Changes in Basal and Bolus Insulin Requirements with Tirzepatide as an Adjunctive Therapy in Adults with Type 1 Diabetes Using Tandem Control-IQ.

INTRODUCTION: This study was aimed at investigating changes in insulin requirements and glycemic outcomes in adults with type 1 diabetes (T1D) using Control IQ (Tandem Diabetes) automated insulin delivery system (AID) over 8 months of tirzepatide treatment. METHODS: In this single-center, observational study, we collected demographic, A1c, weight, sensor glucose, and insulin dose data for adults with T1D who were using AID and initiated tirzepatide adjunct therapy for clinical indications (n = 11, median age 37, 64% female and mean body mass index of 39.6 kg/m2). Data were compared from baseline and over 8 months. RESULTS: Within 2 months of tirzepatide treatment, there were significant reductions in total daily insulin [median (IQR) 73.9 (47.6-95.8) to 51.7 (46.7-66.8) units/day, p < 0.001], basal insulin [47 (28.2-51.8) to 32.4 (25.5-46.3) units/day, p < 0.001], and bolus insulin [31.4 (19.9-38.3) to 17.9 (14.9-22.2) units/day, p < 0.001] requirements. Insulin dose reduction from 2 to 8 months was modest. The frequency of user-initiated boluses did not differ throughout the study. Despite reductions in total insulin requirement, time in range (70-180 mg/dl) increased by 7%, A1c reduced by 0.5%, weight reduced by 9%, without increase in time below 70 mg/dl. CONCLUSIONS: This pilot study provides clinical guidance on insulin titration for adults with T1D who may initiate tirzepatide therapy. Based on the findings of this study, we recommend reducing 25% of total daily insulin dose at tirzepatide initiation in adults with T1D using AID with baseline A1c of less than 7.5%. Higher doses of tirzepatide were associated with greater weight loss, however, the reduction in insulin requirement was minimal.

Reduced Efficacy of Glucagon-Like Peptide-1 Receptor Agonists Therapy in People With Type 1 Diabetes and Genetic Forms of Obesity.

BACKGROUND: Once weekly Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) have been shown to improve glycemic outcomes and cause significant weight loss. However, 9% to 27% of individuals have little or no response to these drugs. In this article, we investigated the efficacy of GLP-1 RA therapy among adults with type 1 diabetes and obesity likely related to genetic mutations compared with obesity likely unrelated to genetic mutations. METHODS: In this retrospective study, we compared body weight and glycated hemoglobin (HbA1c) change with the use of GLP-1 RA therapy (including a dual agonist, Tirzepatide) over six months among adults with type 1 diabetes and obesity likely (n = 11, median age 39.5 years with a median BMI of 43.0 kg/m2) versus unlikely related to genetic mutation(s) (n = 15, median age 45.8 years with a median BMI of 38.7 kg/m2). RESULTS: Six months of GLP-1 RA treatment resulted in a numerically lower reduction of weight (-5.75 ± 9.46 kg vs -8.65 ± 9.36 kg, P = .44) and HbA1c (-0.28 ± 0.96% vs -0.43 ± 0.57%, P = .64) among individuals with obesity likely versus unlikely related to a genetic mutation(s), respectively. Fewer individuals with genetic obesity met goal weight loss ≥5% or HbA1c decrease ≥0.4% than did individuals with obesity unlikely related to a genetic cause (36.4% vs 80.0%, P = .04). CONCLUSIONS: The weight loss and glycemic lowering effects of GLP-1 RA therapy may be decreased in people with type 1 diabetes and obesity likely related to genetic causes. Further research is needed to understand GLP-1 RA mechanisms via energy regulating genes.

The Association of High and Low Glycation With Incident Diabetic Retinopathy in Adults With Type 1 Diabetes.

BACKGROUND: We investigated the risk of incident diabetic retinopathy (DR) among high glycator compared to low glycator patients based on the hemoglobin glycation index (HGI). Visit-to-visit variations in HGI also were assessed. METHODS: Glycated hemoglobin (HbA1c) and continuous glucose monitoring data were collected up to 7 years prior to the date of eye examination defining incident DR or no retinopathy (control). Hemoglobin glycation index was calculated as difference in measured HbA1c and an estimated A1c from sensor glucose (eA1c) to define high (HbA1c - eA1c >0%) or low (HbA1c - eA1c <0%) glycator. Stable glycators were defined as ≥75% of visits with same HGI category. Logistic regression was used to assess the association between glycation category and incident DR. RESULTS: Of 119 adults with type 1 diabetes (T1D), 49 (41%) were stable low glycator (HbA1c - eA1c <0%), 36 (30%) were stable high glycator (HbA1c - eA1c >0%), and 34 (29%) were unstable glycator. Using alternate criteria to define high vs low glycator (consistent difference in HbA1c - eA1c of > 0.4% or <0.4%, respectively), 53% of the adults were characterized as unstable glycator. Compared to low glycators, high glycators did not have a significantly higher risk for incident DR over time when adjusted for age, T1D duration and continuous glucose monitoring (CGM) sensor type (odds ratio [OR] = 1.31, 95% confidence interval [CI] = 0.48-3.62, P = .15). CONCLUSIONS: The risk of diabetic retinopathy was not found to differ significantly comparing high glycators to low glycators in adults with T1D. Moreover, HbA1c - eA1c relationship was not stable in nearly 30% to 50% adults with T1D, suggesting that discordance in HbA1c and eA1c are mostly related either HbA1c measurements or estimation of A1c from sensor glucose rather than physiological reasons.

Continuous Glucose Monitoring for Prediabetes: What Are the Best Metrics?

BACKGROUND: Continuous glucose monitoring (CGM) has transformed the care of type 1 and type 2 diabetes, and there is potential for CGM to also become influential in prediabetes identification and management. However, to date, we do not have any consensus guidelines or high-quality evidence to guide CGM goals and metrics for use in prediabetes. METHODS: We searched PubMed for all English-language articles on CGM use in nonpregnant adults with prediabetes published by November 1, 2023. We excluded any articles that included subjects with type 1 diabetes or who were known to be at risk for type 1 diabetes due to positive islet autoantibodies. RESULTS: Based on the limited data available, we suggest possible CGM metrics to be used for individuals with prediabetes. We also explore the role that glycemic variability (GV) plays in the transition from normoglycemia to prediabetes. CONCLUSIONS: Glycemic variability indices beyond the standard deviation and coefficient of variation are emerging as prominent identifiers of early dysglycemia. One GV index in particular, the mean amplitude of glycemic excursion (MAGE), may play a key future role in CGM metrics for prediabetes and is highlighted in this review.

Maternal diabetes and fracture risk in offspring: a population-based analysis.

Factors affecting intrauterine environment exerts influence on skeletal health and fracture risk in later life. Diabetes during pregnancy is known to influence birth weight and is associated with fetal overgrowth. However, the effects of maternal diabetes on fracture risk in offspring is unknown. This study was aimed to evaluate the association between maternal diabetes and fracture risk in offspring. Using population-based administrative health data for Manitoba, Canada, we identified deliveries complicated by gestational diabetes and type 2 diabetes between April 1, 1980, and March 31, 2020. The cohort was followed for a median of 15.8 yr. The primary outcome was any incident fracture in offspring. Secondary outcomes were long bone upper extremity fracture, long bone lower extremity fracture, vertebral fracture, and any non-trauma fractures. Cox proportional hazard regression models were used to estimate fracture risk in offspring by maternal diabetes status adjusted for relevant covariates. Of the 585 176 deliveries, 26 397 offspring were born to women with diabetes (3.0% gestational diabetes and 1.5% type 2 diabetes), and 558 779 were born to women without diabetes. The adjusted risk for any fracture was 7% (hazard ratio, 1.07; 95% CI, 2.7-11.5%) higher in the offspring of mothers with diabetes than offspring of mothers without diabetes. Types of fractures were similar between the 2 groups with a predominance of long bone upper extremity fractures. In conclusion, maternal diabetes was associated with a modest increase in fracture risk in offspring. Longitudinal prospective studies are needed to understand intrauterine and postnatal factors that may influence fracture risk in the offspring of mothers with diabetes.

Efficacy and Safety of Tirzepatide in Adults With Type 1 Diabetes: A Proof of Concept Observational Study.

BACKGROUND: Tirzepatide is approved by the United States Food and Drug Administration (FDA) for the management of type 2 diabetes. The efficacy and safety of this drug have not been studied in people with type 1 diabetes (T1D). METHODS: In this single-center, retrospective, observational study, hemoglobin A1C (HbA1c), weight, body mass index (BMI), and continuous glucose monitoring (CGM) data were collected from electronic health records of adults with T1D at initiation of tirzepatide and at subsequent clinic visits over 8 months. Primary outcomes were reduction in HbA1c and percent change in body weight and secondary outcomes were change in CGM metrics and BMI over 8 months from baseline. RESULTS: The mean (±SD) age of the 26 adults (54% female) with T1D was 42 ± 8 years with a mean BMI of 36.7 ± 5.3 kg/m2. There was significant reduction in HbA1c by 0.45% at 3 months and 0.59% at 8 months, and a significant reduction in body weight by 3.4%, 10.5%, and 10.1% at 3, 6, and 8 months after starting tirzepatide. Time in target range (TIR = 70-180 mg/dL) and time in tight target range (TITR = 70-140 mg/dL) increased (+12.6%, P = .002; +10.7%, P = .0016, respectively) and time above range (TAR >180 mg/dL) decreased (-12.6%, P = .002) at 3 months, and these changes were sustained over 8 months. The drug was relatively safe and well tolerated with only 2 patients discontinuing the medication. CONCLUSIONS: Tirzepatide significantly reduced HbA1c and body weight in adults with T1D. A randomized controlled trial is needed to establish efficacy and safety of this drug in T1D.

Time in Range Is Associated with Incident Diabetic Retinopathy in Adults with Type 1 Diabetes: A Longitudinal Study.

Abstract Objective: To evaluate the association between continuous glucose monitoring (CGM)-based time in various ranges and the subsequent development of diabetic retinopathy (incident DR) in adults with type 1 diabetes. Methods: Between June 2018 and March 2022, adults with type 1 diabetes with incident DR or no retinopathy (control) were identified. CGM data were collected retrospectively for up to 7 years before the date of eye examination defining incident DR or control. Associations between incident DR and CGM metrics were evaluated using logistic regression models. Results: This analysis included 71 adults with incident DR (mean age 27 years, 52% females, and mean diabetes duration 15 years) and 92 adults without DR (mean age 38 years, 48% females, and mean diabetes duration 20 years). Adjusting for age, diabetes duration, and CGM type, each 0.5% increase in glycated hemoglobin (HbA1c), 10 mg/dL increase in mean glucose, 5% decrease in time in target range 70-180 mg/dL (TIR), 5% decrease in time in tight target range 70-140 mg/dL (TITR), and 5% increase in time above 180 mg/dL (TAR) were associated with 24%, 22%, 18%, 28%, and 20% increase in odds of incident DR, respectively. Spearman correlations of TIR, TITR, TAR, and mean glucose with each other were all ≥0.97. Conclusion: Similar to HbA1c, TIR, TITR, TAR, and mean glucose were associated with increased risk for incident DR in adults with type 1 diabetes. These CGM metrics are highly correlated indicating that they provide similar information on glycemic control and diabetic retinopathy risk.

Association between continuous glucose monitoring metrics and clinical outcomes in adults with type 1 diabetes in a real-world setting.

AIMS: Continuous glucose monitoring (CGM) metrics can assist diabetes management. Consensus statements recommend > 70 % time in range (TIR) and ≤ 36 % glucose coefficient of variation (CV). However, how these targets perform in clinical practice is unknown. This retrospective, longitudinal cohort study analyzed relationships between TIR, CV, glycated hemoglobin (HbA1c), and hypoglycemia in a real-world setting. METHODS: Data of 542 adults with type 1 diabetes who used CGM (January 2014-July 2020) were analyzed. Associations between TIR and HbA1c at the same and subsequent visits, incidence rate ratios (IRRs) for hypoglycemia at different CVs, and number of hypoglycemic events at cross-sections of HbA1c and CV were estimated by regression. RESULTS: TIR was inversely related to HbA1c; for every 10 % increase in TIR, HbA1c was significantly reduced by 0.34 % (4 mmol/mol) and 0.20 % (2 mmol/mol) at the same and subsequent visits, respectively. Level 2 hypoglycemia was significantly reduced at CV < 30 %, 30-33 %, 33.1-36 %, and 36.1-40 %: adjusted IRRs vs CV ≥ 40.1 % of 0.14, 0.28, 0.32, and 0.50, respectively. Hypoglycemic events were reduced at lower CV across HbA1c levels and at higher HbA1c across CV levels. CONCLUSION: This study quantifies HbA1c improvements with increased TIR and hypoglycemia reductions with improved CV in clinical practice.

Control-IQ Technology Use in Individuals With High Insulin Requirements: Results From the Multicenter Higher-IQ Trial.

BACKGROUND: Control-IQ technology version 1.5 allows for a wider range of weight and total daily insulin (TDI) entry, in addition to other changes to enhance performance for users with high basal rates. This study evaluated the safety and performance of the updated Control-IQ system for users with basal rates >3 units/h and high TDI in a multicenter, single arm, prospective study. METHODS: Adults with type 1 diabetes (T1D) using continuous subcutaneous insulin infusion (CSII) and at least one basal rate over 3 units/h (N = 34, mean age = 39.9 years, 41.2% female, diabetes duration = 21.8 years) used the t:slim X2 insulin pump with Control-IQ technology version 1.5 for 13 weeks. Primary outcome was safety events (severe hypoglycemia and diabetic ketoacidosis (DKA)). Central laboratory hemoglobin A1c (HbA1c) was measured at system initiation and 13 weeks. Participants continued using glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose transport protein 2 (SGLT-2) inhibitors, or other medications for glycemic control and/or weight loss if on a stable dose. RESULTS: All 34 participants completed the study. Fifteen participants used a basal rate >3 units/h for all 24 hours of the day. Nine participants used >300 units TDI on at least one day during the study. There were no severe hypoglycemia or DKA events. Time in range 70-180 mg/dL was 64.8% over the 13 weeks, with 1.0% time <70 mg/dL. Hemoglobin A1c decreased from 7.69% at baseline to 6.87% at 13 weeks (-0.82%, P < .001). CONCLUSIONS: Control-IQ technology version 1.5, with wider range of weight and TDI input and enhancements for users with high insulin requirements, was safe in individuals with T1D in this study.

Safety and Efficacy of Switching SAR341402 Insulin Aspart and Originator Insulin Aspart vs Continuous Use of Originator Insulin Aspart in Adults With Type 1 Diabetes: The GEMELLI X Trial.

BACKGROUND: SAR341402 insulin aspart (SAR-Asp) is a rapid-acting insulin analog developed as an interchangeable biosimilar to the marketed insulin aspart reference product (NovoLog; NN-Asp). GEMELLI X was a randomized controlled trial to assess outcomes with a biosimilar in line with the US Food and Drug Administration requirements for designation as an interchangeable biosimilar. This report assessed whether multiple switches between SAR-Asp and NN-Asp lead to equivalent safety and efficacy compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D) treated with multiple daily injections, using once-daily insulin glargine U100 (Lantus) as the basal insulin. METHODS: This open-label randomized (1:1), parallel-group, phase 3 trial compared four × four weeks of alternating use of individually titrated SAR-Asp and NN-Asp (NN-Asp for first four weeks, SAR-Asp in last four weeks; switching group) vs 16 weeks of continuous use of NN-Asp (nonswitching group). End points included pharmacokinetics, immunogenicity, adverse events, hypoglycemia, insulin dose, and change in efficacy parameters. RESULTS: Of the 210 patients randomized, 200 (95.5%) completed the trial. Patients assigned to switching group (n = 104) and nonswitching group (n = 106) showed similar safety and tolerability, including anti-insulin aspart antibody responses, adverse events, and hypoglycemia. At week 16, there was no relevant difference between switching vs nonswitching groups in the change from baseline in glycated hemoglobin (least square [LS] mean difference = 0.05% [95% confidence interval [CI] = -0.13, 0.22]; 0.50 mmol/mol [-1.40, 2.39]), fasting plasma glucose (LS mean difference = 0.23 mmol/L [95% CI = -1.08, 1.53]; 4.12 mg/dL [-19.38, 27.62]), and changes in insulin dosages. CONCLUSIONS: Alternating doses of SAR-Asp and NN-Asp compared with continuous use of NN-Asp showed similar safety, immunogenicity, and clinical efficacy in adults with T1D. This study supports interchangeability between SAR-Asp and NN-Asp in T1D management.

Safety and Feasibility Evaluation of Automated User Profile Settings Initialization and Adaptation With Control-IQ Technology.

BACKGROUND: Optimization of automated insulin delivery (AID) settings is required to achieve desirable glycemic outcomes. We evaluated safety and efficacy of a computerized system to initialize and adjust insulin delivery settings for the t:slim X2 insulin pump with Control-IQ technology in adults with type 1 diabetes (T1D). METHODS: After a 2-week continuous glucose monitoring (CGM) run-in period, adults with T1D using multiple daily injections (MDI) (N = 33, mean age 36.1 years, 57.6% female, diabetes duration 19.7 years) were transitioned to 13 weeks of Control-IQ technology usage. A computerized algorithm generated recommendations for initial pump settings (basal rate, insulin-to-carbohydrate ratio, and correction factor) and weekly follow-up settings to optimize glycemic outcomes. Physicians could override the automated settings changes for safety concerns. RESULTS: Time in range 70 to 180 mg/dL improved from 45.7% during run-in to 69.1% during the last 30 days of Control-IQ use, a median improvement of 18.8% (95% confidence interval [CI]: 13.6-23.9, P < .001). This improvement was evident early in the study and was sustained over 13 weeks. Time <70 mg/dL showed a gradual decreasing trend over time. Percentage of participants achieving HbA1c <7% went from zero at baseline to 55% at study end (P < .001). Only six of the 318 automated settings adaptations (1.9%) were overridden by study investigators. CONCLUSIONS: Computerized initiation and adaptation of Control-IQ technology settings from baseline MDI therapy was safe in adults with T1D. The use of this simplified system for onboarding and optimizing Control-IQ technology may be useful to increase uptake of AID and reduce staff and patient burden in clinical care.

Multicenter Evaluation of Ultra-Rapid Lispro Insulin with Control-IQ Technology in Adults, Adolescents, and Children with Type 1 Diabetes.

Objective: To evaluate the safety and explore the efficacy of use of ultra-rapid lispro (URLi, Lyumjev) insulin in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology in children, teenagers, and adults living with type 1 diabetes (T1D). Methods: At 14 U.S. diabetes centers, youth and adults with T1D completed a 16-day lead-in period using lispro in a t:slim X2 insulin pump with Control-IQ 1.5 technology, followed by a 13-week period in which URLi insulin was used in the pump. Results: The trial included 179 individuals with T1D (age 6-75 years). With URLi, 1.7% (3 participants) had a severe hypoglycemia event over 13 weeks attributed to override boluses or a missed meal. No diabetic ketoacidosis events occurred. Two participants stopped URLi use because of infusion-site discomfort, and one stopped after developing a rash. Mean time 70-180 mg/dL increased from 65% ± 15% with lispro to 67% ± 13% with URLi (P = 0.004). Mean insulin treatment satisfaction questionnaire score improved from 75 ± 13 at screening to 80 ± 11 after 13 weeks of URLi use (mean difference = 6; 95% confidence interval 4-8; P < 0.001), with the greatest improvement reported for confidence avoiding symptoms of high blood sugar. Mean treatment-related impact measure-diabetes score improved from 74 ± 12 to 80 ± 12 (P < 0.001), and mean TRIM-Diabetes Device (score improved from 82 ± 11 to 86 ± 12 (P < 0.001). Conclusions: URLi use in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology was safe for adult and pediatric participants with T1D, with quality-of-life benefits of URLi use perceived by the study participants. Clinicaltrials.gov registration: NCT05403502.

Tirzepatide-Induced Rapid Weight Loss-Related Thyrotoxicosis.

This Teachable Moment describes a 62-year-old man with thyrotoxicosis due to excess levothyroxine exposure during tirzepatide treatment that induced rapid weight loss.