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BackgroundChronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D.MethodsFLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒100‒ResultsEnrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression.ConclusionFLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.

BACKGROUND AND AIMS Chronic kidney disease (CKD) in type 2 diabetes (T2D) is the most common cause of kidney failure. Despite treatment advances, there is still a large unmet need to prevent CKD progression, which can increase the risk for cardiovascular (CV) disease and kidney failure. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have beneficial effects on glycaemic control and body weight. Some agents have also shown CV benefit and can be used in people with T2D regardless of CKD status (except in end-stage renal disease). CV outcomes trials have suggested that GLP-1RAs may have kidney-protective effects, reducing albuminuria and preserving estimated glomerular filtration rate (eGFR). FLOW (NCT03819153) is a dedicated kidney outcomes trial designed to evaluate the effect of the once-weekly (OW) GLP-1RA semaglutide on major kidney outcomes in subjects with T2D and CKD; we report the blinded baseline characteristics of the FLOW trial population. METHOD FLOW is an ongoing randomized, double-blinded, multinational, phase 3b trial in which 3535 subjects with T2D with an eGFR ≥25–≤75 mL/min/1.73 m², and urine albumin-to-creatinine ratio (UACR) >100 to RESULTS Baseline characteristics from FLOW are shown in the Table 1. Overall, mean eGFR at baseline was 47.0 mL/min/1.73 m2 with 79.6% of subjects having an eGFR of CONCLUSION The FLOW trial will evaluate the efficacy and safety of semaglutide on kidney outcomes in subjects with T2D and high risk of kidney disease progression, a group for which additional therapies are urgently required.

Aims Both acute pancreatitis (AP) and pancreatic cancer (PC) have been areas of focus for studies of incretin drugs. This 5‐year prospective cohort study aimed to quantify possible associations between liraglutide and risk of AP and PC as compared to other antidiabetic drugs (ADs). Materials and methods Patients initiating liraglutide or other ADs who were enrolled in a US health plan (2010‐2014) were included. Comparisons of AP and PC incidence rates were made between matched cohorts of liraglutide initiators and initiators of other ADs. Adjudicated AP cases and algorithm‐based PC cases were identified. Propensity score‐matched intention‐to‐treat (ITT) and time‐on‐drug (TOD) analyses were completed using Poisson regression. A latency analysis was performed for PC. Results Median follow‐up was 405 days for AP cohorts (9995 liraglutide, 1:1 matched to all comparators) and 503 days for PC cohorts (35 163 liraglutide, 1:1 matched to all comparators). In the primary AP analysis, “current” use of liraglutide was not significantly associated with elevated risk across comparators (all comparators relative risk [RR] = 1.2; 95% confidence interval [CI], 0.6‐2.3). ITT results were similar where, in the primary analysis, no RRs were significantly associated with PC (all comparators RR = 0.7; 95% CI, 0.3‐1.4); latency and TOD analyses did not alter findings. There was no evidence of a dose‐response effect. Conclusions Liraglutide was not associated with an increased risk of AP or PC, although risk estimates were more variable for AP, and numbers of cases for both outcomes were limited because of the rarity of outcomes.

Donnie Funch,1 Kathleen Mortimer,1 Najat J Ziyadeh,1 John D Seeger,1 Li Zhou,1 Eva Ng,1 Douglas Ross,2,3 Atheline Major-Pedersen,4 Heidrun Bosch-Traberg,5 Helge Gydesen,6 David D Dore1,7 1Optum Epidemiology, Boston, MA, USA; 2Massachusetts General Hospital, Thyroid Associates, Boston, MA, USA; 3Harvard Medical School, Department of Medicine, Boston, MA, USA; 4Global Safety, Novo Nordisk A/S, Copenhagen, Denmark; 5Global Development, Novo Nordisk A/S, Copenhagen, Denmark; 6Epidemiology, Novo Nordisk A/S, Copenhagen, Denmark; 7Department of Health Services, Policy & Practice, Brown University School of Public Health, Providence, RI, USACorrespondence: Najat J ZiyadehOptum Epidemiology, 1325 Boylston Street, 11th Floor, Boston, MA, 02215, USAEmail najat.ziyadeh@optum.comBackground: Quantify association between the glucagon-like peptide-1 receptor agonist liraglutide and risk of thyroid cancer (TC) compared to other antidiabetics.Patients and Methods: Initiators of liraglutide, exenatide, metformin, pioglitazone or groups of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US health plan (2010– 2014) and followed for a median of 17 months. Thyroid cancer cases during follow-up were identified via a validated algorithm. Incidence rates of TC among liraglutide and comparators were assessed using relative risks estimated within propensity score-matched cohorts using intention to treat (ITT) and time on drug analyses. Latency effects and potential surveillance bias were evaluated.Results: Relative risks from ITT analyses ranged from 1.00 (95% confidence interval (CI) 0.56– 1.79) versus metformin to 1.70 (95% CI 1.03– 2.81) versus all comparators excluding exenatide. Effect estimates from latency analyses were slightly attenuated. Time on drug analyses suggested no increased risk for either longer duration or higher cumulative dose of liraglutide. Medical record review found 85% were papillary or a follicular variant of papillary or both; 46% were microcarcinomas (≤ 10 millimeters), which were more prevalent in the liraglutide cohort (67% versus 43% in all comparators).Conclusion: Relative risks were elevated for several comparisons, which should be interpreted cautiously because of potential residual confounding and surveillance bias. Liraglutide cases had smaller thyroid nodules and shorter time-to-diagnosis, suggesting increased surveillance for TC among liraglutide initiators, especially shortly after the drug´s approval. After adjusting the primary analyses (ITT) for latency, no significant elevated risk of TC was observed among liraglutide initiators.Keywords: glucagon-like peptide-1 receptor agonist, type 2 diabetes, administrative claims, intention-to-treat, time-on-drug

Purpose Manufacturing processes for polypeptide/protein drugs are designed to ensure robust quality, efficacy and safety. Process differences introduced by follow-on manufacturers may result in changes in quality and clinical outcomes. This study investigated the impact of production methods on the stability and impurities of liraglutide and semaglutide drug substances/products, and the potential impact on drug quality, efficacy and safety. Methods State-of-the-art analytical methods were used to compare physical and chemical stability, and impurity profiles of drug substances/products from different suppliers. Identified polypeptide-related impurities were evaluated for immunogenicity potential by in silico T cell epitope prediction. Semaglutide immunogenicity in clinical trials (SUSTAIN) was evaluated using a tiered antibody analysis. Results Manufacturing scale and process strongly impacted the physical stability of the products. Trace metals increased high-molecular-weight protein formation for liraglutide and semaglutide. Synthetic and recombinant liraglutide produced by five suppliers had distinct impurity profiles compared with the originator. In silico evaluation suggested that new impurities could be immunogenic. Immunogenicity of semaglutide in clinical trials was lower than for liraglutide. Conclusions Differences in manufacturing processes affect chemical/physical stability and impurity profile, and may impact immunogenicity. Follow-on versions of liraglutide and semaglutide, and possibly other polypeptides, should be clinically evaluated for efficacy and safety.

Aims To assess health‐related quality of life (HRQoL) in people with type 2 diabetes (T2D) participating in the LEADER cardiovascular outcomes trial using the five‐dimension European Quality of Life questionnaire (EQ‐5D). Materials and methods The EQ‐5D was administered every 12 months in a subset of patients from Canada, Denmark, Germany, Ireland, Italy, Netherlands, Spain, Sweden, the United Kingdom and the United States. We compared changes in utility index scores and visual analogue scale (VAS) scores from baseline to 36 months in participants treated with liraglutide and placebo. We also assessed which complications had the greatest impact on quality of life. Results At 36 months, less deterioration in EQ‐5D utility index score was seen in the liraglutide group (−0.058) than in the placebo group (−0.082; estimated treatment difference [ETD] 0.023, 95% confidence interval [CI] 0.004;0.043; P = 0.020). A smaller decrease in EQ‐5D VAS score was also demonstrated in the liraglutide group (−3.51) vs. the placebo group (−5.45; ETD 1.94, 95% CI 0.32;3.57; P = 0.019). The benefits of liraglutide treatment compared with placebo were driven primarily by shifts in the domains of mobility and self‐care. The most influential events contributing to poorer HRQoL were stroke, heart failure, malignant neoplasm and confirmed hypoglycaemia. Conclusions Liraglutide demonstrated a modest but significant benefit in patient‐reported health status using the EQ‐5D, compared with placebo. This benefit may be of clinical relevance and requires further study.

Aims/Introduction To determine the efficacy and safety of adding liraglutide to three different insulin regimens in Japanese patients with type 2 diabetes mellitus. Materials and Methods In this post‐hoc analysis, results from a 36‐week, randomized, double‐blind, placebo‐controlled, parallel‐group trial are reported. Individuals with type 2 diabetes mellitus were stratified according to their pre‐trial insulin regimen (basal, basal–bolus and premix). The primary objective was to determine whether adding liraglutide (0.9 mg/day) to fixed‐dose insulin therapy was superior vs fixed‐dose insulin monotherapy, assessed by the effect on glycemic control after 16 weeks of treatment. Results The treatment effect on glycated hemoglobin reduction was independent of the pre‐trial insulin regimen. Comparing liraglutide with a placebo, liraglutide was associated with glycated hemoglobin reduction in all insulin regimens, with placebo‐corrected reductions at 16 weeks ranging from −1.45 to −1.17%, and maintained at 36 weeks. Liraglutide resulted in a greater reduction in mean plasma glucose obtained from seven‐point self‐monitoring, and greater proportions of patients achieved target glycated hemoglobin. With liraglutide, slightly higher proportions of patients receiving basal and basal–bolus insulin reported confirmed hypoglycemia from 0 to 16 weeks. Conclusions The efficacy and safety of adding liraglutide to insulin therapy was confirmed, regardless of pre‐trial insulin regimen.

Aims/Introduction The aim of this post hoc analysis was to investigate the safety and efficacy of liraglutide in combination with one oral antidiabetic drug (OAD) across different OAD classes. Materials and Methods This was a post hoc analysis using data from a 52-week, open-label, parallel-group trial, in which patients with type 2 diabetes inadequately controlled with a single OAD (α-glucosidase inhibitor, glinide, metformin or thiazolidinedione) were randomized to either pre-trial OAD in combination with liraglutide 0.9 mg/day (liraglutide group) or pre-trial OAD in combination with an additional OAD (additional OAD group). The primary outcome investigated in this post hoc analysis was incidence of adverse events (AEs). Results The proportions of patients experiencing AEs across the different groups of pre-trial OADs were comparable between liraglutide and additional OAD (α-glucosidase inhibitor 74.6% vs 70.0%; glinide 93.1% vs 87.1%; metformin 91.8% vs 87.1%; thiazolidinedione 86.2% vs 96.4%, respectively). Minor hypoglycemia was infrequent (seven episodes in two patients randomized to liraglutide, and two episodes in two patients randomized to additional OAD). Mean reduction in glycated hemoglobin (HbA1c) appeared greater with liraglutide therapy, estimated mean treatment difference (95% confidence interval [CI]) for liraglutide versus additional OAD ranging from −0.14% (−0.48;0.21) [–1.5 mmol/mol (–5.2;2.3)] to −0.44% (–0.79;–0.09) [−4.8 mmol/mol (−8.6;−1.0)]. Conclusions This analysis suggests that Japanese patients on OAD monotherapy may benefit from a greater improvement in glycemic control, without impacting tolerability, by combining their OAD with liraglutide rather than another OAD, regardless of which OAD monotherapy they are receiving. This article is protected by copyright. All rights reserved.

OBJECTIVE To compare the efficacy and safety of liraglutide versus lixisenatide as add-on to metformin in patients with type 2 diabetes not achieving adequate glycemic control on metformin alone. RESEARCH DESIGN AND METHODS In this 26-week, randomized, parallel-group, open-label trial, 404 patients were randomized 1:1 to liraglutide 1.8 mg or lixisenatide 20 µg as add-on to metformin. Liraglutide was administered once daily at any time of the day. Lixisenatide was administered once daily within 1 h prior to the morning or evening meal. RESULTS At week 26, liraglutide reduced HbA1c (primary end point) more than lixisenatide (estimated treatment difference −0.62% [95% CI −0.8; −0.4]; P < 0.0001), with more patients reaching HbA1c CONCLUSIONS At the dose levels studied, liraglutide was more effective than lixisenatide as add-on to metformin in improving glycemic control. Body weight reductions were similar. Both treatments were well tolerated, with low risk of hypoglycemia and similar gastrointestinal adverse event profiles.

Introduction The LEADER trial was a cardiovascular (CV) outcomes trial in patients with type 2 diabetes at high CV risk that compared liraglutide (n = 4668) with placebo (n = 4672) using a primary composite endpoint of 3-point major adverse CV events. The objective of this post hoc analysis was to investigate glycaemic outcomes across both treatment groups. Methods Glycated haemoglobin (HbA1c) was measured at randomisation, month 3, month 6 and every 6 months thereafter. Cox regression was used to analyse time to a composite endpoint of glycaemic deterioration, defined as a specified change in HbA1c or a substantial intensification of insulin or oral antihyperglycaemic drug (OAD). The individual components of the composite were also analysed. Results Baseline characteristics, including insulin and OAD use, were balanced between treatment groups. HbA1c decreased from baseline in both groups, but the reduction was greater with liraglutide [estimated treatment difference at month 36: − 0.40%; 95% confidence interval (CI) − 0.45, − 0.34] despite the addition of more OADs and higher insulin use in the placebo group. Fewer of the patients treated with liraglutide (n = 3202, 68.6%) experienced glycaemic deterioration compared with those administered the placebo (n = 3988, 85.4%; average hazard ratio: 0.50; 95% CI 0.48, 0.53; p

Combining GLP-1 analogs and insulin has complementary benefits, but long-term data are sparse. In the LEADER cardiovascular (CV) outcomes trial (N=9340; median follow-up 3.8 years; NCT01179048), rates of major CV events and hypoglycemia were lower when liraglutide vs. placebo was added to standard care (frequently including insulin) in patients with type 2 diabetes (T2D) at high risk for CV disease, and there were improvements in control of glycemia, body weight, systolic blood pressure (SBP) and lipids. This post-hoc subgroup analysis assessed these outcomes by baseline insulin use: no insulin vs. basal-only vs. other. At baseline, 5171 (55%) patients were not on insulin treatment, 3159 (34%) were on basal-only insulin and 1010 (11%) were treated with other insulin regimens (9.7% premix). Insulin use at baseline was balanced overall between randomized treatment groups, but fewer patients randomized to liraglutide (29%) vs. placebo (43%) initiated in-trial insulin. In the basal-only subgroup, liraglutide reduced A1C vs. placebo (estimated treatment difference [ETD]: −0.48%, 95% CI: −0.57; −0.38), with a significant reduction in severe hypoglycemia rate (estimated rate ratio: 0.42, 95% CI: 0.26; 0.68). Liraglutide also reduced weight (ETD: −2.5 kg, 95% CI: −3.0; −2.1) and there were trends for reductions in SBP (ETD: −1.1 mmHg, 95% CI: −2.4; 0.1) and LDL cholesterol (ETD: -1.3 mg/dL, 95% CI: -3.6; 1.0). The CV risk reduction observed with liraglutide in the full trial population was similar in the basal-only subgroup (estimated hazard ratio: 0.84, 95% CI: 0.70; 1.00). Results were similar in the no-insulin subgroup. There was heterogeneity in the results for the smaller, other insulin subgroup with reductions in A1C and weight, but no significant differences in other endpoints. In conclusion, in basal insulin-treated patients with T2D and high CV risk, treatment with liraglutide improved glycemic control, reduced body weight and halved the severe hypoglycemia risk, with a similar CV risk reduction to patients not on insulin. Disclosure C. Tack: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S, AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Novo Nordisk A/S. S. Jacob: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, AstraZeneca, Eli Lilly and Company. Board Member; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk Foundation. Advisory Panel; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K., Menarini Group, Roche Diabetes Care Health and Digital Solutions. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Medscape. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Fractyl Laboratories, Inc., GlaxoSmithKline plc., Berlin-Chemie AG, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Berlin-Chemie AG, Merck Sharp & Dohme Corp., Medscape, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Berlin-Chemie AG, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, GlaxoSmithKline plc., Novo Nordisk A/S. Consultant; Self; Nordic Bioscience, Empros. J. Petrie: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Pfizer Inc.. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Merck KGaA, Itamar Medical Ltd., Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Diabetes UK, Applied Clinical Intelligence Ltd, Bayer AG, QuintilesIMS. N.R. Poulter: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc.. Research Support; Self; Servier. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc., Servier. Other Relationship; Self; International Society of Hypertension. R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc. H. Stegmann: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. H. Bosch-Traberg: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. E. Startseva: Employee; Self; Novo Nordisk A/S. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott.

Aims/Introduction To assess efficacy and safety of liraglutide in combination with insulin compared with insulin monotherapy in Japanese patients with type 2 diabetes. Materials and methods This was a 36-week, multicenter, double-blind, parallel-group trial, where patients on stable insulin therapy (basal/premixed/basal–bolus) were randomized 1:1 to additional liraglutide 0.9 mg/day (n = 127) or placebo (n = 130). The insulin dose was fixed for 16 weeks, and titrated based on self-measured plasma glucose thereafter. The primary end-point was change in glycosylated hemoglobin after 16 weeks. Results Superiority of liraglutide plus insulin versus insulin monotherapy was confirmed based on estimated mean difference in glycosylated hemoglobin after 16 weeks of −1.30% (−14 mmol/mol; 95% confidence interval −1.47 to −1.13 [−16, −12]; P < 0.0001). Statistical significance was maintained to week 36. More patients on liraglutide achieved a glycosylated hemoglobin target of

Introduction The safety and efficacy of liraglutide in combination with an oral antidiabetic drug (OAD) compared with combination of two OADs were assessed in Japanese patients with type 2 diabetes. Materials and Methods This was a 52‐week, open‐label, parallel‐group trial in which patients whose type 2 diabetes was inadequately controlled with a single OAD (glinide, metformin, α‐glucosidase inhibitor or thiazolidinedione) were randomized 2:1 to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group; n = 240) or pretrial OAD in combination with an additional OAD (additional OAD group; n = 120). The primary outcome measure was the incidence of adverse events (AEs). Results Overall, 86.3% of patients in the liraglutide group and 85.0% of patients in the additional OAD group experienced AEs; these were similar in nature and severity. Adverse event rates were 361 and 331 per 100 patient‐years of exposure, respectively. Confirmed hypoglycemia was rare (seven episodes in two patients on liraglutide, and two in two patients on additional OAD). There were no reported pancreatitis events, and no unexpected safety signals were identified. Mean reductions in glycosylated hemoglobin were significantly greater in the liraglutide group than the additional OAD group [estimated mean treatment difference −0.27% (95% confidence interval (CI) −0.44, −0.09; P = 0.0026)]; reductions in mean fasting plasma glucose levels were also greater with liraglutide [estimated mean difference −5.47 mg/dL (−0.30 mmol/L; 95% CI: −10.83, −0.10; P = 0.0458)]. Conclusions Liraglutide was well tolerated and effective as combination therapy with an OAD in Japanese patients with type 2 diabetes.

The causal relationship between low-density lipoprotein cholesterol (LDL-C) and atherosclerotic cardiovascular events has been well established. In people with type 2 diabetes mellitus, LDL-C lowering with statins is strongly endorsed by clinical practice guidelines, with suggested LDL-C target levels including

Objectifs Evaluer l’efficacite a long terme (jusqu’a 5 ans) du liraglutide sur le controle glycemique dans l’etude LEADER (n = 9340). Methodes Analyse selon le modele de Fine et Gray, du temps jusqu’a deterioration du controle glycemique definie par un critere composite : HbA1c ≥ 8,0 % et diminution Resultats La baisse d’HbA1c etait plus importante a 36 mois sous liraglutide : −1,16 % versus −0,77 % dans le bras controle malgre un ajout plus frequent d’autres hypoglycemiants dans le bras controle et moins d’hypoglycemies dans le bras liraglutide. Les deux composants de ce critere composite ont ete reduits : deterioration du controle glycemique, augmentation de l’HbA1c chez les patients avec un taux initial d’HbA1c eleve non repondeurs/perte de reponse a l’objectif cible (HbA1c Discussion Dans la population de LEADER (diabetiques de type 2 a un stade avance de la maladie), la diminution du taux d’HbA1c a ete plus importante et le risque de deterioration du controle glycemique moindre sous liraglutide que sous placebo. Le risque d’hypoglycemie a egalement ete reduit chez les patients traites par liraglutide.

AIMS To compare the efficacy and safety of liraglutide versus sitagliptin as add-on to metformin after 26 weeks of treatment in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS This 26-week open-label, active comparator trial (NCT02008682) randomized patients (aged 18-80 years) with T2DM inadequately controlled with metformin [glycated haemoglobin (HbA1c) 7.0-10.0% (53-86 mmol/mol)] 1 : 1 to once-daily subcutaneously administered liraglutide 1.8 mg (n = 184) or once-daily oral sitagliptin 100 mg (n = 184), both as add-on to metformin. The primary endpoint was change in HbA1c from baseline to week 26. RESULTS Liraglutide was superior to sitagliptin in reducing HbA1c from baseline [8.1% (65 mmol/mol)] to 26 weeks, as evidenced by estimated mean HbA1c change of -1.65% (-18.07 mmol/mol) versus -0.98% (-10.72 mmol/mol), respectively [estimated treatment difference for liraglutide vs sitagliptin of -0.67% (95% CI -0.86, -0.48) or -7.35 mmol/mol (95% CI -9.43; -5.26); p < 0.0001]. More patients receiving liraglutide (76.5%) than sitagliptin (52.6%) achieved the HbA1c target of

OBJECTIVE Renal impairment in type 2 diabetes limits available glucose-lowering treatment options. This trial was conducted to establish the efficacy and safety of liraglutide as an add-on to existing glucose-lowering medications in patients with inadequately controlled type 2 diabetes and moderate renal impairment. RESEARCH DESIGN AND METHODS In this 26-week, double-blind trial, 279 patients with HbA1c 7–10%, BMI 20–45 kg/m2, and moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2; MDRD) were randomized (1:1) to once-daily liraglutide 1.8 mg (n = 140) or placebo (n = 139). RESULTS The estimated treatment difference in HbA1c from baseline to week 26 was −0.66% (−7.25 mmol/mol) (95% CI −0.90 to −0.43 [−9.82 to −4.69]), P < 0.0001). Fasting plasma glucose decreased more with liraglutide (−1.22 mmol/L [−22.0 mg/dL]) than with placebo (−0.57 mmol/L [−10.3 mg/dL], P = 0.036). There was a greater reduction in body weight with liraglutide (−2.41 kg) than with placebo (−1.09 kg, P = 0.0052). No changes in renal function were observed (eGFR relative ratio to baseline: −1% liraglutide, +1% placebo; estimated treatment ratio [ETR] 0.98, P = 0.36). The most common adverse events were gastrointestinal (GI) adverse effects (liraglutide, 35.7%; placebo, 17.5%). No difference in hypoglycemic episodes was observed between treatment groups (event rate/100 patient-years of exposure: liraglutide, 30.47; placebo, 40.08; P = 0.54). The estimated ratio to baseline for lipase was 1.33 for liraglutide and 0.97 for placebo (ETR 1.37, P < 0.0001). CONCLUSIONS Liraglutide did not affect renal function and demonstrated better glycemic control, with no increase in hypoglycemia risk but with higher withdrawals due to GI adverse events than placebo in patients with type 2 diabetes and moderate renal impairment.

Objectif Comparer l'efficacite et la tolerance du liraglutide par rapport au lixisenatide en association a la metformine (MET) chez des patients diabetiques de type 2 (DT2) insuffisamment controles sous MET seule. Materiels et Methodes Essai randomise controle, en ouvert de 26 semaines. Des patients DT2 (âge≥18 ans, 7,5 %≥HbA 1c ≤10,5 %, IMC≥20kg/m 2 ) ont ete randomises selon un ratio 1 : 1 pour recevoir soit le liraglutide 1,8mg/j, soit le lixisenatide 20μg/j en association a la la MET. Le liraglutide etait administre a n'importe quel moment de la journee, le lixisenatide etait administre une heure avant le repas du matin ou du soir. Resultats 404 patients DT2 (60 % d'hommes, âge moyen 56 ans, IMC 35kg/m 2 , HbA 1c 8,4 %, duree du diabete 6,4 ans) ont ete randomises. Apres 26 semaines de traitement, la reduction de l'HbA 1c sous liraglutide a ete superieure par rapport au lixisenatide (1,83 vs 1,21 %, p 1c vs 45,5 %, p vs 1,70mmol/l, P p =ns). Les profils de tolerance ont ete globalement comparables. Les evenements indesirables les plus frequents etaient digestifs (nausees : 21,8 % pour lira et lixi ; diarrhees : 12,4 % pour lira, 9,9 % pour lixi). Les episodes d'hypoglycemies confirmees ont ete rares (hypoglycemie severe ou glycemie Conclusions Le liraglutide en association a la metformine a ete plus efficace que le lixisenatide en termes de controle glycemique. Une perte ponderale significative a ete observee avec les deux traitements. Les profils de tolerance ont ete similaires avec essentiellement des troubles digestifs et un risque hypoglycemique faible.

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.

Objectif Evaluer l'efficacite et la tolerance du liraglutide chez des patients diabetiques de type 2 (DT2) mal controles avec une insuffisance renale (IR) moderee. Patients et methodes LIRA-RENAL est un essai randomise, controle en double aveugle vs placebo de 26 semaines, dans lequel des sujets DT2 avec IR moderee (stade 3 de la maladie renale chronique [MRC], avec un debit de filtration glomerulaire estime [DFG] 30-59ml/min/1,73 m 2 ), ont recu soit le liraglutide 1,8mg ( n =140) soit le placebo ( n =137) 1 fois par jour, en ajout de leur traitement antidiabetique prealable (oral ± insuline). Resultats Apres 26 semaines de traitement, le liraglutide a permis un controle glycemique superieur par rapport au placebo chez les DT2 avec IR moderee, avec des reductions plus importantes d'HbA1c (1,05 vs – 0,38 %) et du poids corporel (-2,41 vs – 1,09kg), avec moins d'episodes d'hypoglycemie (5,7 % vs 10,9 %). Les effets indesirables (EI) les plus frequents etaient d'ordre gastrointestinal (liraglutide 35,7 % ; placebo 17,5 %). L'incidence des EI conduisant a des sorties d'essai etait plus elevee dans le groupe liraglutide (13,6 %) par rapport au placebo (2,9 %). Aucune deterioration de la fonction renale n'a ete observee (differences DFGe par rapport a l'inclusion : liraglutide – 1 % ; placebo +1 %). Conclusion Chez des patients DT2 avec une IR moderee, le liraglutide a demontre une efficacite superieure en termes de reduction de l'HbA1C et de la perte ponderale, avec une tolerance gastro-intestinale acceptable, une incidence moindre d'hypoglycemies et sans deterioration de la fonction renale. Declaration d’interet Les auteurs declarent avoir un interet avec un organisme prive, industriel ou commercial en relation avec le sujet presente. Le 1 er auteur declare travailler pour le laboratoire Novo Nordisk.

Objectif Evaluer l’efficacite et la tolerance du liraglutide chez des patients diabetiques de type 2 (DT2) mal controles avec une insuffisance renale (IR) moderee. Patients et methodes LIRA-RENAL est un essai randomise, controle en double insu versus placebo de 26 semaines, dans lequel des sujets DT2 avec IR moderee (stade 3 de la maladie renale chronique [MRC], avec un debit de filtration glomerulaire estime [DFG] 30–59 mL/min/1,73 m2), ont recu soit le liraglutide 1,8 mg (n = 140) soit le placebo (n = 137) 1 fois par jour, en ajout de leur traitement antidiabetique prealable (oral ± insuline). Resultats Apres 26 semaines de traitement, le liraglutide a permis un controle glycemique superieur par rapport au placebo chez les DT2 avec IR moderee, avec des reductions plus importantes d’HbA1c (–1,05 vs –0,38 %) et du poids corporel (–2,41 vs –1,09 kg), avec moins d’episodes d’hypoglycemie (5,7 % vs 10,9 %). Les effets indesirables (EI) les plus frequents etaient d’ordre gastrointestinal (liraglutide 35,7 % ; placebo 17,5 %). L’incidence des EI conduisant a des sorties d’essai etait plus elevee dans le groupe liraglutide (13,6 %) par rapport au placebo (2,9 %). Aucune deterioration de la fonction renale n’a ete observee (differences DFGe par rapport a l’ inclusion : liraglutide –1 % ; placebo +1 %). Discussion Chez des patients DT2 avec une IR moderee, le liraglutide a demontre une efficacite superieure en termes de reduction de l’HbA1C et de la perte ponderale, avec une tolerance gastrointestinale acceptable, une incidence moindre d’hypoglycemies et sans deterioration de la fonction renale.