The effect of AZD9567 vs. prednisolone on glycaemic control in patients with type 2 diabetes mellitus: Results from a phase 2a clinical trial.

AIMS: Corticosteroids are the treatment of choice for many inflammatory diseases but often lead to adverse effects, including hyperglycaemia. This study investigated the mechanisms driving differential effects on glucose control for AZD9567, an oral nonsteroidal selective glucocorticoid receptor modulator vs. prednisolone in 46 patients with type 2 diabetes mellitus. METHODS: In this randomized, double-blind, 2-way cross-over study (NCT04556760), participants received either AZD9567 72 mg and prednisolone 40 mg daily (cohort 1); AZD9567 40 mg and prednisolone 20 mg daily (cohort 2); or placebo and prednisolone 5 mg daily (cohort 3). Treatment duration was 3 days with a 3-week washout between treatment periods. Glycaemic control was assessed after a standardized meal and with continuous glucose monitoring. RESULTS: A significant difference between AZD9567 and prednisolone in favour of AZD9567 was observed for the change from baseline to Day 4 glucose excursions postmeal in cohort 1 (glucose area under the curve from 0 to 4 h -4.54%; 95% confidence interval [CI]: -8.88, -0.01; P = .049), but not in cohort 2 (-5.77%; 95% CI: -20.92, 12.29; P = .435). In cohort 1, significant differences between AZD9567 and prednisolone were also seen for the change from baseline to day 4 in insulin and glucagon secretion postmeal (P < .001 and P = .005, respectively) and change from baseline to Day 4 in GLP-1 response (P = .022). Significant differences between AZD9567 and prednisolone for 24-h glucose control were observed for both cohort 1 (-1.507 mmol/L; 95% CI: -2.0820, -0.9314; P < .001) and cohort 2 (-1.110 mmol/L; 95% CI -1.7257, -0.4941; P < .001). CONCLUSION: AZD9567 significantly reduced treatment-induced hyperglycaemia compared with prednisolone.

Effects of Tirzepatide vs Semaglutide on ß-cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test.

CONTEXT: In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. OBJECTIVE: To evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. DESIGN: A 28-week double-blind, randomized, placebo-controlled trial. SETTING: Two clinical research centers in Germany. PATIENTS: Patients with type 2 diabetes treated with metformin. INTERVENTIONS: Tirzepatide 15 mg, semaglutide 1 mg, placebo. MAIN OUTCOME MEASURES: Glycemic control, model-derived ß-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), ß-cell glucose (ß-CG) sensitivity, insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. RESULTS: Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < 0.01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < 0.01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < 0.01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < 0.05), showing improved ß-CG responsiveness. MMTT-derived ß-CG sensitivity was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < 0.01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. CONCLUSIONS: These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.

Pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in individuals with type 1 diabetes.

AIMS: To investigate the pharmacokinetic/pharmacodynamic properties of once-weekly insulin icodec in individuals with type 1 diabetes (T1D). MATERIALS AND METHODS: In this randomized, open-label, two-period crossover trial, 66 individuals with T1D (age 18-64 years; glycated haemoglobin ≤75 mmol/mol [≤ 9%]) were to receive once-weekly icodec (8 weeks) and once-daily insulin glargine U100 (2 weeks) at individualized fixed equimolar total weekly doses established during up to 10 weeks' run-in with glargine U100 titrated to pre-breakfast plasma glucose (PG) of 4.4-7.2 mmol/L (80-130 mg/dL). Insulin aspart was used as bolus insulin. Blood sampling for icodec pharmacokinetics was performed from the first icodec dose until 35 days after the last dose. The glucose infusion rate at steady state was assessed in glucose clamps (target 6.7 mmol/L [120 mg/dL]) at 16-52 h and 138-168 h after the last icodec dose and 0-24 h after the last glargine U100 dose. Icodec pharmacodynamics during 1 week were predicted by pharmacokinetic-pharmacodynamic modelling. Hypoglycaemia was recorded during the treatment periods based on self-measured PG. RESULTS: Icodec reached pharmacokinetic steady state on average within 2-3 weeks. At steady state, model-predicted daily proportions of glucose infusion rate during the 1-week dosing interval were 14.3%, 19.6%, 18.3%, 15.7%, 13.1%, 10.6% and 8.4%, respectively. Rates and duration of Level 2 hypoglycaemic episodes (PG <3.0 mmol/L [54 mg/dL]) were 32.8 versus 23.9 episodes per participant-year of exposure and 33 ± 25 versus 30 ± 18 min (mean ± SD) for icodec versus glargine U100. CONCLUSIONS: The pharmacokinetic/pharmacodynamic properties of icodec suggest its potential to provide basal coverage in a basal-bolus insulin regimen in people with T1D.

Pharmacodynamics, safety, tolerability and pharmacokinetics of a single oral dose of an engineered phenylalanine ammonia-lyase in patients with phenylketonuria.

The cornerstone treatment of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) is a lifelong low-protein diet with phenylalanine (Phe) free L-amino acid supplements. However, the PKU diet has significant shortcomings, and there is a clinically unmet need for new therapeutics to improve patient outcomes. CDX-6114 is a modified phenylalanine ammonia-lyase (PAL) enzyme obtained by a mutation in the Anabaena variabilis PAL sequence. CodeEvolver® protein engineering technology has been applied to improve the degradation resistance of the enzyme. In our first phase I trial, 19 patients were given a single oral dose of CDX-6114 at 7.5 g, 2.5 g, 0.7 g, or placebo in a cross-over design. After an overnight fast, patients received a standardised breakfast of 20 g of protein, thus exceeding the dietary recommendations for a single meal in patients with PKU. Plasma levels of Phe and cinnamic acid (CA) were measured over a 5-h period following CDX-6114 dosing. During the development of CDX-6114, a stability assessment using reverse-phase high-performance liquid chromatography (HPLC) assay revealed two peaks. The second peak was identified as CA. It was not previously known that as part of the mechanism of action, the CA remained associated with the protein following the conversion of Phe. Thus, recalculating the historical PAL enzyme amounts in CDX-6114 bulk substance was necessary. An updated extinction coefficient was achieved by applying a correction factor of 0.771 to previously reported doses. Postprandial plasma levels of Phe increased in all dose cohorts over time between 10% and 30% from baseline, although the actual peak of Phe levels was not achieved within the 5-h observation. When accounting for the interquartile ranges, these concentrations were similar to the placebo. As plasma levels of Phe were no longer a reliable marker for pharmacodynamics, the consistently detectable amount of CA seen in all patients who received CDX-6114 provided proof of the enzymatic activity of CDX-6114 in metabolising gastrointestinal Phe. Peak levels of CA were seen shortly after CDX-6114 intake, with a rapid decline, and remained low compared with the plasma Phe levels. This pattern indicates a short half-life, possibly due to the liquid formulation or the inability to withstand the lower pH in the human stomach compared with animal models in earlier studies. This was the first trial in patients with PKU to establish the safety and tolerability of CDX-6114. A single dose of CDX-6114 was safe and well tolerated, with no serious adverse events or presence of anti-drug antibodies detected. Efficacy will be explored in future trials using an optimised formulation.

Randomized Trial Comparing SGLT2 Inhibition and Hydrochlorothiazide on Sympathetic Traffic in Type 2 Diabetes.

Introduction: Reductions in sympathetic nervous system activity may contribute to beneficial effects of sodium glucose cotransporter 2 (SGLT2) inhibition on cardiovascular outcomes. Therefore, we tested the hypothesis that SGLT2 inhibition with empagliflozin (Empa) lowers muscle sympathetic nerve activity (MSNA) in patients with type 2 diabetes mellitus (T2DM) compared with hydrochlorothiazide (HCT) to discern SGLT2-specific actions from responses to increased natriuresis. Methods: We randomized patients with T2DM on metformin monotherapy to either 25 mg/d Empa (n = 20) or 25 mg/d HCT (n = 21) for 6 weeks in a parallel, double-blind fashion. We assessed MSNA by peroneal microneurography, blood pressure, cardiovascular and metabolic biomarkers at baseline and at the end of treatment. Results: Both drugs elicited volume depletion, as indicated by increased thoracic impedance. Compared with HCT, Empa caused 1.23 kg more body weight loss (P = 0.011) and improved glycemic control. Seated systolic blood pressure decreased with both treatments (P < 0.002). MSNA did not change significantly with either treatment; however, MSNA changes were negatively correlated with changes in body weight on Empa (P = 0.042) and on HCT(P = 0.001). The relationship was shifted to lower MSNA on Empa compared with HCT (P = 0.002). Conclusion: Increased renal sodium excretion eliciting body weight loss may promote sympathetic activation. However, sympathetic excitation in the face of increased sodium loss may be attenuated by SGLT2 inhibitor-specific actions.

Pharmacokinetic and pharmacodynamic bioequivalence of Gan & Lee insulin analogues aspart (rapilin®), lispro (prandilin®) and glargine (basalin®) with EU- und US-sourced reference insulins.

AIM: For the successful approval and clinical prescription of insulin biosimilars, it is essential to show pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence to the respective reference products sourced from the European Union and the United States. METHODS: Three phase 1, randomized, double-blind, three-period crossover trials compared single doses of the proposed biosimilar insulin analogues aspart (GL-Asp, n = 36), lispro (GL-Lis, n = 38) and glargine (GL-Gla, n = 113), all manufactured by Gan & Lee pharmaceuticals, to the respective EU- and US-reference products in healthy male participants (GL-Asp and GL-Lis) or people with type 1 diabetes (GL-Gla). Study participants received 0.2 U/kg (aspart and lispro) or 0.5 U/kg (glargine) of each treatment under automated euglycaemic clamp conditions. The clamp duration was 12 h (aspart and lispro) or 30 h (glargine). Primary PK endpoints were the total area under the PK curves (AUCins.total ) and maximum insulin concentrations (Cins.max ). Primary PD endpoints were the total area under the glucose infusion rate curve (AUCGIR.total ) and maximum glucose infusion rate (GIRmax ). RESULTS: Bioequivalence to both EU- and US-reference products were shown for all three GL insulins. Least squares mean ratios for the primary PK/PD endpoints were close to 100%, and both 90% and 95% confidence intervals were within 80%-125% in all three studies. There were no noticeable differences in the safety profiles between test and reference insulins, and no serious adverse events were reported for the GL insulins. CONCLUSION: GL-Asp, GL-Lis and GL-Gla are bioequivalent to their EU- and US-reference products.

Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in People With Type 2 Diabetes.

OBJECTIVE: To evaluate the effects of tirzepatide on body composition, appetite, and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. RESEARCH DESIGN AND METHODS: In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo (N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28. RESULTS: Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. CONCLUSIONS: Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure.

A co-formulation of pramlintide and insulin A21G (ADO09) improves postprandial glucose and short-term control of mean glucose, time in range, and body weight versus insulin aspart in adults with type 1 diabetes.

AIM: Pramlintide improves postprandial glucose but requires additional injections. We investigated the pharmacokinetics/pharmacodynamics, efficacy and safety of ADO09, pramlintide/insulin A21G co-formulation, in type 1 diabetes (T1D). MATERIALS AND METHODS: This double-blinded, randomized, two-period cross-over study compared prandial administration of ADO09 or insulin aspart over 24 days in T1D using either ≤40 U bolus insulin per day [low-dose group (LD), n = 28] or 40-75 U [high-dose group (HD), n = 16]. Glycaemic responses through continuous glucose monitoring, and pharmacokinetics/pharmacodynamics profiles following mixed-meal-tolerance tests were evaluated at baseline and at the end of treatment. RESULTS: Glucose increments from 0 to 4 h after mixed-meal-tolerance test (primary endpoint) were 39% (not statistically significantly) lower with ADO09 in the low-dose group and 69% lower in the high-dose group. Mean continuous glucose monitoring glucose during ambulatory treatment was lower with ADO09 than with aspart (LD: -8.2 ± 7.9 mg/dl, p = .0001; HD: -7.0 ± 10 mg/ml, p = .0127), and time-in-range (70-180 mg/dl) improved (LD: +4%, p = .0134; HD: +4%, p = .0432). Body weight declined significantly with ADO09 (LD: -0.8 kg; HD: -1.6 kg). Hypoglycaemic events were slightly more frequent with ADO09 versus aspart (LD: 142 vs. 115; HD: 96 vs. 79). Gastrointestinal events occurred more frequently with ADO09 but were generally transient, and no other safety signals were identified. CONCLUSIONS: In comparison with aspart, ADO09 was well tolerated and effective in T1D across a wide range of dosage, significantly improving the average blood glucose level and body weight during 24 days of ambulatory treatment. Meal test profiles confirmed improvement of glycaemic patterns and other responses with ADO09.

Pharmacokinetic and pharmacodynamic properties of the novel basal insulin Fc (insulin efsitora alfa), an insulin fusion protein in development for once-weekly dosing for the treatment of patients with diabetes.

AIM: To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of basal insulin Fc (BIF; LY3209590), a fusion protein combining a novel single-chain insulin variant together with human IgG2 Fc domain, following single and multiple once-weekly BIF administration. MATERIALS AND METHODS: The single ascending dose, 15-day study assessed four BIF doses (5-35 mg) in healthy participants and people with type 2 diabetes (T2D). In the 6-week multiple ascending dose study, people with T2D, previously treated with basal insulin, received insulin glargine daily or a one-time loading dose of BIF followed by 5 weeks of once-weekly dosing (1-10 mg). Safety, tolerability and PK and glucose PD were examined. RESULTS: Mean ages of people with T2D (N = 57) and healthy participants (N = 16) in the single-dose study were 58.4 and 35.8 years, respectively; mean body mass index values were 29.5 and 26.1 kg/m2 . BIF had a PK half-life of approximately 17 days, which led to a sustained, dose-dependent decrease in fasting blood glucose for 5 days or longer. No severe hypoglycaemia was observed. The 6-week ascending dose study included 33 people with T2D aged 40-69 years. BIF showed a low peak-to-trough ratio of 1.14 after the last dose at week 6 (steady state). Over 6 weeks, BIF seven-point glucose profiles remained constant and were similar to insulin glargine. Rates and duration of BIF hypoglycaemic events were similar to insulin glargine. CONCLUSIONS: BIF was well tolerated and the PK/PD profile enabled once-weekly dosing with minimal variation in exposure in a treatment interval of 1 week. The findings suggest BIF is suitable for further development as a weekly basal insulin in people with diabetes.

Safety, tolerability, pharmacodynamics and pharmacokinetics following once-daily doses of BI 187004, an inhibitor of 11 beta-hydroxysteroid dehydrogenase-1, over 28 days in patients with type 2 diabetes mellitus and overweight or obesity.

AIMS: To study the oral 11 beta-hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibitor BI 187004 (NCT02150824), as monotherapy and in combination with metformin, versus placebo in patients with type 2 diabetes mellitus (T2DM) affected by overweight or obesity. MATERIALS AND METHODS: This Phase II, randomized controlled trial investigated multiple rising doses of BI 187004 as monotherapy (Arm 1: 20, 80 or 240 mg) and in combination with metformin (Arm 2: 240 mg), in adults with T2DM and a body mass index of 28-40 kg/m2 . RESULTS: In total, 103 patients (Arm 1: n = 62, Arm 2: n = 41) were included in this study. BI 187004 was rapidly absorbed and exposure increased approximately dose-dependently. Target engagement of 11ß-HSD1 was observed with near-full inhibition of 11ß-HSD1 in the liver [decreased (5α-tetrahydrocortisol + 5ß-tetrahydrocortisol)/tetrahydrocortisone ratio]; hypothalamic-pituitary-adrenal axis activation was also seen (increased total urinary corticosteroids). No clinically relevant changes from baseline with BI 187004 treatment were observed for bodyweight or meal tolerance test parameters, or in most efficacy endpoints testing glucose and lipid metabolism; a significant increase was observed in weighted mean plasma glucose (p < .05 for 80 and 240 mg BI 187004) but not fasting plasma glucose. Drug-related adverse events were reported for 14 patients (22.6%) in Arm 1 and 10 patients (24.4%) in Arm 2, most frequently headache, diarrhoea, flushing and dizziness. A dose-dependent increase in heart rate was seen with BI 187004 treatment. CONCLUSIONS: BI 187004 was generally well tolerated in patients with T2DM. Despite complete 11ß-HSD1 inhibition, no clinically relevant effects were observed with BI 187004.

Selective Inhibition of 11beta-Hydroxysteroiddehydrogenase-1 with BI 187004 in Patients with Type 2 Diabetes and Overweight or Obesity: Safety, Pharmacokinetics, and Pharmacodynamics After Multiple Dosing Over 14 Days.

OBJECTIVE: To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with the selective 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in male and female patients with type 2 diabetes and overweight or obesity. METHODS: Randomized, double-blind, parallel-group, placebo-controlled multiple rising dose study, with 10-360 mg BI 187004 once daily over 14 days in 71 patients. Assessments included 11beta-HSD1 inhibition in the liver and subcutaneous adipose tissue ex vivo (clinical trial registry number NCT01874483). RESULTS: BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 51.8% (n=29) for BI 187004 and 35.7% (n=5) for placebo. There were no clinically relevant deviations in laboratory or electrocardiogram parameters besides one patient on 360 mg discontinuing treatment due to moderate supraventricular tachycardia.BI 187004 was rapidly absorbed within 2 h; exposure increased non-proportionally. The oral clearance was low, apparent volume of distribution was moderate to large, and terminal half-life with 106-124 h was rather long. Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies was 87.9-99.4% immediately after the second dose and 73.8-97.5% 24 h after the last dose of BI 187004. CONCLUSIONS: BI 187004 was safe and well tolerated over 14 days and could be dosed once daily. Targeted 11beta-HSD1 enzyme inhibition of≥80% could be shown for BI 187004 doses≥40 mg. This dose should be targeted in further studies to test blood glucose lowering in patients with type 2 diabetes and overweight or obesity.

Association of HbA1c with VO2max in Individuals with Type 1 Diabetes: A Systematic Review and Meta-Analysis.

The aim of this systematic review and meta-analysis was to evaluate the association between glycemic control (HbA1c) and functional capacity (VO2max) in individuals with type 1 diabetes (T1DM). A systematic literature search was conducted in EMBASE, PubMed, Cochrane Central Register of Controlled Trials, and ISI Web of Knowledge for publications from January 1950 until July 2020. Randomized and observational controlled trials with a minimum number of three participants were included if cardio-pulmonary exercise tests to determine VO2max and HbA1c measurement has been performed. Pooled mean values were estimated for VO2max and HbA1c and weighted Pearson correlation and meta-regression were performed to assess the association between these parameters. We included 187 studies with a total of 3278 individuals with T1DM. The pooled mean HbA1c value was 8.1% (95%CI; 7.9−8.3%), and relative VO2max was 38.5 mL/min/kg (37.3−39.6). The pooled mean VO2max was significantly lower (36.9 vs. 40.7, p = 0.001) in studies reporting a mean HbA1c > 7.5% compared to studies with a mean HbA1c ≤ 7.5%. Weighted Pearson correlation coefficient was r = −0.19 (p < 0.001) between VO2max and HbA1c. Meta-regression adjusted for age and sex showed a significant decrease of −0.94 mL/min/kg in VO2max per HbA1c increase of 1% (p = 0.024). In conclusion, we were able to determine a statistically significant correlation between HbA1c and VO2max in individuals with T1DM. However, as the correlation was only weak, the association of HbA1c and VO2max might not be of clinical relevance in individuals with T1DM.

A Randomized Controlled Clinical Trial in Healthy Older Adults to Determine Efficacy of Glycine and N-Acetylcysteine Supplementation on Glutathione Redox Status and Oxidative Damage.

Glycine and cysteine are non-essential amino acids that are required to generate glutathione, an intracellular tripeptide that neutralizes reactive oxygen species and prevents tissue damage. During aging glutathione demand is thought to increase, but whether additional dietary intake of glycine and cysteine contributes towards the generation of glutathione in healthy older adults is not well understood. We investigated supplementation with glycine and n-acetylcysteine (GlyNAC) at three different daily doses for 2 weeks (low dose: 2.4 g, medium dose: 4.8 g, or high dose: 7.2 g/day, 1:1 ratio) in a randomized, controlled clinical trial in 114 healthy volunteers. Despite representing a cohort of healthy older adults (age mean = 65 years), we found significantly higher baseline levels of markers of oxidative stress, including that of malondialdehyde (MDA, 0.158 vs. 0.136 µmol/L, p < 0.0001), total cysteine (Cysteine-T, 314.8 vs. 276 µM, p < 0.0001), oxidized glutathione (GSSG, 174.5 vs. 132.3 µmol/L, p < 0.0001), and a lower ratio of reduced to oxidized glutathione (GSH-F:GSSG) (11.78 vs. 15.26, p = 0.0018) compared to a young reference group (age mean = 31.7 years, n = 20). GlyNAC supplementation was safe and well tolerated by the subjects, but did not increase levels of GSH-F:GSSG (end of study, placebo = 12.49 vs. 7.2 g = 12.65, p-value = 0.739) or that of total glutathione (GSH-T) (end of study, placebo = 903.5 vs. 7.2 g = 959.6 mg/L, p-value = 0.278), the primary endpoint of the study. Post-hoc analyses revealed that a subset of subjects characterized by high oxidative stress (above the median for MDA) and low baseline GSH-T status (below the median), who received the medium and high doses of GlyNAC, presented increased glutathione generation (end of study, placebo = 819.7 vs. 4.8g/7.2 g = 905.4 mg/L, p-value = 0.016). In summary GlyNAC supplementation is safe, well tolerated, and may increase glutathione levels in older adults with high glutathione demand. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05041179, NCT05041179.

What is the value of faster acting prandial insulin? Focus on ultra rapid lispro.

Rapid-acting insulins (RAIs) have been instrumental in the management of diabetes because of their improved postprandial glucose (PPG) control compared with regular human insulin. However, their absorption rate and time action following subcutaneous administration still falls short of the normal physiological response to meal consumption, increasing the risk of early postmeal hyperglycaemia and late postmeal hypoglycaemia. Increased demand for faster acting insulins, which can quickly control PPG excursions without increasing the risk of late hypoglycaemia, led to the development of ultra-rapid-acting insulins, including ultra-rapid lispro (URLi). URLi is a novel formulation of insulin lispro with accelerated absorption driven by two excipients: treprostinil, which increases local vasodilation, and citrate, which increases local vascular permeability. Clinical pharmacology studies consistently showed an earlier onset and shorter duration of action with URLi compared with Lispro. In a head-to-head study with Faster aspart, Aspart and Lispro, URLi was absorbed faster, provided earlier insulin action, and more closely matched physiological glucose response than the other insulins tested. URLi's unique pharmacokinetic properties increase its potential for improved PPG control beyond that achieved with RAIs. Indeed, in pivotal phase 3 trials, URLi was superior to Lispro for PPG control both at 1 and 2 hours after a meal in type 1 and type 2 diabetes with multiple daily injections, and in type 1 diabetes with continuous subcutaneous insulin infusion. This was achieved without increasing the risk of hypoglycaemia. In this review, we focus on the clinical and pharmacological evidence for URLi in the treatment of diabetes and discuss the potential benefits and considerations with URLi compared with RAIs.

Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial.

BACKGROUND: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, shows a remarkable ability to lower blood glucose, enabling many patients with long-standing type 2 diabetes to achieve normoglycaemia. We aimed to understand the physiological mechanisms underlying the action of tirzepatide in type 2 diabetes. METHODS: This multicentre, randomised, double-blind, parallel-arm, phase 1 study was done at two centres in Germany. Eligible patients were aged 20-74 years, had type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral antihyperglycaemic medicine, 3 months before study entry. Via a randomisation table, patients were randomly assigned (3:3:2) to subcutaneously receive either tirzepatide 15 mg, semaglutide 1 mg, or placebo once per week. Endpoint measurements were done at baseline and the last week of therapy (week 28). The primary endpoint was the effect of tirzepatide versus placebo on the change in clamp disposition index (combining measures of insulin secretion and sensitivity) from baseline to week 28 of treatment and was analysed in the pharmacodynamic analysis set, which comprised all randomly assigned participants who received at least one dose of a study drug and had evaluable pharmacodynamic data. Safety was analysed in the safety population, which comprised all randomly assigned participants who received at least one dose of a study drug. Secondary endpoints included the effect of tirzepatide versus semaglutide on the change in clamp disposition index from baseline to week 28 of treatment, glucose control, total insulin secretion rate, M value (insulin sensitivity), and fasting and postprandial glucagon concentrations. Exploratory endpoints included the change in fasting and postprandial insulin concentrations. This study is registered with ClinicalTrials.gov, NCT03951753, and is complete. FINDINGS: Between June 28, 2019, and April 8, 2021, we screened 184 individuals and enrolled 117 participants, all of whom were included in the safety population (45 in the tirzepatide 15 mg group, 44 in the semaglutide 1 mg group, and 28 in the placebo group). Because of discontinuations and exclusions due to missing or unevaluable data, 39 patients in each treatment group and 24 patients in the placebo group comprised the pharmacodynamic analysis set. With tirzepatide, the clamp disposition index increased from a least squares mean of 0·3 pmol m-2 L min-2 kg-1 (SE 0·03) at baseline by 1·9 pmol m-2 L min-2 kg-1 (0·16) to total 2·3 pmol m-2 L min-2 kg-1 (SE 0·16) at week 28 and, with placebo, the clamp disposition index did not change much from baseline (least squares mean at baseline 0·4 pmol m-2 L min-2 kg-1 [SE 0·04]; change from baseline 0·0 pmol m-2 L min-2 kg-1 [0·03]; least squares mean at week 28 0·3 [SE 0·03]; estimated treatment difference [ETD] tirzepatide vs placebo 1·92 [95% CI 1·59-2·24]; p<0·0001). The improvement with tirzepatide in clamp disposition index was significantly greater than with semaglutide (ETD 0·84 pmol m-2 L min-2 kg-1 [95% CI 0·46-1·21]). This result reflected significant improvements in total insulin secretion rate (ETD 102·09 pmol min-1 m-2 [51·84-152·33]) and insulin sensitivity (ETD 1·52 mg min-1 kg-1 [0·53-2·52]) for tirzepatide versus semaglutide. On meal tolerance testing, tirzepatide significantly reduced glucose excursions (lower insulin and glucagon concentrations) compared with placebo, with effects on these variables being greater than with semaglutide. The safety profiles of tirzepatide and semaglutide were similar, with gastrointestinal adverse events being the most common (11 [24%], 13 [30%], and seven [25%] with nausea; nine [20%], 13 [30%], and six [21%] with diarrhoea; and three [7%], five [11%], and one [4%] with vomiting, for tirzepatide, semaglutide, and placebo, respectively). There were no deaths. INTERPRETATION: The glycaemic efficacy of GIP/GLP-1 receptor agonist tirzepatide in type 2 diabetes results from concurrent improvements in key components of diabetes pathophysiology, namely ß-cell function, insulin sensitivity, and glucagon secretion. These effects were large and help to explain the remarkable glucose-lowering ability of tirzepatide seen in phase 3 studies. FUNDING: Eli Lilly.

Novel Drugs for Diabetes Therapy.

Since the first use of insulin 100 years ago, there have been marked improvements in diabetes therapy including, but not limited to, the development of oral antidiabetic agents (OADs), incretin mimetics and insulin analogues. Still, there are substantial shortcomings in diabetes therapy: the blood-glucose lowering effect of OADs is often limited, incretin mimetics often induce gastrointestinal side effects and insulins still induce hypoglycaemia and weight gain in many patients.This review evaluates on-going developments of antidiabetic drugs for their potential for future therapy focussing on injectable therapies. Recent data from dual agonists, in particular tirzepatide, a combination of GIP- and GLP-1 receptor agonists, show unprecedented reductions in HbA1c, body weight and cardiovascular risk factors. Once-weekly administrations of incretin mimetics open up the potential of a combination with once-weekly insulins that have been shown to have low peak-to-trough fluctuations. Eventually, it might be feasible to administer incretins and insulins (combinations) orally. While this has already been achieved for incretins, there are still some challenges for the oral application of insulin. Nevertheless, many promising data of novel antidiabetic drugs clearly indicate that therapy of people with diabetes will become easier, safer and more efficacious in the next years.

Comparison of Pharmacokinetics and Pharmacodynamics of Inhaled Technosphere Insulin and Subcutaneous Insulin Lispro in the Treatment of Type 1 Diabetes Mellitus.

BACKGROUND: This study was performed to satisfy a US Food and Drug Administration post-marketing requirement to compare the dose responses for Technosphere® Insulin (TI; MannKind Corporation, Westlake Village, CA, USA) and subcutaneous insulin lispro (LIS) across a wide range of doses. OBJECTIVES: This single-center, open-label, randomized, cross-over study defined the pharmacokinetic/pharmacodynamic curves for inhaled TI vs subcutaneous LIS in persons with type 1 diabetes mellitus. METHODS: Each volunteer received six treatments while undergoing euglycemic clamps: three doses of TI (10, 30 and 120 U) and LIS (8, 30, and 90 U). Primary endpoint was area under the glucose infusion rate vs time curve from start of treatment administration to end of clamp. Key secondary endpoints included readouts of insulin exposure and timing of pharmacokinetic/pharmacodynamic profiles. RESULTS: Insulin exposure was more than dose proportional, increasing with dose1.08 for LIS and dose1.35 for TI. Time to reach 10% of the maximum glucose infusion rate was 7 to 15 min for TI vs 21 to 38 min for LIS. End of effect was dose dependent for both treatments, ranging from 2 to 6 h (TI) and 5 to 10 h (LIS). Glucose infusion rate exhibited saturation for both treatments. Technosphere Insulin produced a lesser total effect per unit insulin than LIS due to its faster absorption and correspondingly shorter duration of exposure. The difference was large enough to require significantly different doses to achieve the same total effect. CONCLUSIONS: Technosphere Insulin has a considerably faster onset and shorter duration of action than LIS. Consequently, the overall effect of TI is smaller than that of LIS and unit-for-unit dose conversion is not appropriate. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02470637; 12 June, 2015.

New Clamp-PID Algorithm for Automated Glucose Clamps Improves Clamp Quality.

BACKGROUND: In automated glucose clamp experiments, blood glucose (BG) concentrations are kept close to a predefined target level using variable glucose infusion rates (GIRs) determined by implemented algorithms. Clamp quality (ie, the ability to keep BG close to target) highly depends on the quality of these algorithms. We developed a new Clamp algorithm based on the proportional-integral-derivative (PID) approach and compared clamp quality between this and the established Biostator (BS) algorithm. METHODS: In numerical simulations, the PID-based algorithm was optimized in silico. The optimized Clamp-PID algorithm was tested in in vitro experiments and finally validated in vivo in a small (n = 5) clinical study. RESULTS: In silico, in vitro, and in vivo experiments showed better clamp quality for the new Clamp-PID algorithm compared with the BS algorithm: precision and absolute control deviation (ACD) decreased from 3.7% to 1.1% and from 2.9 mg/dL to 0.6 mg/dL, respectively, in the numerical simulation. The in vitro validation demonstrated reductions in precision (from 3.3% ± 0.1% (mean ± SD) to 1.4% ± 0.4%) and in ACD (from 2.3 mg/dL ± 0.4 mg/dL to 0.8 mg/dL ± 0.2 mg/dL), respectively. In the clinical study, precision and ACD improved from 6.5% ± 1.3% to 4.0% ± 1.1% and from 3.6 mg/dL ± 0.9 mg/dL to 2.2 mg/dl ± 0.6 mg/dl, respectively. The quality parameter utility did not change. CONCLUSIONS: The new Clamp-PID algorithm improves the clamp quality parameters precision and ACD versus the BS algorithm.

Limited evidence for sympathetic neural overactivation in older patients with type 2 diabetes mellitus.

Introduction: Mechanistic studies suggested that excess sympathetic activity promotes arterial hypertension while worsening insulin sensitivity. Older patients with type 2 diabetes are at particularly high cardiovascular and metabolic risk. However, data on sympathetic activity in this population is scarce. Methods: We studied 61 patients with type 2 diabetes mellitus (22 women, 60.9 ± 1.4 years; 39 men, 60.9 ± 1.4 years). They had to have diabetes for at least 2 years, a hemoglobin A1c of 6.5-10%, a body-mass-index of 20-40 kg/m2, and had to be treated with stable doses of metformin only. We recorded ECG, finger and brachial blood pressure, and muscle sympathetic nerve activity (MSNA). Results: MSNA was 37.5 ± 2.5 bursts/min in women and 39.0 ± 2.0 bursts/min in men (p = 0.55). MSNA expressed as burst incidence was 52.7 ± 2.0 bursts/100 beats in women and 59.2 ± 3.1 bursts/100 beats in men (p = 0.21). Five out of 39 men (12.8%) and two out of 22 women (9.1%) exhibited resting MSNA measurements above the 95th percentile for sex and age. In the pooled analysis, MSNA was not significantly correlated with systolic blood pressure, diastolic blood pressure, body mass index, waist circumference, body composition, or HbA1c (r 2 < 0.02, p > 0.26 for all). Discussion: We conclude that relatively few older patients with type 2 diabetes mellitus exhibit increased MSNA. The large interindividual variability in MSNA cannot be explained by gender, blood pressure, body mass index, or glycemic control.