Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Ultra-Long-Acting GLP-1 Receptor Agonist (ZT002) in Healthy Subjects

ZT002, a novel ultra-long-acting GLP-1RA, is designed for monthly or biweekly subcutaneous administration and has non-inferior advantages and a safety profile to semaglutide. In multiple species (mouse, rat, minipig, monkey), preclinical pharmacokinetics (PK) studies exhibited that ZT002 showed a 2-4-fold longer half-life as compared to semaglutide.

Yuanyuan Zhang & team aimed to examine the safety, tolerability, PK, and pharmacodynamics (PD) of single ascending doses (SAD) of ZT002 in healthy subjects of this first-in-human study. The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st – 24th June 2024. 

The team enrolled 18-55 years overtly healthy adults with the body mass index of 22.0-35.0 kg/m2 from Australia in this phase 1, randomized, double-blind, placebo-controlled, SAD trial were randomized (6:2) to receive ZT002 (0.03, 0.09, 0.13 and 0.26 mg/kg) or placebo. A total of 32 patients [N=20 (male)/12 (female); median age=28 years; median BMI=26.7 kg/m2)] participated in the SAD trial. There were no serious adverse events, deaths or treatment-emergent adverse events (TEAEs) which brought withdrawal. The most frequent TEAEs associated to the study drug were gastrointestinal (nausea and vomiting), and the majority were contemplated mild and transient. The PK profile was dose-proportional across the dose range with a mean half-life of 260-273 hours, supporting a monthly or biweekly injection. The 4 groups had dose-responsive weight loss from baseline at Day 15, and the patients with 0.26mg/kg ZT002 showed mean reduction in body weight (BW) of 2.01 kg from baseline on Day 14 and clinically meaningful weight reduction, than the placebo, was maintained up to Day 71.

The authors concluded that the SAD trial of ZT002 exhibited acceptable safety, tolerability profile, and better PK profiles. Healthy patients had substantial reductions in BW. Additional clinical development of ZT002 as a monthly or biweekly injectable treatment for obesity and type 2 diabetes mellitus (T2DM) is going on.

 

A Randomized Clinical Trial of Automated Insulin Delivery in Elderly with Type 1 Diabetes

Older adults with T1D are an increasing population at risk for severe hypoglycemia. Automated insulin delivery (AID) techniques that can decrease risk have not been adequately analysed in this population. Yogish C Kudva & team aimed to assess the potency of the automated insulin delivery in the elderly patients with type 1 diabetes. The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st – 24th June 2024. 

A multicenter, randomized, crossover trial was conducted on adults ≥65 years with T1D experiencing hypoglycemia (>1.5% time < 70 mg/dL based on CGM). Participants completed 3 sequential 12-week periods of hybrid-closed (HCL) loop with Tandem Control-IQ technology, predictive low glucose suspend (PLGS) with Tandem Basal-IQ technology, and sensor augmented pump (SAP) insulin delivery. The primary outcome was % time <70 mg/dL estimated using Dexcom G6 CGM.

82 randomized participants were of 65-86 years of age, 45% female, with a mean (±SD) baseline HbA1c 7.2±0.9%. AID was active a median of 97% of the time in the HCL period and 96% in the PLGS period. Mean (±SD) time <70 mg/dL was 2.49±1.78% at baseline, 1.58±0.95% in HCL, 1.67±0.96% in PLGS, and 2.57±1.54% in SAP (p<0.001 for HCL vs. SAP and PLGS vs. SAP; Table). HCL and PLGS showed reduction in CGM hypoglycemic events and time <54 mg/dL as compared to SAP. HCL enhanced time in range 70-180 mg/dL (TIR), time >180 mg/dL, time >250 mg/dL, and HbA1c than SAP and PLGS (Table).

The authors concluded that HCL and PLGS both exhibited reduction in hypoglycemia as compared to SAP in older adults with T1D. HCL also enhanced TIR, hyperglycemia, and HbA1c than SAP and PLGS.

 

Time Below Range (TBR) and Its Link to Impaired Awareness of Hypoglycemia (IAH) and Severe Hypoglycemia (SH)—Evidence from the Association of British Clinical Diabetologists (ABCD) Study

Harshal Deshmukh & team aimed to investigate the association among the Time Below Range (TBR) and Impaired Awareness of Hypoglycemia (IAH) and Severe Hypoglycemia (SH). The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st – 24th June 2024. 

The team used data from people with diabetes by isCGM in the ABCD audit. Hypoglycemia awareness was assessed by the Gold score, with a score of ≥4 denoting Impaired Awareness of Hypoglycemia (IAH). SH was described as hypoglycemia necessitating third-party assistance. Logistic regression examination was used to recognize the correlation among TBR% (<70 mg/dl) at the last follow-up (used as a continuous independent variable) and follow-up gold score and the number of SH among isCGM initiation and follow-up. Youden’s J index was used to recognize the optimal TBR% cutoffs for diagnosing IAH and SH.

15,777 people with diabetes with at least one follow-up were enrolled in the study, of which TBR data was available for 5030 people. The median TBR% was 4% (IQR 2%-6.6%) in the study population. After adjustment for age, gender, and BMI, TBR was substantially correlated with both SH (Beta=0.02 p=0.001) and IAH (Beta=0.01 p=0.006). The estimated optimal TBR cutoffs for recognizing follow-up IAH and SH were 3.35% and 3.95%, respectively. These cutoffs provided sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 65%, 43%, 19%, and 85% for IAH and 73%, 42%, 5%, and 97% for SH.

The authors concluded that the study exhibits a clear correlation among TBR% and IAH and SH in people with diabetes based on real-world data. The results broadly allocate with the international consensus recommending a TBR of <4% in individuals with type 1 diabetes. But it was noted that this cutoff has limited discriminatory power in anticipating SH and IAH, highlighting the requirement for nuanced approaches in forming optimal TBR thresholds for definite diabetes-associated outcomes.

 

Glycemic Markers Are Differentially Associated with Cardiovascular Imaging and Outcomes in Long-Duration Type 1 Diabetes

Cardiovascular disease (CVD) is a vital source of mortality in type 1 diabetes (T1D). Although glycemic control is associated to CVD outcomes in T1D, there is limited data on the risk of glycemic excursions and comparative contributions of glycemic markers to CVD in aging populations with T1D. Gregory Yu & team aimed to assess glycemic markers for CVD in patients with long duration type 1 diabetes. The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st– 24th June 2024. 

Between the Joslin “Medalists” with T1D≥50 years (n=1043), mean historical HbA1c was achieved over longitudinal visits (median 4.1 years), although a single consecutive 14-day block of continuous glucose monitoring (CGM) data was moderately acquired from a subset of Medalist CGM users (n=110). Furthermore, Medalists underwent coronary artery calcification scans (CAC; n=153) and cardiac magnetic resonance imaging of left ventricular (LV) structure and function (CMR; n=111). In the overall group, HbA1c was correlated with CVD (p<0.001). CGM metrics for hyperglycemia (mean glucose, p=0.03; glucose management indicator, p=0.03; and time above range>180 mg/dL, p=0.02), but not hypoglycemia or day-to-day glycemic difference, were correlated with LV remodeling. Plasma assays for advanced glycation end-products (AGEs; n=200), N-carboxyethyl-lysine (CEL), N-carboxymethyl-lysine (CML), and methylglyoxal-derived hydroimidazolone (MGH1), exhibited correlations with CVD (p=0.04, p=0.04, and p=0.01, respectively); CAC (p=0.05, p=0.01, and p=0.01, respectively); and LV remodeling (p=0.09, p=0.05, and p=0.04, respectively). The correlation of CEL with CVD copied in a separate Medalist subset (n=311) with self-reported CVD data (p=0.01).

The authors concluded that glycemic parameters evaluating long-term, irreversible markers of hyperglycemia (AGEs) are the robust drivers of CVD in people with long-duration T1D, as compared to hypoglycemia or day-to-day glycemic difference. The findings emphasize the requirement for glycemic control in aging populations with T1D, even after other risk factors like hyperlipidemia and hypertension have been controlled.

 

Declining eGFR over Time Predicts the Risk of a Composite of Primary or Secondary Major Adverse Cardiovascular Events or Heart Failure Hospitalization, in People with Type 2 Diabetes—EXSCEL Post Hoc analysis

Decreasing estimated glomerular filtration rate (eGFR) is a prognosticator for the evolution and progression of chronic kidney disease and incident cardiovascular disease (CVD). Harald Sourij & team aimed to assess the role of eGFR decline a novel statistical approach in anticipating CVD events in people with type 2 diabetes, in both primary and secondary CVD prevention settings. The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st – 24th June 2024. 

Bayesian joint modelling of eGFR repeated estimates and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) to assess the correlation among decreasing eGFR and the occurrence of MACEhF (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, or hospitalization for heart failure), adjusting for age, sex, smoking, hypertension, antihypertensive medication, hyperlipidemia, lipid lowering medication, diabetes duration, atrial fibrillation, HDL-C, total cholesterol, HbA1c and therapy assignment (once-weekly exenatide or placebo).

11374 trial participant’s data with (n=8135) and without (n=3239) previous history of CVD were examined. The mean (SD) eGFR slope/year in participants without and with a history of CVD was -0.69 (1.73) and -0.97 (2.04) respectively. The corresponding 5-year MACEhF incidences were 7.6% (95% CI 6.3-8.9%) and 21% (95% CI 19-22%). A 1 SD reduction in the eGFR slope was correlated with elevated MACEhF risks of 64% (HR 1.64, 95% CI 1.15-2.28, p=0.007) and 22% (HR 1.22, 95%CI 1.03-1.45, p=0.026), respectively.

The authors concluded that declining eGFR over time is a substantial prognosticator of incident MACEhF events in people with type 2 diabetes, both those with and without existing CVD, with a greater hazard ratio for MACEhF in the latter group.

 

Should We Improve or Replace the Antenatal Oral Glucose Tolerance Test for Diagnosis of Gestational Diabetes?

Gestational diabetes, the most frequent medical complication of pregnancy, is detected by an oral glucose tolerance test (OGTT), which has limited precision reproducibility and practicality. Pre-analytical processing of glucose influences diagnosis rates, however the impact of this on a population level is hidden. Laura C. Kusinski & team aimed to evaluate how many cases of gestational diabetes were missed via suboptimal specimen processing, and if replacing the OGTT with a 28-week HbA1c was a suitable substitute for recognition of hyperglycemia pregnancies. The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st – 24th June 2024. 

The team utilized data from a prospective cohort, the observational study of pregnancy hyperglycemia, endocrine causes, lipids, insulin and autoimmunity (OPHELIA), which incorporated pregnant participants from 9 UK centres enrolled at the time of a 75g antenatal OGTT (criteria of the National Institute of Health and Care Excellence). Standard glucose processing (local procedures) was compared to improved glucose processing (storage on ice, rapid centrifugation, aliquoting and freezing <2.5 hrs).

1308 participants were enrolled of mean age 31.5 years (SD 5.0) and BMI 33.0kg/m2 (6.8) of 82.5% white ethnicity, representative of the UK population. Improved glucose processing showed glucose levels ~0.6 mmol/L (10.9 mg/dL) greater as compared to standard processing, correlated with an increase in gestational diabetes diagnosis from 9% to 22%. The 13% of women who had a missed diagnosis because of standard specimen processing were not representative of the whole group: they were more likely to be of white ethnicity with BMI >30 kg/m2. HbA1c was not correlated with most significant pregnancy results and receiver operator curves (ROC) showed that the HbA1c was not a vital predictor of gestational diabetes diagnosis (AUROC 0.74; 95%CI 0.68 to 0.79).

The authors concluded that neither an oral glucose tolerance test with standard glucose processing nor 28-week HbA1c provides constantly precise diagnosis of gestational diabetes.

 

Cardiovascular Disease in India

Rakesh K. Sahay & team aimed to discuss the increasing CVD burden and risk factors in patients with diabetes in India. The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st – 24th June 2024. 

Cardiovascular disease (CVDs) is the leading cause of death among individuals with T2DM, especially in low- and middle-income countries.  From 2000-2019, there was a 3% increase in age-standardized death rates due to diabetes. T2DM accounts for approximately 90% of all diabetes cases, and CV events in T2DM patients contribute significantly to the increased risk of premature mortality. Patient with diabetes and multiple risk factors (serum cholesterol ≥200 mg/dL, current smoker, SBP ≥120 mmHg) showed significant increase in CV death as compared to patients without diabetes.

Diabetes is associated with significant loss of life years. On average, a 50-year-old with diabetes but no history of vascular disease is ~6 years younger at time of death than a counterpart without diabetes. In Worldwide, more than 70% of patients with diabetes die due to atherosclerotic cardiovascular disease (ASCVD) and noncommunicable diseases (NCDs) are the prime determinant of disability and mortality. 1 out of 4 Indians has the highest probability of dying from NCDs before reaching the age of 70 years. Hence NCDs are a significant public health problem in the 21st century. According to ICMR-INDIAB-17 study, metabolic conditions are growing significantly higher than previously estimated. Based on LAI criteria, 60.5% Indian patients included in very high-risk category.

Based on QRISK3 calculation, Indian diabetes patients had an average CKD risk of 12.3% (p<0.001) for females and males.  Diabetes is associated with acute MI is an independent and determinant risk factor in the outcome for diabetic Indians. Complex interplay of population level and biological risk factors responsible for the burgeoning CVD epidemic in Indians. Insulin resistance has been suggested as a possible underlying factor for the highest risk of CVD in Indians. Asian Indian people with T2DM tend to have a higher risk of CAD compared with white individuals. Indians from lower income countries have higher rate of major CVD and mortality compared to high-income countries.

The authors concluded that Indians experience a higher burden of CVD in diabetes, characterized by earlier onset, higher case fatality, and a larger proportion of premature deaths. The development of CVD in diabetes is influenced by a combination of conventional risk factors and additional factors such as education, socio-economic status, fetal programming, and early life influences. Challenges in the treatment of hypertension and diabetes emphasizing the need for improved diagnosis treatment, and overall care to mitigate the impact of CVD in individuals with diabetes.

LAI: Lipid association of India

 

Glycemic Improvement with Use of the Omnipod 5 Automated Insulin Delivery System in Adults with Type 2 Diabetes—Results of the SECURE-T2D Pivotal Trial

The SECURE-T2D pivotal trial, the first large-scale, multicenter study analysing the Omnipod® 5 AID System, a novel insulin pump, in a racially diverse group of adults with type 2 diabetes. The Omnipod 5 AID System is a tubeless insulin pump that automatically modifies insulin delivery based on CGM data. Dr. Francisco Pasquel & team aimed to enhance glycemic control by responding to glucose levels in real-time, reducing the burden of manual insulin dosing for people with diabetes. The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st – 24th June 2024. 

305 adults aged 18-75 years with type 2 diabetes were included in the multicenter pivotal clinical trial who were utilizing several insulin regimens (basal-bolus, premix, or basal-only) and showed a baseline HbA1c of less than 12.0%. Following a 14-day standard treatment phase, participants changed to 13 weeks of using the Omnipod 5 AID System to begin baseline glycemic control. The primary endpoint was the change in HbA1c from baseline to 13 weeks. The study population was also particularly diverse, with 24% Black and 22% Hispanic/Latino participants.

Key results from the trial exhibited that the use of the Omnipod® 5 AID System showed substantial reduction in HbA1c levels, from a baseline average of 8.2±1.3% to 7.4±0.9% at the end of the study (treatment effect: -0.8%, 95% CI: -1.0 to -0.7, p<0.001). The highest enhancements were shown in participants with the highest baseline HbA1c.

The authors concluded that results from the SECURE-T2D trial highlight the potential of the Omnipod 5 AID System to transform diabetes treatment for adults with type 2 diabetes. The significant enhancements in glycemic control and quality of life, specially between minority populations, are favourable steps toward more unbiased diabetes care.

 

Long-Term Improvement in CGM-Measured Glycemic Control in Adults with Type 2 Diabetes Not Treated with Insulin—Real-Word

Dr. Jennifer E. Layne & team aimed to analyse CGM metrics for one year following CGM initiation in adults with noninsulin treated T2D. The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st – 24th June 2024

The real-world study assessed data from across 3,800 adults by Dexcom G6 and G7 sensors. The participants, earlier not meeting their glycemic targets, exhibited substantial enhancements following 6 months of CGM use, with additional improvement at one year. Major results incorporated a 0.5% reduction in the glucose management indictor, a CGM approximation of A1c, and a 17% increase in Time in Range (TIR), which translates to a further four hours per day spent within the target glucose range. The study also emphasized the benefits of the Dexcom High Alert feature, which reports users when glucose levels surpass their selected targets. Participants who used this characteristic exhibited the highest enhancements in their glucose levels. The constant CGM use across the year recommends sustained advantages and a positive effect on long-term diabetes care.

The authors concluded that CGM substantially improves glycemic control in adults with type 2 diabetes who are not on insulin. These results emphasize the significance of CGM for treating non-insulin treated type 2 diabetes for clinicians and for patient self-management.

 

Common Cholesterol-Lowering Drug Found to Slow Vision Loss in Diabetes Patients

Diabetic retinopathy is a major source of visual loss globally, with elevating prevalence in many regions of the world across the last 30 years. The condition is happened due to high blood sugar levels damaging the blood vessels in the retina, exhibits vision problems and even blindness. To decrease the risk of disease development, efficaciously treating blood glucose levels is significant, however this can be difficult to achieve for many patients and there are no other therapy options available for people with early retinopathy. The Lowering Events in Non-proliferative retinopathy in Scotland (LENS) Trial sought Dr. David Preiss & team aimed to address this challenge by analysing the effect of an existing solution for high cholesterol on diabetic retinopathy outcomes. The findings were presented at the 84th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21st – 24th June 2024. 

This randomized controlled trial was held within Scotland’s Diabetic Eye Screening (DES) program, a national scheme that yields regular retinal imaging to all patients with diabetes, aged 12 years or more, over the country. In the trial, 1,151 adults with early diabetic retinopathy or maculopathy were assigned to receive either 145 mg fenofibrate tablets or placebo. The primary outcome was a composite measure of developing referable diabetic retinopathy or maculopathy (i.e. a grading of diabetic eye disease that warrants specialist ophthalmic review) or needing management with laser, intravitreal injection or vitrectomy.

Findings showed that fenofibrate may be an effectual option for people with early diabetic retinopathy. Across 4 years, participants taking fenofibrate showed a 27% reduction in the develpoment of their eye disease than the placebo (22.7% vs. 29.2%), it was highly statistically substantial result (p=0.006). Furthermore, fenofibrate decreased the chance of any development of retinopathy and it reduced the risk of progressing macular edema (swelling in the retina).                         

The authors concluded that fenofibrate, a medicine utilized for many years to decrease blood fat levels, substantially decreases the progression development of diabetic retinopathy, a diabetes-associated eye disease. Thus, fenofibrate may yield a valuable addition to manage people with diabetic retinopathy.