Early-Onset Type 2 Diabetes and Tirzepatide Treatment: A Post Hoc Analysis From the SURPASS Clinical Trial Program.

OBJECTIVE: We evaluated baseline characteristics of participants with early-onset type 2 diabetes (T2D) from the SURPASS program and tirzepatide's effects on glycemic control, body weight (BW), and cardiometabolic markers. RESEARCH DESIGN AND METHODS: This post hoc analysis compared baseline characteristics and changes in mean HbA1c, BW, waist circumference (WC), lipids, and blood pressure (BP) in 3,792 participants with early-onset versus later-onset T2D at week 40 (A Study of Tirzepatide [LY3298176] in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone [SURPASS-1] and A Study of Tirzepatide [LY3298176] Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes [SURPASS-2]) or week 52 (A Study of Tirzepatide [LY3298176] Versus Insulin Degludec in Participants With Type 2 Diabetes [SURPASS-3]). Analyses were performed by study on data from participants while on assigned treatment without rescue medication in case of persistent hyperglycemia. RESULTS: At baseline in SURPASS-2, participants with early-onset versus later-onset T2D were younger with longer diabetes duration (9 vs. 7 years, P < 0.001) higher glycemic levels (8.5% vs. 8.2%, P < 0.001), higher BW (97 vs. 93 kg, P < 0.001) and BMI (35 vs. 34 kg/m2, P < 0.001), and a similarly abnormal lipid profile (e.g., triglycerides 167 vs. 156 mg/dL). At week 40, similar improvements in HbA1c (-2.6% vs. -2.4%), BW (-14 vs. -13 kg), WC (-10 vs. -10 cm), triglycerides (-26% vs. -24%), HDL (7% vs. 7%), and systolic BP (-6 vs. -7 mmHg) were observed in both subgroups with tirzepatide. CONCLUSIONS: Despite younger age, participants with early-onset T2D from the SURPASS program had higher glycemic levels and worse overall metabolic health at baseline versus those with later-onset T2D. In this post hoc analysis, similar improvements in HbA1c, BW, and cardiometabolic markers were observed with tirzepatide, irrespective of age at T2D diagnosis. Future studies are needed to determine long-term outcomes of tirzepatide in early-onset T2D.

An Economic Evaluation of the Relationship Between Glycemic Control and Total Healthcare Costs for Adults with Type 2 Diabetes: Retrospective Cohort Study.

INTRODUCTION: Glycemic control is associated with better outcomes among individuals with type 2 diabetes (T2D). This research examines total US all-cause medical costs for adults with T2D with recommended glycemic control (HbA1c < 7%) compared to poor glycemic control (HbA1c ≥ 7%). METHODS: The study used administrative claims data linked to HbA1c laboratory test results from January 1, 2015 through June 30, 2021 to identify adults with T2D with a recorded HbA1c test. Patients with recommended glycemic control at index date were propensity score matched to patients with poor glycemic control. General linear models and two-part models were used to compare all-cause outpatient, drug, acute care and total costs for 1 year post index date. RESULTS: The study included 59,830 propensity-matched individuals. Results indicate that recommended glycemic control, compared to poor glycemic control, was associated with statistically significantly lower all-cause acute care ($23,868 ± $21,776 vs. $24,352 ± $22,223), drug ($10,277 ± $14,671 vs. $10,540 ± $14,928), and total medical costs ($41,381 ± $42,757 vs. $42,054 ± $43,422) but significantly higher outpatient costs ($7290 ± $12,028 vs. $7026 ± $11,587) (all p < 0.0001). Sensitivity analyses examined results based upon alternative HbA1c thresholds of ≤ 6.5% and < 8%. Results were generally robust to alternative HbA1c thresholds, with higher HbA1c thresholds associated with higher all-cause total costs as well as increased savings for having HbA1c below threshold. CONCLUSIONS: Glycemic control was associated with significantly lower all-cause total, drug, and acute care medical costs. Given the high prevalence of T2D in the USA, our results suggest potential economic benefits associated with glycemic control for healthcare providers.

Tirzepatide as Monotherapy Improved Markers of Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes (SURPASS-1).

Context: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes (T2D). SURPASS-1, a phase 3 trial of tirzepatide monotherapy in people with early T2D, enables evaluating effects of tirzepatide on pancreatic beta-cell function and insulin sensitivity (IS) without other background antihyperglycemic medications. Objective: Explore changes in biomarkers of beta-cell function and IS with tirzepatide monotherapy. Design: Post hoc analyses of fasting biomarkers with analysis of variance and mixed model repeated measures. Setting: Forty-seven sites in 4 countries. Patients: Four hundred seventy-eight T2D participants. Intervention: Tirzepatide (5, 10, 15 mg), placebo. Main Outcome Measures: Analyze biomarkers of beta-cell function and IS at 40 weeks. Results: At 40 weeks, markers of beta-cell function improved with tirzepatide monotherapy vs placebo with reductions from baseline in fasting proinsulin levels (49-55% vs -0.6%) and in intact proinsulin/C-peptide ratios (47-49% vs -0.1%) (P < .001, all doses vs placebo). Increases from baseline in homeostatic model assessment for beta-cell function (computed with C-peptide) (77-92% vs -1.4%) and decreases in glucose-adjusted glucagon levels (37-44% vs +4.8%) were observed with tirzepatide vs placebo (P < .001, all doses vs placebo). IS improved as indicated by reductions from baseline in homeostatic model assessment for insulin resistance (9-23% vs +14.7%) and fasting insulin levels (2-12% vs +15%), and increases in total adiponectin (16-23% vs -0.2%) and insulin-like growth factor binding protein 2 (38-70% vs +4.1%) with tirzepatide vs placebo at 40 weeks (P ≤ .031, all doses vs placebo, except for fasting insulin levels with tirzepatide 10 mg). Conclusions: As monotherapy for early T2D, tirzepatide achieved significant improvements in biomarkers of both pancreatic beta-cell function and IS.

Relationship between body weight change and glycaemic control with tirzepatide treatment in people with type 2 diabetes: A post hoc assessment of the SURPASS clinical trial programme.

AIM: To assess the relationship between HbA1c and body weight reductions with tirzepatide treatment (5, 10 or 15 mg). MATERIALS AND METHODS: HbA1c and body weight data at 40 weeks (SURPASS-1, -2 and -5) and 52 weeks (SURPASS-3 and -4) were analysed by trial. RESULTS: Across the SURPASS clinical trials, HbA1c reductions from baseline were observed in 96%-99%, 98%-99% and 94%-99% of participants treated with tirzepatide 5, 10 and 15 mg, respectively. Moreover, 87%-94%, 88%-95% and 88%-97% of participants, respectively, experienced weight loss associated with HbA1c reductions. Statistically significant associations (correlation coefficients ranging from 0.1438 to 0.3130 across studies; P ≤ .038) between HbA1c and body weight changes were observed with tirzepatide in SURPASS-2, -3, -4 (all doses) and -5 (tirzepatide 5 mg only). CONCLUSIONS: In this post hoc analysis, consistent reductions in both HbA1c and body weight were observed in most participants treated with tirzepatide at doses of 5, 10 or 15 mg. A statistically significant but modest association between HbA1c and body weight change was observed in SURPASS-2, SURPASS-3 and SURPASS-4, suggesting that both weight-independent and weight-dependent mechanisms are responsible for the tirzepatide-induced improvement in glycaemic control.

The Association Between Obesity and the 5-Year Prevalence of Morbidity and Mortality Among Adults with Type 2 Diabetes.

INTRODUCTION: This retrospective claims database study examined the prevalence of mortality and morbidity among adults with type 2 diabetes (T2D) and obesity. METHODS: The study used deidentified data from 2007 to 2021 from the Optum® Market Clarity Dataset. A cohort of adults with T2D and obesity were identified, and age- and sex-adjusted prevalence rates were calculated for mortality, a composite cardiovascular outcome (CCO), a composite microvascular outcome (CMO), and other complications. Results were examined overall and by obesity class (class 1, class 2, and class 3). RESULTS: For the 15,970 adults included in the study, the prevalence of CCO and CMO after 5 years was 15.3% and 60.7%, respectively. The 5-year prevalence of mortality was 10.9%. There were statistically significant differences in prevalence rates by obesity class, with obesity class 3 associated with higher rates of morbidity and mortality compared to obesity classes 1 or 2. Specifically, after 5 years, the prevalence of mortality was 9.4%, 10.3% and 13.6% for obese classes 1, 2 and 3, respectively (P < 0.05 between class 3 and class 2 or 1). Similarly, For obesity classes 1, 2 and 3, the 5-year prevalence of CCO was 13.0%, 14.5% and 18.4% and the rates for CMO were 58.0%, 57.9% and 64.8%, respectively (both P < 0.05 between class 3 and class 2 or 1). Regarding other complications, differences in the prevalence of atherosclerotic cardiovascular disease (ASCVD) and obstructive sleep apnea (OSA) were statistically significantly higher with increasing obesity class. CONCLUSIONS: The results indicate that for a cohort of adults with T2D and obesity, obesity class 3 is associated with significantly higher mortality and morbidity, including CCO, CMO, ASCVD and OSA. These findings suggest that treatment which reduces obesity among individuals with T2D may have significant health benefits, although additional studies are needed to confirm the results.

Achievement of glycaemic targets with weight loss and without hypoglycaemia in type 2 diabetes with the once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide: A post hoc analysis of the SURPASS-1 to -5 studies.

AIM: To assess composite endpoints combining glycaemic control (HbA1c < 7.0%, ≤ 6.5% or < 5.7%) with weight loss (≥ 5%, ≥ 10% or ≥ 15%) and without hypoglycaemia with tirzepatide in type 2 diabetes (T2D). MATERIALS AND METHODS: Data from the phase 3 SURPASS programme were evaluated post hoc by trial. Participants with T2D were randomized to tirzepatide (5, 10 and 15 mg), placebo (SURPASS-1,5), semaglutide 1 mg (SURPASS-2) or titrated basal insulin (SURPASS-3,4). The proportions of participants achieving the composite endpoints were compared between tirzepatide and the respective comparator groups at week 40/52. RESULTS: The proportions of participants achieving an HbA1c value of less than 7.0% with 5% or more weight loss and without hypoglycaemia ranged from 43% to 82% with tirzepatide across the SURPASS-1 to -5 trials versus 4%-5% with placebo, 51% with semaglutide 1 mg and 5% with basal insulin (P < .001 vs. all comparators). The proportions of participants achieving an HbA1c value of less than 7.0% with 10% or more, or 15% or more weight loss and without hypoglycaemia were significantly higher with all tirzepatide doses versus comparators across trials (P < .001 or P < .05). Similar results were observed for all other combinations of endpoints with an HbA1c value of 6.5% or less, or less than 5.7%, with more tirzepatide-treated participants achieving these endpoints versus those in the comparator groups, including semaglutide. CONCLUSIONS: Across the SURPASS-1 to -5 clinical trials, more tirzepatide-treated participants with T2D achieved clinically meaningful composite endpoints, which included reaching glycaemic targets with various degrees of weight loss and without hypoglycaemia, than those in the comparator groups.

The Association Between Sustained HbA1c Control and Long-Term Complications Among Individuals with Type 2 Diabetes: A Retrospective Study.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) represents a rising burden in the US and worldwide, with the condition shown to be associated with relatively large human and economic costs. Part of the reason for such high costs associated with T2D is that the condition is often accompanied by additional health-related complications. The goal of this research is to examine the association between glycemic control and diabetes-related complications for individuals with T2D. METHODS: The Optum Clinformatics® Data Mart (CDM) database from 2007 to 2020 was used to identify adults with T2D. Individuals were classified as having sustained glycemic control (all hemoglobin A1c [HbA1c] < 7%) or poor glycemic control (all HbA1c ≥ 7%) over the 5-year post-period, and diabetes-related complications were identified based upon the Diabetes Complications Severity Index. Multivariable analyses examined the association between sustained glycemic control and diagnosis of a diabetes-related complication in the post-period. RESULTS: Maintaining HbA1c < 7% over the 5-year post-period, compared to maintaining HbA1c ≥ 7%, was associated with reduced odds of the diabetes-related complications of cardiovascular disease (odds ratio [OR] = 0.76, 95% confidence interval [CI] 0.61-0.94), metabolic disease (OR = 0.37, 95% CI 0.22-0.600), neuropathy (OR = 0.62, 95% CI 0.45-0.84), nephropathy (OR = 0.81, 95% CI 0.69-0.94), and peripheral vascular disease (OR = 0.52, 95% CI 0.33-0.83). There was no statistically significant association between sustained glycemic control and cerebrovascular disease. CONCLUSIONS: Sustained glycemic control was found to be associated with significant reductions in the odds of being diagnosed with diabetes-related complications over a 5-year post-period.

The Association Between HbA1c and 1-Year Diabetes-Related Medical Costs: A Retrospective Claims Database Analysis.

INTRODUCTION: The American Diabetes Association (ADA) has identified a target hemoglobin A1c (HbA1c) < 7% as appropriate for most adults with type 2 diabetes (T2D). This research examines US diabetes-related healthcare costs for adults with T2D for individuals with glycemic control (HbA1c < 7%) compared to poor glycemic control (HbA1c ≥ 7%). METHODS: The Optum Clinformatics® Data Mart database from 2016 to 2020 was used to identify a cohort of adults with T2D who had a recorded HbA1c test (with first such date identified as the index date) and continuous insurance from 1 year prior through 1 year post index date. Patients with glycemic control were propensity matched to patients with poor glycemic control. Generalized linear models and two-part models examined diabetes-related outpatient, drug, acute care, and total costs over the 1-year post-period. RESULTS: There were 34,538 propensity matched individuals included in the study. Results indicate that glycemic control (HbA1c < 7%), compared to poor glycemic control (HbA1c ≥ 7%) ,was associated with statistically significantly lower annual diabetes-related acute ($5671 ± $4216 vs $6138 ± $4211), outpatient ($6051 ± $4216 vs $7259 ± $7771), drug ($3739 ± $4581 vs $4288 ± $4788), and total costs care ($13,704 ± $10,635 vs $16,460 ± $10,885) (all P < 0.0001). Sensitivity analyses also examined results based upon alternative HbA1c thresholds which were chosen on the basis of expert guidelines and prior clinical trial thresholds (< 6%, ≤ 6.5%, < 8%, and ≤ 9%). In all cases, being below threshold was associated with statistically significantly lower diabetes-related total costs and component costs. Results also illustrate that, in general, higher HbA1c thresholds are associated with higher diabetes-related costs. CONCLUSION: Glycemic control was found to be associated with significantly lower annual diabetes-related component and total costs. Results suggest economic benefits associated with having HbA1c at or below target.

Weight Change and the Association with Adherence and Persistence to Diabetes Therapy: A Narrative Review.

PURPOSE: Type 2 diabetes (T2D) medication adherence is poor and is impacted by individual drug characteristics. Treatment-associated weight change can affect medication-taking behavior. This review aimed to explore weight change on T2D therapy and consider its impact on adherence and discontinuation. METHODS: Searches were conducted in MEDLINE and EMBASE (2005 to September 2020), and among recent congress abstract books for studies providing data on medication adherence or discontinuation and weight change in people with T2D (PwD). RESULTS: Nine studies meeting the inclusion criteria were identified from 9188 bibliographic records. All three studies exploring weight change and discontinuation reported weight loss to be associated with higher persistence. Seven studies of varying design explored weight change and adherence. Four reported absolute weight change (kg) and adherence: one pooled data from different diabetes medications and demonstrated that self-reported adherence was significantly associated with weight loss; however, three studies found that weight change in adherent PwD was in the direction of the known weight profile (loss/gain) of the evaluated drug. Categorical weight loss (≥3%) and adherence were reported in two studies: one reported that numerically more adherent versus non-adherent PwD lost ≥3% weight regardless of the drug's weight profile, the other showed that early weight loss with a glucagon-like peptide-1 agonist was significantly associated with better adherence. One study reported adherence by categorical weight change; as weight loss increased, adherence scores improved, regardless of drug type. CONCLUSION: Findings suggest that discontinuation rates may be lower in PwD who lose as compared to those who gain weight on T2D treatment. The evidence base on adherence and weight change is more challenging to interpret due to the range of study designs. Given the importance of weight control in T2D, further research exploring the individual's treatment, weight journey, and behaviors over time should be undertaken.

Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial.

BACKGROUND: Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone. METHODS: We did a 40-week, double-blind, randomised, placebo-controlled, phase 3 trial (SURPASS-1), at 52 medical research centres and hospitals in India, Japan, Mexico, and the USA. Adult participants (≥18 years) were included if they had type 2 diabetes inadequately controlled by diet and exercise alone and if they were naive to injectable diabetes therapy. Participants were randomly assigned (1:1:1:1) via computer-generated random sequence to once a week tirzepatide (5, 10, or 15 mg), or placebo. All participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834. FINDINGS: From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA1c 7·9% [63 mmol/mol], age 54·1 years [SD 11·9], 231 [48%] women, diabetes duration 4·7 years, and body-mass index 31·9 kg/m2) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo for changes from baseline in HbA1c, fasting serum glucose, bodyweight, and HbA1c targets of less than 7·0% (<53 mmol/mol) and less than 5·7% (<39 mmol/mol). Mean HbA1c decreased from baseline by 1·87% (20 mmol/mol) with tirzepatide 5 mg, 1·89% (21 mmol/mol) with tirzepatide 10 mg, and 2·07% (23 mmol/mol) with tirzepatide 15 mg versus +0·04% with placebo (+0·4 mmol/mol), resulting in estimated treatment differences versus placebo of -1·91% (-21 mmol/mol) with tirzepatide 5 mg, -1·93% (-21 mmol/mol) with tirzepatide 10 mg, and -2·11% (-23 mmol/mol) with tirzepatide 15 mg (all p<0·0001). More participants on tirzepatide than on placebo met HbA1c targets of less than 7·0% (<53 mmol/mol; 87-92% vs 20%) and 6·5% or less (≤48 mmol/mol; 81-86% vs 10%) and 31-52% of patients on tirzepatide versus 1% on placebo reached an HbA1c of less than 5·7% (<39 mmol/mol). Tirzepatide induced a dose-dependent bodyweight loss ranging from 7·0 to 9·5 kg. The most frequent adverse events with tirzepatide were mild to moderate and transient gastrointestinal events, including nausea (12-18% vs 6%), diarrhoea (12-14% vs 8%), and vomiting (2-6% vs 2%). No clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycaemia were reported with tirzepatide. One death occurred in the placebo group. INTERPRETATION: Tirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment. FUNDING: Eli Lilly and Company.

Treatment and prevention of severe hypoglycaemia in people with diabetes: Current and new formulations of glucagon.

Some therapies for diabetes increase the risk of hypoglycaemia, in particular all insulins and insulin secretagogues, including the glinides and sulfonylureas. Hypoglycaemia remains a major limiting factor to successful glycaemic management, despite the availability of prevention options such as insulin analogues, continuous glucose monitoring, insulin pumps, and dogs that have been trained to detect hypoglycaemia. Non-severe (self-treated) and severe (requiring assistance for recovery) hypoglycaemia rates are higher in people with type 1 diabetes, but those with insulin-treated type 2 diabetes are also at risk. Education and regular review are essential between people with diabetes and their caregivers and healthcare professionals about symptoms, prevention and treatment. Awareness of the potential dangers of hypoglycaemia is fundamental to the optimal management of diabetes. When therapy is intensified to achieve glycaemic targets, it is important that people at risk of severe hypoglycaemia, and particularly their caregivers, have ready access to effective treatment for hypoglycaemia emergencies. The current and potential formulations of glucagon available for treatment of severe hypoglycaemia are reviewed.

Patient preferences for glucagon-like peptide 1 receptor-agonist treatment attributes.

PURPOSE: The importance of patient-centered care in the management of type 2 diabetes mellitus (T2DM) is widely advocated. Understanding the attributes of T2DM medications important to patients is thus essential for effective management, in order to limit disease progression. This literature review aimed to identify studies comparing patient preferences, based on process and outcome attributes, between GLP1-receptor agonist (RA) profiles and between GLP1 RA and insulin profiles. METHODS: MEDLINE, Embase, PsycINFO, and the Cochrane Library (2005-present) were searched for studies in patients with T2DM or the general population that compared preferences for GLP1 RAs or GLP1 RAs versus insulin using contingent valuation, conjoint analysis (discrete-choice experiments [DCEs], willingness to pay), rating-based approaches of specific attributes, standard gamble, or time trade-off. Studies comparing drug A versus drug B without explicit attribute valuation were excluded. RESULTS: Ten records met eligibility criteria. Eight studies compared preferences for GLP1 RA- profile attributes, one compared GLP1 RA versus insulin glargine profiles, and one addressed both comparisons. Important attributes driving patient preferences in DCEs were dose frequency, type of device, needle size, change in glycated hemoglobin, and adverse-event profile. Time trade-off evaluations demonstrated that weekly GLP1 RA injection-device attributes (reconstitution, waiting during preparation, needle handling) had a measurable impact on preference. Willingness-to-pay analysis showed that patients were more willing to pay extra for attributes of once-daily liraglutide over twice-weekly exenatide or insulin. Direct preference elicitation in DCEs revealed that patients preferred medication profiles representing GLP1 RAs with less frequent dosing and preferred GLP1 RA profiles over insulin. CONCLUSION: Process and outcome attributes are important drivers of patient preference for GLP1 RAs. Findings from patient-preference studies can inform clinical decision-making and help align care with patient values, which has the potential to improve medication adherence and outcomes.

Effect of once weekly dulaglutide by baseline beta-cell function in people with type 2 diabetes in the AWARD programme.

Glucagon-like peptide-1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose-dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta-cell function (as measured by HOMA2-%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide-treated patients from AWARD-1, AWARD-3 and AWARD-6 clinical studies were categorised based on their homeostatic model assessment of beta-cell function (HOMA2-%B) tertiles. Changes in glycaemic measures in response to treatment with once-weekly dulaglutide were evaluated in each HOMA2-%B tertile. Patients with low HOMA2-%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P < .001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB-2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; -1.55% vs. -0.98% [-16.94 vs. -10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; -1.00 vs. -1.18% [-10.93 vs. -12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C-peptide were observed in the low tertile. Similar increases in HOMA2-%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta-cell function.

Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers.

Approximately 90% of T2D patients in the US are diagnosed and treated in the primary care setting, and the majority of the burden of disease management falls to primary care providers. Here, we discuss the clinical data for once weekly dulaglutide, e.g. the results of seven completed Phase 3 trials, patient preference studies, patient reported outcomes (PRO), and clinical data surrounding the dulaglutide administration device. Dulaglutide 1.5 mg once weekly demonstrated superiority to placebo, metformin, sitagliptin, exenatide BID, and insulin glargine (in 2 trials), and non-inferiority to liraglutide in reduction of HbA1c from baseline, with an acceptable safety profile. Dulaglutide-treated patients achieved the composite endpoint of an HbA1c <7.0% with no hypoglycemia, no severe hypoglycemia, and no weight gain significantly more than metformin, sitagliptin, exenatide BID or insulin glargine treated patients. Dulaglutide consistently showed an early onset of glycemic control, lasting up to 104 weeks. Additionally, PRO and patient preference data support the benefit of once weekly dulaglutide for the treatment of T2D.

The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects.

PURPOSE: Prasugrel is a novel thienopyridine prodrug metabolised to an active metabolite that binds irreversibly to the platelet P2Y(12) receptor and inhibits adenosine diphosphate (ADP)-induced platelet aggregation. We compared prasugrel pharmacokinetics, pharmacodynamics, and tolerability in healthy Chinese, Japanese, Korean and Caucasian subjects. METHODS: In an open-label, single-centre, parallel-design study, 89 healthy subjects (25 Chinese, 20 Japanese, 22 Korean and 22 Caucasian) aged 20-65 years were given a prasugrel 60-mg loading dose (LD) followed by daily 10-mg maintenance doses (MD) for 7 days and then 5-mg MD for 10 days. Plasma concentrations of prasugrel's active metabolite and inhibition of ADP-induced platelet aggregation (IPA) were determined. RESULTS: Mean exposure to prasugrel's active metabolite in all treatment regimens was higher in each of the Asian groups than in the Caucasian group, although there was considerable overlap between individual exposure estimates in Asians and Caucasians. The mean IPA was also higher in Asians than in Caucasians following a prasugrel 60-mg LD, although the difference did not consistently achieve statistical significance. Prasugrel 10-mg or 5-mg MD produced statistically significantly higher IPA in each Asian group compared with that in the Caucasians. Prasugrel was well tolerated during the LD and MD regimens by all groups. CONCLUSIONS: Mean exposure to the prasugrel active metabolite following prasugrel 60-mg LD and during daily 10-mg or 5-mg MD was higher in each of the Asian groups than in the Caucasian group, which resulted in greater platelet inhibition.

Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage-specific programming.

STAT4 is a critical component in the development of inflammatory adaptive immune responses. It has been extensively characterized as a lineage-determining factor in Th1 development. However, the genetic program activated by STAT4 that results in an inflammatory cell type is not well defined. In this report, we use DNA isolated from STAT4-chromatin immunoprecipitation to perform chromatin immunoprecipitation-on-chip analysis of over 28,000 mouse gene promoters to identify STAT4 targets. We demonstrate that STAT4 binds multiple gene-sets that program distinct components of the Th1 lineage. Although many STAT4 target genes display STAT4-dependent IL-12-inducible expression, other genes displayed IL-12-induced histone modifications but lack induction, possibly due to high relative basal expression. In the subset of genes that STAT4 programs for expression in Th1 cells, IL-12-induced mRNA levels remain increased for a longer time than mRNA from genes that are not programmed. This suggests that STAT4 binding to target genes, while critical, is not the only determinant for STAT4-dependent gene programming during Th1 differentiation.

Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells.

T-cell responses to a cytokine milieu instruct the development of multiple effector phenotypes. While transforming growth factor-beta(1) (TGF-beta(1)) inhibits the development of T helper type 1 (Th1) and Th2 cells, we demonstrate that like interleukin-6 (IL-6) and IL-4, IL-12 can inhibit the development of TGF-beta(1)-induced Foxp3-expressing adaptive T regulatory (aTreg) cells. Signal transducer and activator of transcription 4 (STAT4) is critical for the response to IL-12, although there is a parallel pathway involving T box expressed in T cells (T-bet), and cells from mice double-deficient in STAT4 and T-bet are refractory to the inhibition of aTreg-cell development by IL-12. While the ability of these cytokines to promote Th differentiation may contribute to this effect, we observe that culture with IL-12, or other instructive cytokines, results in an increase in repressive chromatin modifications at the Foxp3 locus that limit STAT5 binding to Foxp3, without observed effects on IL-2 signalling pathways. In a model of allergic lung inflammation there are increased percentages of Treg cells in the lungs of Stat4(-/-) mice, compared with wild-type mice, and increases in Treg cells correlate with decreased allergic inflammation. Overall, these results suggest an important role for STAT4 in regulating Treg-cell development.

Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination.

Transcriptional regulatory networks direct the development of specialized cell types. The transcription factors signal tranducer and activator of transcription 4 (Stat4) and T-bet are required for the interleukin-12 (IL-12)-stimulated development of T helper 1 (Th1) cells, although the hierarchy of activity by these factors has not been clearly defined. In this report, we show that these factors did not function in a linear pathway and that each factor played a unique role in programming chromatin architecture for Th1 gene expression, with subsets of genes depending on Stat4, T-bet, or both for expression in Th1 cells. T-bet was not able to transactivate expression of Stat4-dependent genes in the absence of endogenous Stat4 expression. Thus, T-bet requires Stat4 to achieve complete IL-12-dependent Th1 cell-fate determination. These data provide a basis for understanding how transiently activated and lineage-specific transcription factors cooperate in promoting cellular differentiation.

The SH3 domain of Lck modulates T-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of Raf-1.

Engagement of the T-cell antigen receptor (TCR) results in the proximal activation of the Src family tyrosine kinase Lck. The activation of Lck leads to the downstream activation of the Ras/Raf/MEK/ERK signaling pathway (where ERK is extracellular signal-related kinase). Under conditions of weak, but not strong, stimulation through the TCR, a version of Lck that contains a single point mutation in the SH3 (Src homology 3) domain (W97ALck) fails to support the activation of ERK, despite initiating signaling through the TCR, as demonstrated by the robust activation of ZAP-70, PLC-gamma, and Ras. We determined that the signaling lesion in W97ALck-expressing cells lies at the level of Raf-1 activation and is dependent on the presence of tyrosines 340/341 in the Raf-1 sequence. These data demonstrate a second function for Lck in TCR-mediated signaling to ERK. Additionally, we found that a significant fraction of Lck is localized to the Golgi apparatus and that, compared with wild-type Lck, W97ALck displays aberrant Golgi membrane localization. Our results support a model where under conditions of weak stimulation through the TCR, in addition to activated Ras, Golgi apparatus-localized Lck is needed for the full activation of Raf-1.