Demonstration of non-inferiority between MYL-1501D and reference insulin glargine for reduction of HbA1c during 24 weeks of treatment was achieved. The two treatment groups were similar in terms of secondary endpoints, including hypoglycaemia and nocturnal hypoglycaemia, local and systemic reactions, other safety variables, and immunogenicity.

Fibrates are widely prescribed lipid-lowering drug in the treatment of dyslipidemia. Their main clinical effects, mediated by peroxisome proliferative activated receptor (PPAR) alpha activation, are a moderate reduction in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, a marked reduction in triglycerides (TG) and an increase in high-density lipoprotein cholesterol (HDL-C), usually dependent of their baseline levels and dyslipidemia type. A beneficial effect on cardiovascular outcomes but also on inflammatory and thrombogenesis pathways as well as antioxidant properties have been evidenced conferring other pleiotropic effects to fibrates. Diabetic retinopathy, nephropathy and neuropathy are the major microvascular complications of Type 2 diabetes mellitus (T2DM) and their presence can accentuate the risk of cardiovascular disease. Hyperglycemia, hypertension, genetic susceptibility among other risk factors play a significant role in the development and progression of these complications. Plasma lipid abnormalities are also involved in the pathogenesis of microvascular diseases suggesting a potential benefit of lipid lowering drugs in their prevention. Clofibrate was the first fibrate in the 60's to show an improvement in the retinal hard exudation in subjects with diabetic retinopathy. Recently, in the Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) study fenofibrate treatment demonstrated a significant 30% reduction in the need for laser therapy in patients with and without known diabetic retinopathy, and more particularly in the first course of laser treatment for both macular edema and proliferative retinopathy. In addition, fenofibrate treatment was associated with less albuminuria progression and reduced risk of non traumatic distal amputations. These results, along with previous evidence of positive effects on microvascular complications, suggest that fibrates, and particularly fenofibrate, offer good opportunity to prevent the most serious complications of diabetes.

Aims To assess the efficacy, insulin dose, safety and immunogenicity when people with type 1 diabetes mellitus switched between MYL‐1501D and reference insulin glargine (Lantus®; Sanofi‐Aventis US LLC, Bridgewater, New Jersey). Materials and methods Eligible participants from INSTRIDE 1 who completed 52 weeks of reference insulin glargine treatment were randomized 1:1 to the reference sequence (n = 63; reference insulin glargine for 36 weeks) or to the treatment‐switching sequence (n = 64; MYL‐1501D [weeks 0–12], reference insulin glargine [weeks 12–24] and MYL‐1501D [weeks 24–36]). Change in glycated haemoglobin (HbA1c) from baseline to week 36 was the primary efficacy endpoint used to demonstrate equivalence between the two treatment sequences. Secondary endpoints included: change in fasting plasma glucose (FPG), self‐monitored blood glucose (SMBG) and insulin dose; immunogenicity; and adverse events, including hypoglycaemia. Results Mean changes in HbA1c (least squares [LS] mean [SE]) from baseline to week 36 were −0.05 (0.032) and −0.06 (0.034) for the treatment‐switching and reference sequences, respectively (LS mean difference 0.01 [95% CI −0.085 to 0.101]). Treatment sequences were comparable in terms of secondary endpoints, including FPG, SMBG and insulin dose, and the safety and immunogenicity profiles of the two sequences were similar. Conclusions Switching participants between MYL‐1501D and reference insulin glargine demonstrated equivalent efficacy and similar safety and immunogenicity, showing that people taking reference insulin glargine can safely switch to MYL‐1501D.

ObjectivesTo compare the progression of diabetic retinopathy (DR) in people with type 2 diabetes treated with fibrates with that of non-exposed controls.DesignRetrospective, matched cohort study.SettingUK Clinical Practice Research Datalink (CPRD).Participants5038 people with type 2 diabetes with a history of fibrate exposure but without evidence of DR were identified. Three thousand one hundred and seventy-six (63%) people could be randomly matched to one non-exposed control; of these, 2599 (81.8%) were matched without any missing blood pressure or glycated haemoglobin (HbA1c) values.Main outcome measuresThe primary endpoint was first recorded DR with a secondary endpoint of all-cause mortality or first DR. Time to clinical endpoints was compared using Cox proportional hazards models.ResultsMean follow-up was 5.1 and 5.0 years for fibrate-exposed and non-exposed patients, respectively. For fibrate-exposed participants, there was a reduction in DR: 33.4 events/1000 person-years vs 40.4 (p=0.002), and in death or DR: 50.6 vs 60.2 (p<0.001). For those matched with full systolic blood pressure and HbA1c data, crude event rates were 34.3 versus 43.9 for DR (p<0.001) and 51.2 vs 63.4 (p<0.001) for death or DR. Following adjustment, DR was significantly delayed for those treated with fibrates, with an adjusted HR (aHR) of 0.785 (p<0.001) for participants with complete data and an aHR of 0.802 (p<0.001) for all participants.ConclusionsThe treatment with fibrates in people with type 2 diabetes was independently associated with reduced progression to a first diagnosis of DR.

Subjects treated with fenofibric acid had a modest improvement in TMV, although the study was probably underpowered to detect a benefit over placebo after 1 year.

Aims To report phase 1 bioequivalence results comparing MYL‐1501D, US reference insulin glargine (US IG), and European reference insulin glargine (EU IG). Materials and methods The double‐blind, randomized, three‐way crossover study compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MYL‐1501D, US IG and EU IG. In total, 114 patients with type 1 diabetes (T1DM) received 0.4 U/kg of each study treatment under automated euglycaemic clamp conditions. Insulin metabolite M1 concentrations, insulin glargine (IG) and glucose infusion rates (GIRs) were assessed over 30 hours. Primary PK endpoints were area under the serum IG concentration–time curve from 0 to 30 hours (AUCins.0–30h) and maximum serum IG concentration (Cins.max). Primary PD endpoints were area under the GIR–time curve from 0 to 30 hours (AUCGIR0–30h) and maximum GIR (GIRmax). Results Bioequivalence among MYL‐1501D, US IG and EU IG was demonstrated for the primary PK and PD endpoints. Least squares mean ratios were close to 1, and 90% confidence intervals were within 0.80 to 1.25. The PD GIR–time profiles were nearly superimposable. There were no noticeable differences in the safety profiles of the three treatments, and no serious adverse events were reported. Conclusions Equivalence with regard to PK and PD characteristics was shown among MYL‐1501D, US IG and EU IG in patients with T1DM, and each treatment was well tolerated and safe.

SUMMARYAims: Guidelines propose additional therapy to statin to treat elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDLC) in dyslipidemic patients. We evaluated the effects of new fixed-dose combinations (FDC) of fenofibrate/simvastatin on plasma lipids versus simvastatin or fenofibrate monotherapies. Methods: Subjects with mixed dyslipidemia at high or very high cardiovascular risk on stable statin therapy for at least 3 months were included in a randomized, double-blind, active-control, parallel-group study. Patients were treated with FDC fenofibrate/simvastatin 145/20 mg or 145/40 mg, simvastatin 20 mg or 40 mg, or fenofibrate 145 mg for 12 weeks. Plasma lipids, C-reactive protein, and cystatin C were measured before and after treatments. Differences in % changes were compared between FDC fenofibrate/simvastatin and monotherapies. Results: Significant differences between FDC fenofibrate/simvastatin and simvastatin monotherapies were observed for the % change of TG (LS mean difference [two-sided 95% CI]: À32.2% [À38.6%, À25.8%], P < 0.001) and HDL-C (7.5% [4.7%, 10.2%], P < 0.001). A significant difference between the FDC fenofibrate/simvastatin and fenofibrate was observed for LDLC % changes (À34.7% [À40.8%, À28.5%], P < 0.001). Significant differences between FDC fenofibrate/simvastatin and their respective monotherapies were also observed for Apo B and non-HDLC % changes. The FDC were well tolerated with a similar safety profile compared with monotherapies. Conclusions: FDC fenofibrate/simvastatin are effective and well-tolerated therapies to improve the TG and HDLC profile in high-risk patients with mixed dyslipidemia.

Background MYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies. Methods INSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti–host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2). Results Total enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P > 0.999). Conclusions In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively. Trial registration ClinicalTrials.gov, INSTRIDE 1 (NCT02227862; date of registration, August 28, 2014); INSTRIDE 2 (NCT02227875; date of registration, August 28, 2014).