The 200 units/mL formulation of insulin degludec (IDeg 200 units/mL) contains equal units of insulin in half the volume compared with the 100 units/mL formulation. We compared the efficacy and safety ...of IDeg 200 units/mL once daily with 100 units/mL insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs.
In this 26-week, open-label, treat-to-target trial, subjects (n = 457; mean HbA1c 8.3% 67 mmol/mol, BMI 32.4 kg/m(2), and fasting plasma glucose FPG 9.6 mmol/L 173.2 mg/dL) were randomized to IDeg 200 units/mL or IGlar, both given once daily in combination with metformin with or without a dipeptidyl peptidase-4 inhibitor. Basal insulin was initiated at 10 units/day and titrated weekly to an FPG target of <5 mmol/L (<90 mg/dL) according to mean prebreakfast self-measured blood glucose values from the preceding 3 days.
By 26 weeks, IDeg reduced HbA1c by 1.30% and was not inferior to IGlar. Mean observed FPG reductions were significantly greater with IDeg than IGlar (-3.7 vs. -3.4 mmol/L -67 vs. -61 mg/dL; estimated treatment difference: -0.42 95% CI -0.78 to -0.06, P = 0.02). Despite this difference, rates of overall confirmed hypoglycemia were not higher with IDeg than with IGlar (1.22 and 1.42 episodes/patient-year, respectively), as were rates of nocturnal confirmed hypoglycemia (0.18 and 0.28 episodes/patient-year, respectively). Mean daily basal insulin dose was significantly lower by 11% with IDeg 200 units/mL compared with IGlar. IDeg was well-tolerated, and the rate of treatment-emergent adverse events was similar across groups.
In this treat-to-target trial in insulin-naïve patients with T2DM, IDeg 200 units/mL improved glycemic control similarly to IGlar with a low risk of hypoglycemia.
In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe ...complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia. Evidence now warrants a focus on the beta cell itself and how to avoid its dysfunction, which is putatively caused by cytokine-driven inflammation and other stress factors, leading to low insulin-secretory capacity, autoantigen presentation and immune-mediated destruction. Correspondingly, beta cell rescue strategies are being pursued, which include antigen vaccination using, for example, oral insulin or peptides, as well as agents with suggested benefits on beta cell stress, such as verapamil and glucagon-like peptide-1 receptor agonists. Whilst autoimmune-focused prevention approaches are central in type 1 diabetes and will be a requirement in the advent of stem cell-based replacement therapies, managing the primarily cardiometabolic complications of established type 1 diabetes is equally essential. In this review, we outline selected recent and suggested future attempts to address the evolving profile of the person with type 1 diabetes.
Graphical abstract
Aim
Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec (IDeg) has an ultra‐long and stable glucose‐lowering effect, with low ...day‐to‐day variability. This pre‐planned meta‐analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM).
Methods
Pooled patient‐level data for self‐reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat‐to‐target trials in the IDeg clinical development programme comparing IDeg once‐daily (OD) vs. IGlar OD were analysed.
Results
Four thousand three hundred and thirty subjects (2899 IDeg OD vs. 1431 IGlar OD) were analysed. Among insulin‐naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs. IGlar: estimated rate ratio (RR):0.830.70;0.9895%CI, RR:0.640.48;0.8695%CI and RR:0.140.03;0.7095%CI. In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar RR:0.830.74;0.9495%CI and RR:0.680.57;0.8295%CI). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment (RR:0.750.60;0.9495%CI). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations.
Conclusions
The limitations of this study include the open‐label design and exclusion of subjects with recurrent severe hypoglycaemia. This meta‐analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes.
CTLA4 gene polymorphism and autoimmunity Gough, Stephen C. L.; Walker, Lucy S. K.; Sansom, David M.
Immunological reviews,
April 2005, Letnik:
204, Številka:
1
Journal Article
Recenzirano
CD28 and cytotoxic T‐lymphocyte antigen‐4 (CTLA4) are two receptors that have critical but opposing functions in T‐cell stimulation. CD28 promotes a number of T‐cell activities, whereas in contrast ...CTLA4 is an essential inhibitor of T‐cell responses. Because of its inhibitory role, CTLA4 is a strong candidate susceptibility gene in autoimmunity and several studies suggest disease‐associated polymorphisms. In this review, we discuss recent progress in relating CTLA4 polymorphisms to disease susceptibility and consider the putative mechanisms by which CTLA4 may act to inhibit autoimmunity.
The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows ...associations at P < 5 × 10−7 between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (Pfollow-up ≤ 1.35 × 10−9; Poverall ≤ 1.15 × 10−14), leaving eight regions with small effects or false-positive associations. We also obtained evidence for chromosome 18q22 (Poverall = 1.38 × 10−8) from a GWA study of nonsynonymous SNPs. Several regions, including 18q22 and 18p11, showed association with autoimmune thyroid disease. This study increases the number of T1D loci with compelling evidence from six to at least ten.
ABSTRACT
Background
Chronic 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.
Methods
FLOW 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‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin–angiotensin–aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes.
Results
Enrolled 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.
Conclusion
FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.
Graphical Abstract
Graphical Abstract
All the basal insulin products currently available have suboptimal pharmacokinetic (PK) properties, with none reliably providing a reproducible and peakless pharmacodynamic (PD) effect that endures ...over 24 h from once‐daily dosing. Insulin degludec is a novel acylated basal insulin with a unique mechanism of protracted absorption involving the formation of a depot of soluble multihexamer chains after subcutaneous injection. PK/PD studies show that insulin degludec has a very long duration of action, with a half‐life exceeding 25 h. Once‐daily dosing produces a steady‐state profile characterized by a near‐constant effect, which varies little from injection to injection in a given patient. Clinically, insulin degludec has been shown consistently to carry a lower risk of nocturnal hypoglycaemia than once‐daily insulin glargine, in both basal+bolus and basal‐only insulin regimens. The constancy of the steady‐state profile of insulin degludec also means that day‐to‐day irregularities at the time of injection have relatively little PD influence, thereby offering the possibility of greater treatment flexibility for patients.
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.
Summary
Background
Non‐alcoholic fatty liver disease has reached epidemic proportions in type 2 diabetes (T2D). Glucagon‐like peptide‐1 analogues are licensed in T2D, yet little data exist on ...efficacy and safety in liver injury.
Aim
To assess the safety and efficacy of 26‐week liraglutide on liver parameters in comparison with active‐placebo.
Methods
Individual patient data meta‐analysis was performed using patient‐level data combined from six 26‐week, phase‐III, randomised controlled T2D trials, which comprise the ‘Liraglutide Effect and Action in Diabetes’ (LEAD) program. The LEAD‐2 sub‐study was analysed to assess the effect on CT‐measured hepatic steatosis.
Results
Of 4442 patients analysed, 2241 (50.8%) patients had an abnormal ALT at baseline mean ALT 33.8(14.9) IU/L in females; 47.3(18.3) IU/L in males. Liraglutide 1.8 mg reduced ALT in these patients vs. placebo (−8.20 vs. −5.01 IU/L; P = 0.003), and was dose‐dependent (no significant differences vs. placebo with liraglutide 0.6 or 1.2 mg). This effect was lost after adjusting for liraglutide's reduction in weight (mean ALT difference vs. placebo −1.41 IU/L, P = 0.21) and HbA1c (+0.57 IU/L, P = 0.63). Adverse effects with 1.8 mg liraglutide were similar between patients with and without baseline abnormal ALT. In LEAD‐2 sub‐study, liraglutide 1.8 mg showed a trend towards improving hepatic steatosis vs. placebo (liver‐to‐spleen attenuation ratio +0.10 vs. 0.00; P = 0.07). This difference was reduced when correcting for changes in weight (+0.06, P = 0.25) and HbA1c (0.00, P = 0.93).
Conclusions
Twenty‐six weeks' liraglutide 1.8 mg is safe, well tolerated and improves liver enzymes in patients with type 2 diabetes. This effect appears to be mediated by its action on weight loss and glycaemic control.
To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: ...type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.
PDF
