9] years) and had diabetes for longer duration (1 MACE: mean [SD] duration, 13.4 [8.3] years; >1 MACE: 14.4 [8.7] years) compared with patients without MACE (mean [SD] age, 64.1 [7.1] years; mean [SD] duration, 12.7 [7.9] years). Fewer first and recurrent MACE occurred in the liraglutide group (n = 4668; 608 first and 127 recurrent events) than in the placebo group (n = 4672; 694 first and 176 recurrent events). Liraglutide was associated with a 15.7% relative risk reduction in total MACE (hazard ratio [HR], 0.84; 95% CI, 0.76-0.93) and a 13.4% reduction in total expanded MACE (HR, 0.87; 95% CI, 0.81-0.93) compared with placebo. For most individual cardiovascular end points, liraglutide was associated with lower risk vs placebo. Conclusions and Relevance: These results suggest that liraglutide treatment is associated with reduced total MACE compared with placebo among patients with type 2 diabetes and high risk of cardiovascular events. This analysis supports the findings of an absolute benefit of liraglutide treatment with respect to the overall burden of cardiovascular events in this high-risk patient population

A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study

WSTĘP. Celem opisanego w niniejszym artykule, trwającego 52 tygodnie otwartego badania klinicznego typu non-inferiority (sprawdzenie, czy badany lek spełnia warunek nie mniejszej skuteczności) było porównanie bezpieczeństwa i skuteczności eksenatydu (leku stymulującego efekt inkretynowy) oraz dwufazowej insuliny aspart. MATERIAŁ I METODY. Pacjentów uprzednio leczonych metforminą i pochodnymi sulfonylomocznika losowo przydzielano do grupy, w której stosowano eksenatyd (n = 253; 5 &#956;g 2 x d. przez 4 tygodnie, następnie 10 &#956;g 2 x d.) lub do grupy leczonej dwufazową insuliną aspart (n = 248; 2 x d. w dawkach odpowiednich do uzyskania optymalnej kontroli glikemii). W czasie trwania badania wszyscy pacjenci kontynuowali przyjmowanie metforminy i pochodnych sulfonylomocznika. WYNIKI. Kontrola glikemii w trakcie leczenia eksenatydem nie była gorsza od wartości stwierdzanych w grupie otrzymującej dwufazową insulinę aspart [wartość średnia &#177; SEM; zmiana stężenia HbA1c: eksenatyd -1,04 &#177; 0,07%, dwufazowa insulina aspart -0,89 &#177; 0,06%: różnica -0,15% (95% CI: -0,32 do 0,01)]. U pacjentów przyjmujących eksenatyd stwier dzano spadek masy ciała, natomiast w grupie leczonej dwufazową insuliną aspart odnotowywano przyrosty masy ciała [różnica między grupami: -5,4 kg (95% CI: -5,9 do -5,0]. Oba schematy leczenia przyczyniły się do zmniejszenia wartości glikemii na czczo (eksenatyd: -1,8 &#177; 0,2 mmol/l, p < 0,002; dwufazowa insulina aspart: -1,7 &#177; 0,2 mmol/l, p < 0,001). Większą redukcję poposiłkowych wahań glikemii rano (p < 0,001), w południe (p < 0,001) i wieczorem (p < 0,001) odnotowano wśród pacjentów leczonych eksenatydem. Odsetek pacjentów, którzy wycofali się z leczenia, wyniósł w grupie eksenatydu 21,3% (54/253), a w grupie leczonej dwufazową insuliną aspart - 10,1% (25/248). W pierwszej z wymienionych grup najczęściej występującym działaniem niepożądanym leczenia były nudności (częstość występowania: 33%; była to przyczyna zaprzestania leczenia u 3,5% pacjentów). WNIOSKI/INTERPRETACJA. Leczenie eksenatydem powodowało obniżenie stężenia HbA1c w podobnym stopniu jak zastosowanie dwufazowej insuliny aspart, ale zapewniało lepszą kontrolę glikemii po posiłkach. Postępowanie takie może więc się stać alternatywą w leczeniu cukrzycy typu 2. Stosowanie dwufazowej insuliny aspart wiązało się w badanej grupie z przyrostem masy ciała, ale także z mniejszą częstością występowania działań niepożądanych ze strony przewodu pokarmowego. Wprawdzie dostępność leków hipoglikemicznych powodujących chudnięcie można uznać za istotną zaletę (w leczeniu cukrzycy typu 2), jednak odległe skutki postępującego spadku masy ciała, obserwowanego u osób leczonych eksenatydem, wymagają przeprowadzenia dalszych badań.AIMS/HYPOTHESIS. The aim of this 52-week, openlabel, noninferiority trial was to compare the safety and efficacy of exenatide (an incretin mimetic) with that of biphasic insulin aspart. MATERIALS AND METHODS. Patients on metformin and a sulfonylurea were randomised to exenatide (n = 253; 5 &#956;g twice daily for 4 weeks, 10 &#956;g thereafter) or biphasic insulin aspart (n = 248; twice-daily doses titrated for optimal glucose control), while continuing with metformin and sulfonylurea treatment. RESULTS. Glycaemic control achieved with exenatide exenatide was non-inferior to that achieved with biphasic insulin aspart [mean &#177; SEM, HbA1c change: exenatide -1.04 &#177; 0.07%, biphasic insulin aspart -0.89 &#177; 0.06%; difference -0.15% (95% CI -0.32 to 0.01)]. Exenatide-treated patients lost weight, while patients treated with biphasic insulin aspart gained weight [betweengroup difference -5.4 kg (95% CI -5.9 to -5.0)]. Both treatments reduced fasting serum glucose (exenatide -1.8 &#177; 0.2 mmol/l; p < 0.001; biphasic insulin aspart -1.7 &#177; 0.2 mmol/l; p < 0.001). Greater reductions in postprandial glucose excursions following morning (p < 0.001), midday (p = 0.002) and evening meals (p < 0.001) were observed with exenatide. The withdrawal rate was 21.3% (54/253) for exenatide and 10.1% (25/248) for biphasic insulin aspart. Nausea (33% incidence, 3.5% discontinuation) was the most common adverse event observed with exenatide. CONCLUSIONS/INTERPRETATION. Exenatide treatment resulted in HbA1c reduction similar to biphasic insulin aspart and provided better postprandial glycaemic control, making it a potential alternative for the treatment of type 2 diabetes. Treatment with biphasic insulin aspart was associated with weight gain and lower risk of adverse gastrointestinal events. Although the availability of glucose-lowering agents associated with weight reduction may be considered a therapeutic advance, the long-term implications of progressive weight reduction observed with exenatide have yet to be defined

Validation of distinct type 2 diabetes clusters and their association with diabetes complications in the DEVOTE, LEADER and SUSTAIN-6 cardiovascular outcomes trials

Aims: To validate the clusters of Swedish individuals with recent-onset diabetes at differential risk of complications, which were identified in a previous study, in three global populations with long-standing type 2 diabetes (T2D) who were at high cardiovascular risk, and to test for differences in the risk of major diabetes complications and survival endpoints. Materials and methods: We assigned participants from recent global outcomes trials (DEVOTE [n = 7637], LEADER [n = 9340] and SUSTAIN-6 [n = 3297]) to the previously defined clusters according to age at diabetes diagnosis, baseline glycated haemoglobin (HbA1c) and body mass index (BMI). Outcomes were assessed using Kaplan–Meier analysis and log-rank tests. Results: The T2D clusters were consistently replicated across the three trial cohorts. The risk of major adverse cardiovascular events and cardiovascular death differed significantly, in all trials, across clusters over a median follow-up duration of 2.0, 3.8 and 2.1 years, respectively, and was highest for the cluster of participants with high HbA1c and low BMI (P < 0.05 in DEVOTE and LEADER). In LEADER and SUSTAIN-6, the risk of nephropathy differed across clusters (P < 0.0001 and P = 0.003, respectively). The risk of severe hypoglycaemia differed in DEVOTE (P = 0.006). Conclusions: Previously identified clusters can be replicated in three geographically diverse cohorts of long-standing T2D and are associated with cluster-specific risk profiles for additional clinical and survival outcomes, providing further validation of the clustering methodology. The external validity and stability of clusters across cohorts provides a premise for future work to optimize the clustering approach to yield T2D subgroups with maximum predictive validity who may benefit from subtype-specific treatment paradigms

Effects of liraglutide compared with placebo on events of acute gallbladder or biliary disease in patients with type 2 diabetes at high risk for cardiovascular events in the LEADER randomized trial

Objective: To explore gallbladder- and biliary tract-related events reported for the liraglutide and placebo groups in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. Research Design and Methods: LEADER was an international, randomized, double-blind, controlled cardiovascular (CV) outcomes trial. Participants with type 2 diabetes at high risk for CV events (n = 9,340) were randomized 1:1 to receive either liraglutide (≤1.8mg daily; n = 4,668) or placebo (n = 4,672), with both groups also receiving standard care (treatment period: 3.5-5 years). Acute gallstone disease was a medical event of special interest. This post hoc analysis categorized captured events of acute gallbladder or biliary disease into four groups: uncomplicated gallbladder stones, complicated gallbladder stones, cholecystitis, and biliary obstruction. Time to first event by treatment group was analyzed using Cox regression. Results: There was an increased risk of acute gallbladder or biliary disease with liraglutide versus placebo (n = 141 of 4,668 vs. n = 88 of 4,672 patients, respectively; hazard ratio [HR] 1.60; 95% CI 1.23, 2.09; P < 0.001). Similar trends were observed for each of the four categories of gallbladder- or biliary tract-related events. Cholecystectomy was performed more frequently in liraglutide-treated patients (HR 1.56; 95% CI 1.10, 2.20; P = 0.013) but for similar proportions of the patients who experienced gallbladder- or biliary tract-related events (57% with liraglutide vs. 59% with placebo). Conclusions: Although LEADER was not specifically designed to assess acute gallbladder or biliary disease, the trial showed an increased risk of gallbladder- or biliary tract-related events with liraglutide versus placebo, which appeared to be consistent across four categories of these events. Further studies should investigate the relevant mechanisms

Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treatedwith liraglutide: Results from the LEADER randomized trial

Objective: To evaluate serum amylase and lipase levels and the rate of acute pancreatitis in patients with type 2 diabetes and high cardiovascular risk randomized to liraglutide or placebo and observed for 3.5-5.0 years. Research Design and Methods: Atotal of 9,340 patientswith type 2 diabeteswere randomized to either liraglutide or placebo (median observation time 3.84 years). Fasting serum lipase and amylase were monitored. Acute pancreatitis was adjudicated in a blinded manner. Results: Compared with the placebo group, liraglutide-treated patients had increases in serum lipase and amylase of 28.0% and 7.0%, respectively. Levels were increased at 6 months and then remained stable. During the study, 18 (0.4% [1.1 events/1,000 patient-years of observation] [PYO]) liraglutide-treated and 23 (0.5% [1.7 events/ 1,000 PYO]) placebo patients had acute pancreatitis confirmed by adjudication.Most acute pancreatitis cases occurred ≥12months after randomization. Liraglutide-treated patients with prior history of pancreatitis (n = 147) were not more likely to develop acute pancreatitis than similar patients in the placebo group (n = 120). Elevations of amylase and lipase levels did not predict future risk of acute pancreatitis (positive predictive value <1.0%) in patients treated with liraglutide. Conclusions: In a population with type 2 diabetes at high cardiovascular risk, there were numerically fewer events of acute pancreatitis among liraglutide-treated patients (regardless of previous history of pancreatitis) comparedwith the placebo group. Liraglutide was associated with increases in serum lipase and amylase, which were not predictive of an event of subsequent acute pancreatitis

Duration of diabetes and cardiorenal efficacy of liraglutide and semaglutide: A post hoc analysis of the LEADER and SUSTAIN 6 clinical trials

Cardiovascular risk reduction with liraglutide and semaglutide in patients with type 2 diabetes was demonstrated in the LEADER (ClinicalTrials.gov: NCT01179048) and SUSTAIN 6 (ClinicalTrials.gov: NCT01720446) cardiovascular outcome trials. This post hoc analysis assessed the impact of diabetes duration (<5, 5 to <15, 15 to <25 and ≥25 years at baseline) on cardiorenal efficacy of these human glucagon-like peptide-1 analogues using a Cox proportional hazards model. Proportions of patients in the LEADER trial across diabetes duration strata were 15% (<5 years, n = 1377), 50% (5 to <15 years, n = 4692), 27% (15 to <25 years, n = 2504) and 8% (≥25 years, n = 748); corresponding proportions in the SUSTAIN-6 trial were 13% (<5 years, n = 422), 48% (5 to <15 years, n = 1582), 30% (15 to <25 years, n = 977) and 10% (≥25 years, n = 316). Overall, longer diabetes duration was associated with higher age; higher prevalence of females; history of ischaemic stroke, peripheral arterial disease and insulin use; and inferior renal function. There was an increased frequency of major adverse cardiovascular events (MACE), expanded MACE and nephropathy events with increasing diabetes duration. Liraglutide and semaglutide consistently reduced the risk of cardiorenal outcomes across categories of diabetes duration (P-interaction was not significant for all endpoints analysed)