Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective.

Tirzepatide is a novel glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes and under investigation for use in chronic weight management, major adverse cardiovascular events and the management of other conditions, including heart failure with preserved ejection fraction and obesity and non-cirrhotic non-alcoholic steatohepatitis. The Phase 3 SURPASS 1-5 clinical trial programme was designed to assess efficacy and safety of once-weekly subcutaneously injected tirzepatide (5, 10 and 15 mg), as monotherapy or combination therapy, across a broad spectrum of people with type 2 diabetes. Use of tirzepatide in clinical studies was associated with marked reductions of glycated haemoglobin (-1.87 to -2.59%, -20 to -28 mmol/mol) and body weight (-6.2 to -12.9 kg), as well as reductions in parameters commonly associated with heightened cardiometabolic risk such as blood pressure, visceral adiposity and circulating triglycerides. In SUPRASS-2, these reductions were greater than with the GLP-1 receptor agonist semaglutide 1 mg. Tirzepatide was well tolerated, with a low risk of hypoglycaemia when used without insulin or insulin secretagogues and showed a generally similar safety profile to the GLP-1 receptor agonist class. Accordingly, evidence from these clinical trials suggests that tirzepatide offers a new opportunity for the effective lowering of glycated haemoglobin and body weight in adults with type 2 diabetes.

A detailed exploration of early infant milk feeding in a prospective birth cohort study in Ireland: combination feeding of breast milk and infant formula and early breast-feeding cessation.

Breast-feeding initiation and continuation rates in the UK and Ireland are low relative to many European countries. As a core outcome of the prospective Cork Nutrition and Development Maternal-Infant Cohort (COMBINE) study (Cork, Ireland), we aimed to describe infant milk feeding practices in detail and examine the prevalence and impact of combination feeding of breast milk and infant formula on breast-feeding duration. COMBINE recruited 456 nulliparous mothers (2015-2017) for maternal-infant follow-up via interview at hospital discharge (median 3 (interquartile range (IQR) 2, 4) d (n 453)), 1 (n 418), 2 (n 392), 4 (n 366), 6 (n 362) and 9 (n 345) months of age. Median maternal age was 32 (IQR 29, 34) years, 97 % of mothers were of white ethnicity, 79 % were Irish-born and 75 % were college-educated. Overall, 75 % breastfed to any extent at discharge and 44 % breastfed solely. At 1, 2, 4, 6 and 9 months, respectively, 40, 36, 33, 24 and 19 % breastfed solely. Combination feeding of breast milk and infant formula was common at discharge (31 %) and 1 month (20 %). Reasons for combination feeding at 1 month included perceived/actual hunger (30 %), healthcare professional advice (31 %) and breast-feeding difficulties (13 %). Of mothers who breastfed to any extent at discharge, 45 % stopped within 4 months. Mothers who combination fed were more likely to cease breast-feeding than those who breastfed solely (relative risk 2·3 by 1 month and 12·0 by 2 months). These granular data provide valuable insight to early milk feeding practices and indicate that supporting early breast-feeding without formula use may be key to the successful continuation of breast-feeding.

Effects of Tirzepatide Versus Basal Insulins in People With Type 2 Diabetes and Different Baseline Glycemic Patterns: Post Hoc Analyses of the SURPASS-3 and SURPASS-4 Trials.

OBJECTIVE: This post hoc analysis assessed change from baseline to week 52 in glycemic parameters for tirzepatide (5, 10, 15 mg) versus insulin degludec (SURPASS-3 trial) and glargine (SURPASS-4 trial) in people with type 2 diabetes and different baseline glycemic patterns, based on fasting serum glucose (FSG) and postprandial glucose (PPG) values. RESEARCH DESIGN AND METHODS: Participant subgroups with low FSG/low PPG, low FSG/high PPG, high FSG/low PPG, and high FSG/high PPG were defined according to the median values of these measures. RESULTS: All tirzepatide doses and basal insulins were associated with decreased HbA1c, FSG, and PPG values from baseline to week 52 in all subgroups (P < 0.05). Within each subgroup, HbA1c and PPG decreases were greater with tirzepatide than insulin (P < 0.05). FSG decreases were generally similar. There were no differential treatment effects by FSG/PPG subgroup. CONCLUSIONS: In this post hoc analysis, tirzepatide was associated with superior glycemic control compared with insulin, irrespective of baseline glycemic pattern.

Time to Reach Glycaemic and Body Weight Loss Thresholds with Tirzepatide in Patients with Type 2 Diabetes: A Pre-planned Exploratory Analysis of SURPASS-2 and SURPASS-3.

INTRODUCTION: Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, provides clinically meaningful improvements in glycaemic control and body weight loss in people with type 2 diabetes. The early efficacy profile of tirzepatide after treatment initiation is of interest. In this exploratory pre-planned analysis, we evaluated the time to achieve glycaemic control and body weight loss thresholds with tirzepatide. METHODS: In two randomised studies, we compared time to achieve HbA1c (< 7.0% and ≤ 6.5%) and weight loss (≥ 5%, SURPASS-2 only) thresholds among people treated with tirzepatide (5, 10, and 15 mg), semaglutide 1 mg in SURPASS-2, and titrated insulin degludec in SURPASS-3. Longitudinal logistic regression models were used to explore the proportion of participants achieving HbA1c and body weight loss thresholds at 4, 12, and 24 weeks. The time to achieve these thresholds was analysed and compared between groups using the Cox proportional-hazards model. RESULTS: Overall, greater proportions of participants achieved the HbA1c and body weight loss thresholds at 4, 12, and 24 weeks with tirzepatide compared with semaglutide 1 mg and insulin degludec. The median time to achieve HbA1c < 7.0% (8.1 weeks with each tirzepatide dose, 12.0 weeks with semaglutide 1 mg, and 12.1 weeks with insulin degludec) and ≤ 6.5% (12.1, 15.7, and 24.1 weeks, respectively) was faster with tirzepatide than semaglutide 1 mg and insulin degludec. In SURPASS-2, the median time to first achieve a body weight loss of ≥ 5% was faster with tirzepatide 5 mg (16.0 weeks) and 10 and 15 mg (12.4 weeks) than with semaglutide 1 mg (24.0 weeks). CONCLUSION: Analyses of data from SURPASS-2 and -3 revealed that tirzepatide treatment enabled more people with type 2 diabetes to achieve glycaemic thresholds and these were achieved faster than with semaglutide 1 mg or insulin degludec. Tirzepatide-treated participants also achieved a body weight loss of ≥ 5% significantly faster with tirzepatide than with semaglutide 1 mg. TRIAL REGISTRATION NUMBERS: NCT03987919; NCT03882970.

Effects of Tirzepatide Versus Insulin Glargine on Cystatin C-Based Kidney Function: A SURPASS-4 Post Hoc Analysis.

OBJECTIVE: Tirzepatide reduces HbA1c and body weight, and creatinine-based estimated glomerular filtration rate (eGFR) decline. Unlike creatine-derived eGFR (eGFR-creatinine), cystatin C-derived eGFR (eGFR-cystatin C) is unaffected by muscle mass changes. We assessed effects of tirzepatide on eGFR-creatinine and eGFR-cystatin C. RESEARCH DESIGN AND METHODS: Our primary outcome was eGFR change from baseline at 52 weeks with pooled tirzepatide (5, 10, and 15 mg) and titrated insulin glargine in adults with type 2 diabetes and high cardiovascular risk (SURPASS-4). RESULTS: Least squares mean (SE) eGFR-creatinine (mL/min/1.73 m2) changes from baseline with tirzepatide and insulin glargine were -2.5 (0.38) and -3.9 (0.38) (between-group difference, 1.4 [95% CI 0.3-2.4]) and -3.5 (0.37) and -5.3 (0.37) (between-group difference, 1.8 [95% CI 0.8-2.8]) for eGFR-cystatin C. Baseline, 1-year, and 1-year change from baseline values significantly correlated between eGFR-cystatin C and eGFR-creatinine. Measures of eGFR changes did not correlate with body weight changes. CONCLUSIONS: Tirzepatide slows the eGFR decline rate, supporting a kidney-protective effect.

Exploring the concept of functional vitamin D deficiency in pregnancy: impact of the interaction between 25-hydroxyvitamin D and parathyroid hormone on perinatal outcomes.

Background: Associations of vitamin D with perinatal outcomes are inconsistent and few studies have considered the wider calcium metabolic system. Objectives: We aimed to explore functional vitamin D deficiency in pregnancy by investigating associations between vitamin D status, parathyroid hormone (PTH), and perinatal outcomes. Design: SCOPE (Screening for Pregnancy Endpoints) Ireland is a prospective cohort study of low-risk, nulliparous pregnant women. We measured serum 25-hydroxyvitamin D [25(OH)D] and PTH at 15 wk of gestation in 1754 participants. Results: Mean ± SD 25(OH)D was 56.6 ± 25.8 nmol/L (22.7 ± 10.3 ng/mL) and geometric mean (95% CI) PTH was 7.84 pg/mL (7.7, 8.0 pg/mL) [0.86 pmol/L (0.85, 0.88 pmol/L)]. PTH was elevated in 34.3% of women who had 25(OH)D <30 nmol/L and in 13.9% of those with 25(OH)D ≥75 nmol/L. Whereas 17% had 25(OH)D <30 nmol/L, 5.5% had functional vitamin D deficiency, defined as 25(OH)D <30 nmol/L with elevated PTH. Elevated mean arterial pressure (MAP), gestational hypertension, pre-eclampsia, and small-for-gestational-age (SGA) birth were confirmed in 9.2%, 11.9%, 3.8%, and 10.6% of participants, respectively. In fully adjusted regression models, neither low 25(OH)D nor elevated PTH alone increased the risk of any individual outcome. The prevalence of elevated MAP (19.1% compared with 9.7%) and SGA (16.0% compared with 6.7%) were highest (P < 0.05) in those with functional vitamin D deficiency compared with the reference group [25(OH)D ≥75 nmol/L and normal PTH]. The adjusted prevalence ratio (PR) and RR (95% CIs) for elevated MAP and SGA were 1.83 (1.02, 3.27) and 1.53 (0.80, 2.93), respectively. There was no effect of functional vitamin D deficiency on the risk of gestational hypertension (adjusted RR: 1.00; 95% CI: 0.60, 1.67) or pre-eclampsia (adjusted RR: 1.17; 95% CI: 0.32, 4.20). Conclusion: The concept of functional vitamin D deficiency, reflecting calcium metabolic stress, should be considered in studies of vitamin D in pregnancy. The SCOPE pregnancy cohort is registered at http://www.anzctr.org.au as ACTRN12607000551493.

Interactions between Vitamin D Status, Calcium Intake and Parathyroid Hormone Concentrations in Healthy White-Skinned Pregnant Women at Northern Latitude.

Adverse effects of low vitamin D status and calcium intakes in pregnancy may be mediated through functional effects on the calcium metabolic system. Little explored in pregnancy, we aimed to examine the relative importance of serum 25-hydroxyvitamin D (25(OH)D) and calcium intake on parathyroid hormone (PTH) concentrations in healthy white-skinned pregnant women. This cross-sectional analysis included 142 participants (14 ± 2 weeks' gestation) at baseline of a vitamin D intervention trial at 51.9 °N. Serum 25(OH)D, PTH, and albumin-corrected calcium were quantified biochemically. Total vitamin D and calcium intakes (diet and supplements) were estimated using a validated food frequency questionnaire. The mean ± SD vitamin D intake was 10.7 ± 5.2 µg/day. With a mean ± SD serum 25(OH)D of 54.9 ± 22.6 nmol/L, 44% of women were <50 nmol/L and 13% <30 nmol/L. Calcium intakes (mean ± SD) were 1182 ± 488 mg/day and 23% of participants consumed <800 mg/day. The mean ± SD serum albumin-adjusted calcium was 2.2 ± 0.1 mmol/L and geometric mean (95% CI) PTH was 9.2 (8.4, 10.2) pg/mL. PTH was inversely correlated with serum 25(OH)D (r = -0.311, p < 0.001), but not with calcium intake or serum calcium (r = -0.087 and 0.057, respectively, both p > 0.05). Analysis of variance showed that while serum 25(OH)D (dichotomised at 50 nmol/L) had a significant effect on PTH (p = 0.025), calcium intake (<800, 800⁻1000, ≥1000 mg/day) had no effect (p = 0.822). There was no 25(OH)D-calcium intake interaction effect on PTH (p = 0.941). In this group of white-skinned women with largely sufficient calcium intakes, serum 25(OH)D was important for maintaining normal PTH concentration.

Vitamin D in pregnancy: current perspectives and future directions.

As neonatal vitamin D status is determined by circulating maternal 25-hydroxyvitamin D [25(OH)D] concentrations, prevention of maternal vitamin D deficiency during pregnancy is essential for the avoidance of neonatal deficiency. However, a high prevalence of vitamin D deficiency has been extensively reported among gravidae and neonates from ethnic minorities and white populations resident at high latitude. Currently, regulatory authorities recommend vitamin D intakes for pregnant women that are similar to non-pregnant adults of the same age, at 10-15 µg/day (400-600 IU), to meet 25(OH)D thresholds of 25-50 nmol/liter. The lack of pregnancy-specific dietary recommendations is due to inadequate data indicating whether nutritional requirements for vitamin D during pregnancy differ from the non-pregnant state. In addition, there are few dose-response studies to determine the maternal 25(OH)D response to vitamin D intake throughout pregnancy at high latitude. These data are also required to determine vitamin D requirements during pregnancy for prevention of neonatal deficiency, an outcome which is likely to require a higher maternal 25(OH)D concentration than prevention of maternal deficiency only. With regard to the impact of vitamin D on perinatal health outcomes, which could guide pregnancy-specific 25(OH)D thresholds, dietary intervention studies to date have been inconsistent and recent systematic reviews have highlighted issues of low quality and a high risk of bias as drawbacks in the trial evidence to date. Many observational studies have been hampered by a reliance on retrospective data, unclear reporting, suboptimal clinical phenotyping and incomplete subject characterization. Current investigations of vitamin D metabolism during pregnancy have potentially exciting implications for clinical research. This paper provides an update of current dietary recommendations for vitamin D in pregnant women and a synopsis of the evidence relating vitamin D status with maternal and infant health.