Baseline Fasting Plasma Glucose Research Articles

6907 Continued Improvements in Hypertension and Diabetes During Long-Term Osilodrostat Therapy in Patients with Cushing’s Disease: A Pooled Analysis from the Phase III LINC 3 and LINC 4 Studies

Abstract Disclosure: M. Fleseriu: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). R. Pivonello: Consulting Fee; Self; Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, H Lundbeck A/S. Grant Recipient; Self; Recordati AG, Corcept Therapeutics, Xeris Pharmaceuticals (Strongbridge), Neurocrine Biosciences. J. Newell-Price: Consulting Fee; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Recordati Rare Diseases. Grant Recipient; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Recordati Rare Diseases. M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Ipsen, Pfizer, Inc., Crinetics Pharmaceuticals, Novo Nordisk. R.J. Auchus: Consulting Fee; Self; Xeris Pharmaceuticals (Strongbridge), Spruce Biosciences, Neurocrine Biosciences, Corcept Therapeutics, Diurnal, Sparrow Pharmaceuticals, Crinetics Pharmaceuticals, Recordati Rare Diseases, Adrenas Therapeutics, Janssen Pharmaceuticals, Quest Diagnostics, H Lundbeck A/S, Novo Nordisk, Besins Pharmaceuticals. Grant Recipient; Self; Xeris Pharmaceuticals (Strongbridge), Spruce Biosciences, Neurocrine Biosciences, Corcept Therapeutics, Diurnal, Sparrow Pharmaceuticals, Crinetics Pharmaceuticals, Recordati Rare Diseases. R. Feelders: Consulting Fee; Self; Recordati. A. Lacroix: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Pfizer, Inc.. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Pfizer, Inc. A. Shimatsu: Advisory Board Member; Self; Recordati. Consulting Fee; Self; Recordati. Speaker; Self; Recordati. P. Witek: Speaker; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. Other; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. M. Bex: Consulting Fee; Self; Recordati. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati, Camurus. B.M. Biller: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; H Lundbeck A/S, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Introduction: Alleviating the burden of comorbidities such as hypertension (HTN) and diabetes mellitus (DM), through control of hypercortisolism, is an important treatment goal in the management of Cushing’s syndrome. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid, sustained cortisol normalization in Cushing’s disease (CD) patients (pts) in two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734), with improvements in clinical manifestations of hypercortisolism. Here, we report on the long-term changes in blood pressure (BP) and markers of glucose homeostasis in a large, pooled pt population from both trials at weeks (W) 48 and 72. Methods: LINC 3 comprised a 48W core phase, including an 8W randomized withdrawal phase for eligible pts. LINC 4 included an upfront 12W, double-blind, randomized, placebo-controlled period and 36W of open-label osilodrostat. Both studies had an optional extension. Baseline (BL) HTN was defined as prior diagnosis, taking antihypertensive medication, and/or systolic/diastolic BP (SBP/DBP) >130/>90 mmHg. BL DM was defined as prior diagnosis, taking antidiabetic medication, HbA1c ≥6.5%, and/or fasting plasma glucose (FPG) ≥126 mg/dL. Data from LINC 3 and LINC 4 were pooled in a secondary exploratory analysis for all pts with data at BL and the given visit, excluding periods where pts were randomized to placebo. No formal statistical hypothesis testing was performed; all analyses are descriptive. Results: In pts with BL HTN (n=174/210; 82.9%), mean (95% CI) change in SBP/DBP was -13.9 (-18.5, -9.4)/-9.1 (-12.4, -5.8) mmHg at W48 and -14.7 (-20.1, -9.4)/-9.4 (-13.0, -5.7) mmHg at W72 for those not receiving antihypertensive medication during the study, and -8.4 (-11.9, -4.9)/-5.3 (-7.5, -3.1) mmHg at W48 and -10.1 (-14.3, -5.8)/-5.7 (-8.1, -3.2) mmHg at W72 for those who received antihypertensives. Of pts with BL SBP >130 mmHg (n=110), 50.0% had SBP ≤130 mmHg at W48 and 49.1% at W72. Of pts with BL DBP >90 mmHg (n=65), 64.6% had DBP ≤90 mmHg at W48 and 58.5% at W72. The proportion of pts taking antihypertensive medication declined from 54.3% at BL to 47.3% at W72. Mean (95% CI) change in potassium levels was -0.1 (-0.1, 0.0) mmol/L at W48 and 0.0 (-0.1, 0.1) mmol/L at W72 in pts with BL HTN, and -0.1 (-0.3, 0.1) mmol/L at both W48 and W72 in pts without BL HTN. 40.0% (n=84/210) of pts had BL DM. Of pts with BL FPG ≥100 mg/dL (n=60), 43.3% and 33.3% had FPG <100 mg/dL at W48 and W72, respectively. The proportion of pts taking antidiabetic medication declined from 21.9% at BL to 17.1% at W72. Conclusions: Many pts with CD and HTN or DM showed improvements during osilodrostat therapy, which were maintained or further improved with long-term therapy. Cortisol normalization is associated with improvements in hypercortisolism-associated comorbidities in pts with CD. Presentation: 6/2/2024

One-year Efficacy and Safety of Dulaglutide in Patients with Type 2 Diabetes and Chronic Kidney Disease: A Retrospective Study of Asian Patients

PurposeDulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys and has proven efficacy and safety in patients with diabetic kidney disease. We aimed to evaluate the 1-year efficacy of dulaglutide in patients with diabetic kidney disease who have used the drug for more than 1 year. MethodsThis retrospective, observational study comprised 131 patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 who had received dulaglutide for more than one year between June 2016 and May 2023. The primary outcome measures were changes in glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and body weight from baseline to the 12-month follow-up, with assessments performed at six-month intervals. Subgroup analyses were conducted based on age, sex, baseline body mass index, FPG, and HbA1c, and insulin administration at baseline and last follow-up. FindingsThe mean age was 60.0 ± 10.2 years, and 61.1% of the participants were males. Baseline HbA1c, FPG, and body weight were 9.1% (76.0 mmol/mol), 186.8 mg/dL, and 79.3 kg, respectively. Dulaglutide significantly reduced HbA1c, FPG, and body weight from baseline to the 12-month follow-up (mean ± standard error: –1.2 ± 0.1%, –34.8 ± 6.9 mg/dL, and –2.3 ± 0.5 kg, respectively; P < 0.001). Subgroup analysis revealed significant differences in HbA1c reduction based on baseline HbA1c. ImplicationsDulaglutide exhibited sustained glucose-lowering and weight-reduction effects during the initial 1 year of treatment in patients with diabetic kidney disease. Altogether, dulaglutide could serve as a favorable long-term therapeutic option for patients with diabetic kidney disease in real-world clinical settings.

Metabolic Score for Insulin Resistance and New-Onset Type 2 Diabetes in a Middle-Aged and Older Adult Population: Nationwide Prospective Cohort Study and Implications for Primary Care.

The metabolic score for insulin resistance (METS-IR) has emerged as a noninsulin-based index for the approximation of insulin resistance (IR), yet longitudinal evidence supporting the utility of METS-IR in the primary prevention of type 2 diabetes mellitus (T2DM) remains limited. We aimed to investigate the longitudinal association between METS-IR, which combines fasting plasma glucose (FPG), lipid profiles, and anthropometrics that can be routinely obtained in resource-limited primary care settings, and the incidence of new-onset T2DM. We conducted a closed-cohort analysis of a nationwide, prospective cohort of 7583 Chinese middle-aged and older adults who were free of T2DM at baseline, sampled from 28 out of 31 provinces in China. We examined the characteristics of participants stratified by elevated blood pressure (BP) at baseline and new-onset T2DM at follow-up. We performed Cox proportional hazard regression analysis to explore associations of baseline METS-IR with incident T2DM in participants overall and in participants stratified by baseline BP. We also applied net reclassification improvement and integrated discrimination improvement to examine the incremental value of METS-IR. During a mean follow-up period of 6.3 years, T2DM occurred in 527 participants, among which two-thirds (332/527, 62.9%; 95% CI 58.7%-67.1%) had baseline FPG<110 mg/dL. A SD unit increase in baseline METS-IR was associated with the first incidence of T2DM (adjusted hazard ratio [aHR] 1.33, 95% CI 1.22-1.45; P<.001) in all participants. We obtained similar results in participants with normal baseline BP (aHR 1.41, 95% CI 1.22-1.62; P<.001) and elevated baseline BP (aHR 1.29, 95% CI 1.16-1.44; P<.001). The predictive capability for incident T2DM was improved by adding METS-IR to FPG. In study participants with new-onset T2DM whose baseline FPG was <126 mg/dL and <110 mg/dL, 62.9% (332/527; 95% CI 60%-65.9%) and 58.1% (193/332; 95% CI 54.3%-61.9%) of participants had baseline METS-IR above the cutoff values, respectively. METS-IR was significantly associated with new-onset T2DM, regardless of baseline BP level. Regular monitoring of METS-IR on top of routine blood glucose in clinical practice may add to the ability to enhance the early identification of primary care populations at risk for T2DM.

Abstract PO4-12-12: An Updated analysis of risk factor identification and Hyperglycemia prevention with alpelisib + fulvestrant in PIKC3A-mutated, hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer

Abstract Background: SOLAR-1 investigated use of alpelisib (ALP) + fulvestrant (FLV) in patients (pts) with hormone-receptor positive (HR+)/human epidermal growth factor-2 negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) after progression on endocrine-based therapy and demonstrated a clinically significant increase in all-grade (G) and G3-4 hyperglycemia (HG) compared to placebo + FLV. Current guidance recommends an insulin sensitizer (metformin, thiazolidinedione, SGLT2i) at HG onset. Given high rates of HG, a preventative protocol and identification (ID) of associated risk factors (RFs) was implemented to minimize HG, dose reductions and discontinuation. Although METALLICA investigated the implementation of metformin for hyperglycemia prophylaxis, there is limited data for alpelisib use and hyperglycemia prevention in high risk or controlled type 2 diabetic patients. Duke Breast Oncology Clinic (DBOC) implemented a preventive strategy to minimize HG and treatment disruptions in patients receiving alpelisib, including pre-diabetic and controlled-diabetic patients. Methods: This single-center, retrospective study included pts receiving at least one 28-day cycle of ALP+FLV between June 2019 and April 2023. One week prior to ALP initiation, pts initiated an insulin-sensitizer. Pts had fasting plasma glucose (FPG) levels drawn on day 8, 15, 28, and monthly while on ALP. The primary outcome was incidence of G2-4 HG. Descriptive statistics were used to summarize results. Number of RFs for HG (age ≥ 65 years, BMI ≥ 25 kg/m2, baseline FPG ≥ 100 mg/dL, and A1c ≥ 5.7%) were compared between pts with and without HG using Wilcoxon rank-sum test. Results A total of 30 pts (29 females; 1 male) were included with a median age of 60 years. The cohort was 70% White, 23% Black, while 67% were overweight/obese, and 50% had a history of type 2 diabetes mellitus (T2DM), gestational diabetes, or pre-diabetes. 29 pts received a CDK4/6 inhibitor prior to starting ALP. By day 28, 13 pts (43%) had G2-4 HG, with only 4 (13%) having G3 HG and zero having grade 4. Pts with G2-4 HG had a median of 2 RFs compared to only 1 RF if no HG. 8 pts (27%) required a temporary hold of ALP and 5 pts (17%) required a dose reduction in ALP due to HG. 25 pts permanently discontinued ALP; 14 due to disease progression and 8 due to an adverse event with only 3 due to HG. Median duration of ALP was 86 days (range 24-442), with 5 pts continuing to receive ALP at time of analysis. Patients with grade 2-4 HG by day 28 after ALP initiation had an older median age (66 years), higher BMI (median 28.1 kg/m2), higher baseline FPG (median 100 mg/dL), and higher baseline HbA1c (median 5.6%) compared to those without grade 2-4 HG (Table). Conclusions: Implementation of a HG prevention protocol with ALP in the real-world setting demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (13% vs 36.6%) but slightly higher than METALLICA (6%) although we included a higher risk patient population. An increase in HG-associated RFs correlated with a higher incidence of G2-4 HG. Early risk identification and optimization of prophylactic antihyperglycemics can reduce ALP dose reductions and discontinuations secondary to HG. ALP use in higher-risk patients can be considered with a HG prevention protocol. Table 1. Hyperglycemia outcomes Citation Format: Heather Moore, Sarah Burnette, Emily Poehlein, Hui-Jie Lee, Kelly Westbrook, Thomas Bagwell, Kervin Novido, Susan Dent. An Updated analysis of risk factor identification and Hyperglycemia prevention with alpelisib + fulvestrant in PIKC3A-mutated, hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-12.

Fasting hyperglycaemia and fatty liver drive colorectal cancer: a retrospective analysis in 1145 patients

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) represents the hepatic manifestation of increased adiposopathy, whose pathogenetic features have been proposed as tumourigenic triggers for colorectal cancer (CRC). We aim to identify specific metabolic signatures involved in CRC development that may be used as non-invasive biomarkers, paving the way for specific and personalized strategies of CRC prevention and early detection.MethodsWe retrospectively assessed CRC onset during a time frame of 8 years in a cohort of 1145 out-patients individuals who had previously been evaluated for Metabolic Syndrome.Results28 patients developed CRC. No association between CRC development and visceral and general obesity was detected, while baseline fasting plasma glucose (FPG) and non-invasive liver fibrosis scores were significantly higher in patients with CRC, compared to those who did not develop cancer. Liver steatosis and MASLD were more frequently diagnosed in patients who developed CRC compared to no cancer developers. Canonical correlations among metabolic biomarkers were not present in CRC developers, differently from no cancer group. In ROC analysis, FPG and non-invasive scores also showed good sensitivity and specificity in predicting colon cancer. We then calculated ORs for metabolic biomarkers, finding that higher FPG and non-invasive scores were associated with an increased risk of developing CRC.ConclusionMASLD and increased FPG may play a role in the clinical background of CRC, bringing to light the fascinating possibility of a reversed gut–liver axis communication in the pathogenesis of CRC. Thus, the use of non-invasive scores of fatty liver may be helpful to predict the risk of CRC and serve as novel prognostic factors for prevention and therapeutic strategies.

Real-World Study on Effectiveness of Insulin Glargine U300 After Oral Antidiabetic Drug Failure in Patients with Type 2 Diabetes in the Gulf Region.

The effectiveness and safety of long-acting insulin glargine U300 (Gla-300), in patients with type2 diabetes mellitus (T2DM) requiring insulin, has not been reported in the Gulf region. Insulin-naïve patients with T2DM, uncontrolled on OADs, and prescribed Gla-300 were followed up in a 12-month prospective observational study. Gla-300 was titrated to glycemic targets. The primary endpoint (achieving glycemic targets) was evaluated at month 6 of treatment. The need for treatment intensification, safety, and patient-reported outcomes (PRO) were also reported. The study included 412 patients (61.7% men; age 52.2 ± 11.1years and T2DM duration 10.7 ± 6.8years). Almost 50% were on more than 3 OADs, mostly biguanides, sulfonylureas, and dipeptidyl-peptidase-4 inhibitors. Baseline HbA1c level was 9.2% ± 1.1% and targets were set at 6.9% ± 0.4%. Baseline fasting plasma glucose was 11.5 ± 3.8mmol/l. Fifty-seven patients (13.8%) achieved glycemic targets at month 6, hindered by baseline HbA1c ≥ 10%, frequent co-morbidities, older age, suburban/rural residence, and full-time employment. Levels of HbA1c dropped progressively by 0.96% ± 0.07% (month 3), 1.29% ± 0.08% (month 6), and 1.76% ± 0.06% (month 12). Gla-300 dose was 17.0 ± 9.0IU/day at baseline, 24.6 ± 9.6 IU/day at month 3, 28.5 ± 9.9IU/day at month 6, and 30.7 ± 10.7IU/day at month 12. Three patients experienced non-severe hypoglycemia and a slight decrease in body weight and PROs improved. In the Gulf, Gla-300 in patients with T2DM uncontrolled on OADs improved glycemic control, with low rates of hypoglycemia and improved PROs. Gla-300 dose up-titration from baseline to month 6 did not, however, result in a vast proportion of patients achieving their pre-determined HbA1c targets. ClinicalTrials.gov identifier: NCT03703869.

Association of pro-inflammatory cytokines, adipokines and hepatokine with incident diabetes in India: a nested case-control study within CARRS cohort.

To study the association of pro-inflammatory markers with incident diabetes in India. We did a nested case-control study within the CARRS (Centre for ArdiometabolicRiskReduction inSouth Asia) cohort. Of the 5739 diabetes-free individuals at the baseline, 216 participants with incident diabetes and 432 age-, gender- and city-matched controls at 2-year follow-up were included. We measured high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 ( MCP-1), adiponectin, leptin and fetuin-A in the stored baseline blood samples. We did multivariate conditional logistic regression to estimate association of inflammatory markers (as quartiles) and incident diabetes. Covariates were baseline fasting plasma glucose (FPG) and lipids, body mass index (BMI), family history of diabetes, smoking and alcohol use. Baseline hsCRP and TNF-α were higher, and IL-6 and adiponectin were lower among cases vs. controls. In multivariate conditional logistic regression models, only quartile-3 (odds ratio [OR]: 2.96 [95% CI:1.39, 6.30]) and quartile-4 (OR: 2.58 [95% CI:1.15, 5.79]) of TNF-α and quartile-4 of MCP-1 (OR: 2.55 [95% CI:1.06, 6.16]) were positively associated with diabetes after adjusting for baseline FPG and BMI. These associations did not remain after adjusting for family history. High level (quartile-4) of IL-6 was negatively associated with diabetes after adjusting for all factors (OR: 0.18 [95% CI:0.06, 0.55]). Higher TNF-α and MCP-1 levels and lower IL-6 were associated with higher risk of developing diabetes. Better understanding and potential methods of addressing these biomarkers, especially in relation to family history, are needed to address diabetes in South Asians.

MARKERS OF GLUCOSE METABOLISM ARE ASSOCIATED WITHCCOGNITIVE DECLINE AMONG FAMILIES WITH EXCEPTIONAL SURVIVAL

Abstract Although the connection between type 2 diabetes (T2D) and dementia is known, it is less clear whether this relationship extends to cognitive decline. Our aim was to examine whether baseline fasting plasma glucose, insulin, HOMA-IR, and HbA1c, and T2D status predict cognitive decline in a multicenter cohort study of families with a clustering of exceptional survival. We analyzed change across five cognitive tests collected over 7.9 years: Mini-Mental State Examination, Digit Span, Logical Memory, Animal Fluency and Digit Symbol Substitution. Among 2,175 family members (mean age 63±11 years (range 32-100); 54% women), 39.8% had prediabetes and 6.8% had T2D. Multiple linear mixed models were adjusted for age, sex, field center, education, APOEε4 status, BMI and family relatedness. A trend was observed for immediate (p=0.047) and delayed (p=0.037) memory, with normal glucose tolerance (NGT) predicting increased scores, prediabetes showing no change, and T2D predicting decreased scores. Among those without T2D (N=2,026), each standard deviation (SD) higher glucose (11.5 mg/dl) was related to a greater decline in delayed memory (-0.34±0.16mg/dl; p=0.032), each SD higher HbA1c (0.32%) was related to a greater decline in immediate (-0.36±0.15 mg/dl; p=0.016) and delayed (-0.31±0.16 %; p=0.05) memory, while each SD higher HOMA-IR (1.5) was related to a greater decline in Digit Span Backwards (-0.13±0.06; p=0.047). Findings suggest that among individuals with a clustering of exceptional survival, T2D, glucose, and HbA1c may predict greater decline in episodic memory, an ability typically affected early in Alzheimer dementia. The possible mechanisms, including genetic and metabolic mediators, warrant further investigation.

Abstract 11900: Potassium Magnesium Citrate is Superior to Potassium Chloride in Reversing Metabolic Side Effects of Chlorthalidone

Thiazide-type diuretics (TD) are the first-line treatment of hypertension in many guidelines because of its consistent benefit in lowering BP and cardiovascular risk. TD is also known to cause excess risk of diabetes mellitus (DM), which may limit its long-term use. Although hypokalemia was thought to be the main mechanism of TD-induced dysglycemia, potassium (K) supplementation alone does not consistently prevent TD-induced elevation in fasting plasma glucose (FPG). In addition to reducing serum K, TD triggers magnesium (Mg) depletion. However, it is unknown if Mg supplementation attenuates metabolic side effects of TD. Accordingly, we conducted a randomized double-blinded clinical trial in 60 hypertensive patients without DM to compare effects of KCl (40 meq daily) vs. KMgCitrate (Cit) powder containing identical amount of K, 20 meq of Mg, and 74 meq of Cit daily during chlorthalidone (CTD) treatment. Each patient received CTD alone (25 mg/day) for 3 weeks prior to randomization. The primary endpoint was the change in FPG after 4-month of treatment from baseline (CTD alone) after adjusting for baseline FPG as a covariate. The mean age of subjects was 59±11 years (45% Female, 30% Black participants). We found that CTD induced a significant rise in FPG, insulin, and a significant fall in serum K and 24-h urinary citrate excretion (all p &lt; 0.05). We found that KMgCit significantly increased serum K, 24-hour urinary Mg, and 24-hour urinary Cit excretion; and attenuated the rise in FPG which was not observed with KCl (Figure 1 A-C). There were no significant differences in liver fat by MRI or fasting plasma insulin between the 2 groups. In conclusion, our study showed beneficial effects of magnesium supplementation in maintaining serum K and reversing effects CTD on plasma glucose, which may improve safety profile and optimize long-term cardiovascular outcomes in hypertensive patients.

Trajectory patterns of metabolic syndrome severity score and risk of type 2 diabetes

BackgroundThe available evidence indicates that the severity of metabolic syndrome tends to worsen progressively over time. We assessed the trajectory of age and sex-specific continuous MetS severity score (cMetS-S) and its association with the development of diabetes during an 18-year follow-up.MethodsIn a prospective population-based Tehran Lipid and Glucose Study, 3931 eligible participants free of diabetes, aged 20–60 years, were followed at three-year intervals. We examined the trajectories of cMetS-S over nine years using latent growth mixture modeling (LGMM) and subsequent risks of incident diabetes eight years later. The prospective association of identified trajectories with diabetes was examined using the Cox proportional hazard model adjusting for age, sex, education, and family history of diabetes, physical activity, obesity (BMI ≥ 30 kg/m2), antihypertensive and lipid-lowering medication, and baseline fasting plasma glucose in a stepwise manner.ResultsAmong 3931 participants, three cMetS-S trajectory groups of low (24.1%), medium (46.8%), and high (29.1%) were identified during the exposure period. Participants in the medium and high cMetS-S trajectory classes had HRs of 2.44 (95% CI: 1.56–3.81) and 6.81 (95% CI: 4.07–10.01) for future diabetes in fully adjusted models, respectively. Normoglycemic individuals within the high cMetS-S class had an over seven-fold increased risk of diabetes (HR: 7.12; 95% CI: 6.05–12.52).ConclusionAlthough most adults exhibit an unhealthy metabolic score, its severity usually remains stable throughout adulthood over ten years of follow-up. The severity score of metabolic syndrome has the potential to be utilized as a comprehensive and easily measurable indicator of cardiometabolic dysfunction. It can be employed in clinical settings to detect and track individuals at a heightened risk of developing T2DM, even if their glucose levels are normal.

Changes in fasting plasma glucose and subclinical atherosclerosis: A cohort study from VIPVIZA trial

Background and aimsStudies on the influence of fasting plasma glucose (FPG) on the development of carotid plaque (CP) and intima media thickness (CIMT) mainly focused on single FPG measures. We investigated whether changes in FPG (ΔFPG) are associated with incident CP and CIMT change (ΔCIMT) over time. MethodsAnalyses were based on information from 1896 participants from the VIPVIZA trial (Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention), with baseline and 3-year follow-up data on FPG, ultrasonographic CP (none or ≥1 lesion/s) and CIMT assessments. We studied the association between baseline FPG (prior to intervention) or 3-year ΔFPG (mmol/L) and incident CP (logistic regression) or ΔCIMT (linear regression). Analyses were adjusted for multiple potential confounders. Results1896 and 873 individuals, respectively, were included in the analysis on incident CP and ΔCIMT. Participants were 60 years old at baseline and 61% and 54% were females, in the CP and CIMT analyses, respectively. Every mmol/L increase in FPG was associated with an increased odds of incident CP (odds ratio: 1.42, 95% confidence interval [CI]: 1.17, 1.73), but there was no association with ΔCIMT (mean difference: 0.002 mm, 95% CI: −0.003, 0.008) after 3 years. Baseline FPG was not associated with incident CP nor ΔCIMT progression. ConclusionsIn middle-aged individuals with low to moderate risk for cardiovascular diseases, 3-year ΔFPG was positively associated with the risk of incident CP, but not with ΔCIMT. Single measures of FPG may not be sufficient in estimating cardiovascular risk among individuals with low to moderate risk.

THU054 A Post Hoc Analysis Of The Phase IV B2219 Study To Determine Predictive Factors For Hyperglycemia During Treatment With Pasireotide

Abstract Disclosure: S.L. Samson: Consulting Fee; Self; Novartis Pharmaceuticals, Chiasma. M. Bolanowski: Grant Recipient; Self; Amryt, Recordati, Pfizer, Inc., Novartis Pharmaceuticals, Ipsen, IBSA, Teva Pharmaceutical Industries Ltd., Berlin Chemie. Speaker; Self; Amryt, Recordati, Pfizer, Inc., Novartis Pharmaceuticals, Ipsen, IBSA, Teva Pharmaceutical Industries Ltd., Berlin Chemie. S. Zhang: None. Y. Yu: None. P. Witek: Grant Recipient; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. Speaker; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. N. Kietsiriroje: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. U. Feldt-Rasmussen: Advisory Board Member; Self; Novartis Pharmaceuticals, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Ipsen, Recordati, Novo Nordisk. Speaker; Self; Ipsen, Recordati, Novo Nordisk. Introduction: Pasireotide efficacy and safety in persons with acromegaly or Cushing’s disease (CD) is confirmed in a comprehensive clinical trial program. Pasireotide-induced hyperglycemia events, expected based on the drug’s mechanism of action, are manageable with low rates of treatment discontinuation. To advance knowledge on pasireotide-induced hyperglycemia management, a prospective randomized Phase IV study (B2219, NCT02060383) was conducted. This secondary analysis assessed factors that might predict development of pasireotide-induced hyperglycemia. Methods: In B2219, participants (Pts) with acromegaly or CD who did not need therapy for hyperglycemia or were managed with metformin alone entered the non-randomized observational arm. Pts who developed hyperglycemia not managed with metformin alone were randomized to incretin-based therapy or insulin. This analysis evaluated Pts according to whether therapy for hyperglycemia during pasireotide treatment was needed. Logistic regression analyses evaluated quantitative and qualitative predictive factors associated with pasireotide-induced hyperglycemia. Results: Of 190 Pts with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication during pasireotide treatment; Pt characteristics were generally balanced across subgroups at study baseline (BL). Most Pts who did not develop hyperglycemia had a mean age of &amp;lt;40 years (acromegaly 62.5%, CD 86.7%), BL glycated hemoglobin (HbA1c) &amp;lt;6.5% (acromegaly 98.9%, CD 100.0%) and BL fasting plasma glucose (FPG) &amp;lt;100 mg/dL (acromegaly 76.1%, CD 100.0%). Age (odds ratio [OR] 1.0, 95% CI 1.0−1.1), BL HbA1c (OR 3.5, 95% CI 1.3−9.9) and prediabetes or diabetes conditions (OR 3.0, 95% CI 1.2−7.6) were identified as risk factors associated with pasireotide-induced hyperglycemia in Pts with acromegaly. BL FPG (OR 1.2, 95% CI 1.0−1.3) was associated with increased risk of pasireotide-induced hyperglycemia in Pts with CD. Overall, adverse events (AEs) of hyperglycemia and diabetes mellitus (investigator reported) occurred in 21.1% and 14.2% of Pts with acromegaly and 28.8% and 11.9% of Pts with CD, respectively. More Pts who had diabetes or prediabetes conditions at BL had hyperglycemia-related AEs than Pts with normal glucose levels. Hyperglycemia-related AEs were managed with antihyperglycemic medication (acromegaly 26.3%, CD 30.5%); few Pts temporarily interrupted treatment (acromegaly 3.7%, CD 10.2%). Conclusions: These data suggest that age, HbA1c, FPG and having prediabetes or diabetes conditions at BL are associated with increased risk of developing pasireotide-induced hyperglycemia. AEs were manageable with antihyperglycemic medication. Potential risk factors associated with pasireotide-induced hyperglycemia may be used to identify Pts who need vigilant monitoring to ensure optimal outcomes during pasireotide treatment. Presentation: Thursday, June 15, 2023

Association of baseline fasting plasma glucose with 1-year mortality in non-diabetic patients with acute cerebral infarction: a multicentre observational cohort study

ObjectivesEvidence on the association between fasting blood glucose and mortality in non-diabetic patients who had a stroke is limited. We aimed to investigate the association of baseline fasting plasma glucose...

6-Year trajectory of fasting plasma glucose (FPG) and mortality risk among individuals with normal FPG at baseline: a prospective cohort study

BackgroundHigher fasting plasma glucose (FPG) levels were associated with an increased risk of all-cause mortality; however, the associations between long-term FPG trajectory groups and mortality were unclear, especially among individuals with a normal FPG level at the beginning. The aims of this study were to examine the associations of FPG trajectories with the risk of mortality and identify modifiable lifestyle factors related to these trajectories.MethodsWe enrolled 50,919 individuals aged ≥ 20 years old, who were free of diabetes at baseline, in the prospective MJ cohort. All participants completed at least four FPG measurements within 6 years after enrollment and were followed until December 2011. FPG trajectories were identified by group-based trajectory modeling. We used Cox proportional hazards models to examine the associations of FPG trajectories with mortality, adjusting for age, sex, marital status, education level, occupation, smoking, drinking, physical activity, body mass index, baseline FPG, hypertension, dyslipidemia, cardiovascular disease or stroke, and cancer. Associations between baseline lifestyle factors and FPG trajectories were evaluated using multinomial logistic regression.ResultsWe identified three FPG trajectories as stable (n = 32,481), low-increasing (n = 17,164), and high-increasing (n = 1274). Compared to the stable group, both the low-increasing and high-increasing groups had higher risks of all-cause mortality (hazard ratio (HR) = 1.18 (95% CI 0.99–1.40) and 1.52 (95% CI 1.09–2.13), respectively), especially among those with hypertension. Compared to participants with 0 to 1 healthy lifestyle factor, those with 6 healthy lifestyle factors were more likely to be in the stable group (ORlow-increasing = 0.61, 95% CI 0.51–0.73; ORhigh-increasing = 0.20, 95% CI 0.13–0.32).ConclusionsIndividuals with longitudinally increasing FPG had a higher risk of mortality even if they had a normal FPG at baseline. Adopting healthy lifestyles may prevent individuals from transitioning into increasing trajectories.

The association between baseline patient characteristics and alpelisib-induced hyperglycaemia in patients with HR+, HER2-, PIK3CA-mutated metastatic breast cancer.

e13059 Background: Alpelisib (A) is a PI3Kα-selective inhibitor and degrader which, in combination with fulvestrant, has been approved for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC). Hyperglycemia is the most commonly observed adverse event of A. A pooled analysis of X2101 AND SOLAR-1 trials showed the association between five baseline patient characteristics (age, fasting plasma glucose (FPG), glycated haemoglobin, body mass index (BMI) and blood monocyte count (BMC)) and the development of A-induced hyperglycaemia (HG). We examined the association between baseline factors and the A-induced HG grade (G) ≥2 in a real-world setting. Methods: We performed the retrospective observational study and included patients (pts) with HR+, HER2-, PIK3CA-mutated metastatic breast cancer who received A + fulvestrant between Oct 18, 2019, and Oct 13, 2022, at the Institute of Oncology Ljubljana. Electronic records were reviewed. Baseline age, FPG, glycated haemoglobin, BMI and BMC before the start of A therapy and glucose levels during treatment with A were collected. Random plasma glucose values (RPG) were used for HG grading according to CTCAE V. The chi-square test was used to determine the association between the baseline characteristics and A-induced HG G ≥2. Results: Thirty-one female pts were included in the analysis. The median follow-up was 21 months, and the median duration of A treatment was 5.4 months. The baseline pts characteristics were as follows: median age 58 years (range 33–80), median FPG 5.6 mmol/L (range 3.10–8.6), median BMI 21.7 kg/m² (range 18.7–30.4), and median BMC was 10.3% (range 5.3–16.6). Baseline glycated haemoglobin values were only known for 58.1% of patients, so we did not further analyse them. The highest HG grades during treatment with A were as follows: G0 in 14 pts (45.2%), G1 in 5 pts (16.1%), G2 in 6 pts (19.4%), G3 in 6 pts (19.4 %). The calculated cut-off values associated with A-induced HG ≥2 were: age above 65 years, FPG above 5.9 mmol/L and BMC more than 11.5. None of the BMI cut-off values was associated with HG G≥2. Association between the baseline age, FPG and BMC and A-induced HG G≥2. Conclusions: Age over 65 years, FPG more than 5.9 mmol/L and BMC more than 11.5% have a statistically significant higher probability for A-induced HG G≥2. Therefore, these patients need more frequent blood glucose measurements, lifestyle adjustments and early treatment with metformin and/or other oral glucose-lowering agents. [Table: see text]

J-shape relationship between normal fasting plasma glucose and risk of type 2 diabetes in the general population: results from two cohort studies

BackgroundPrevious studies have reported that high fasting plasma glucose (FPG), even that within the normal range, is associated with the risk of type 2 diabetes (T2D). Nevertheless, these findings are limited to specific populations. Thus, studies in the general population are imperative.MethodsThis study included two cohorts comprising 204 640 individuals who underwent physical examinations at the Rich Healthcare Group present at 32 locations in 11 cities of China from 2010 to 2016 and 15 464 individuals who underwent physical tests at the Murakami Memorial Hospital in Japan. Cox regression, restricted cubic spline (RCS), Kaplan–Meier (KM) curves, and subgroup analysis were used to determine the relationship between FPG and T2D. Receiver operating characteristic (ROC) curves were used to evaluate the predictive power of FPG for T2D.ResultsThe mean age of the 220 104 participants (204 640 Chinese and 15 464 Japanese participants) was 41.8 years (41.7 years for the Chinese and 43.7 years for the Japanese participants). During follow-up, 2611 individuals developed T2D (2238 Chinese and 373 Japanese participants). The RCS demonstrated a J-shaped relationship between FPG and T2D risk, with inflexion points of 4.5 and 5.2 for the Chinese and Japanese populations, respectively. Multivariate-adjusted hazard ratio (HR) was 7.75 for FPG and T2D risk after the inflexion point (7.3 for Chinese and 21.13 for Japanese participants).ConclusionsIn general Chinese and Japanese populations, the normal baseline FPG range showed a J-shaped relationship with the risk of T2D. Baseline FPG levels help identify individuals at high risk of T2D and may enable early primary prevention to improve their outcomes.

Glycemia is associated with subclinical atherosclerosis through renal function in nondiabetic apparently healthy adults: a mediation analysis.

The causative associations between glycemia and early alterations in renal and vascular function remain unclear. To examine the interplay among glycemia, renal function, and markers of subclinical atherosclerosis in apparently healthy subjects. Nondiabetic (30-60 years old) individuals (n = 205) without chronic kidney disease or cardiovascular disease were consecutively recruited from a cardiovascular prevention clinic. All subjects underwent arterial stiffness assessment by measuring the carotid-femoral pulse wave velocity (cfPWV). Glomerular filtration rate (GFR) was estimated by CKD-EPI equation. Study procedures were identical in the two visits (median follow-up 66 months). We employed structural equation modeling (SEM) analysis to investigate the directionality of associations. Baseline fasting plasma glucose (FPG) was independently and inversely associated with GFR (p = 0.008). GFR was significantly associated with cfPWV (p < 0.001) at baseline. By SEM analysis decreasing baseline GFR directly correlated with increasing cfPWV (p = 0.003) whereas FPG correlated with cfPWV indirectly through GFR (mediation) (P = 0.032). FPG did not mediate the effect of GFR on cfPWV (P = 0.768). SEM analysis of longitudinal data revealed bidirectional correlations between changes in FPG and GFR (P < 0.001). Alterations in GFR were directly related to changes in cfPWV (p < 0.001) whereas FPG only indirectly correlated with cfPWV through GFR changes (P = 0.002). In apparently healthy nondiabetic subjects, the association between baseline or longitudinal glycemia levels and arterial stiffening was indirect, consistently mediated by renal function status. These findings provide the first clinical evidence supporting the directionality between kidney function and glycemia in nondiabetic subjects leading to vascular dysfunction. In apparently healthy nondiabetic subjects, without cardiovascular disease or chronic kidney disease, the association between baseline or longitudinal glycemia levels and arterial stiffening was indirect, consistently mediated by renal function status.

The modification of individual factors on association between serum 25(OH)D and incident type 2 diabetes: Results from a prospective cohort study.

Several epidemiological studies have suggested an association between low vitamin D status and increased risk for type 2 diabetes (T2D). This study aimed to explore the dose-response relationship of serum 25-hydroxyvitamin D [25(OH)D] concentrations with incident T2D and the interaction between serum 25(OH)D with individual factors on T2D risk. A total of 1,926 adults without diabetes (mean age: 52.08 ± 13.82 years; 42% men) were prospectively followed for 36 months. Cox proportional hazards model and restricted cubic spline analysis were performed to assess the association and dose-response relationship between serum 25(OH)D and T2D incidence. Both additive and multiplicative interactions were calculated between serum 25(OH)D and individual factors. The net reclassification index (NRI) was used to evaluate the improvement of risk prediction of T2D by adding serum 25(OH)D to traditional risk factors. There were 114 new T2D cases over a mean follow-up of 36 months. Serum 25(OH)D was not associated with T2D incidence, and no significant dose-response relationship was found in the total population. However, stratified analyses suggested a non-linear inverse relationship among individuals with baseline fasting plasma glucose (FPG) <5.6 mmol/L (P overall = 0.061, P non-linear = 0.048). And a significant multiplicative interaction was observed between serum 25(OH)D and FPG on T2D risk (P = 0.005). In addition, we found a significant additive interaction of low serum 25(OH)D with older age (RERI = 0.897, 95% CI: 0.080-1.714; AP = 0.468, 95% CI: 0.054-0.881), male (AP = 0.441, 95% CI: 0.010-0.871), and insufficient physical activity (RERI = 0.875, 95% CI: 0.204-1.545; AP = 0.575, 95% CI: 0.039-1.111) on T2D risk. Significant additive interactions were also observed between vitamin D deficiency/insufficiency with male, overweight/obesity, and insufficient physical activity on T2D risk. Moreover, adding low serum 25(OH)D to a model containing established risk factors yielded significant improvements in the risk reclassification of T2D (NRI = 0.205, 95% CI: 0.019-0.391). Our results indicated a non-linear relationship of serum 25(OH)D concentrations with T2D risk among individuals with normal FPG and additive interactions of serum 25(OH)D with gender, overweight/obesity, and physical activity on T2D risk, suggesting the importance of outdoor exercise.

Interaction effect between fasting plasma glucose and lipid profiles on mortality of peritoneal dialysis patients.

Peritoneal dialysis (PD) patients have a high risk of abnormal glucose and lipids metabolism. We investigated the effects of baseline fasting plasma glucose (FPG) as well as its interaction with lipid profiles on all-cause and cardiovascular disease (CVD) cause-specific mortality in PD patients. A total of 1995 PD patients were enrolled. Kaplan-Meier survival curves and Cox regression models were performed to assess the association of FPG levels with mortality in PD patients. During a median (25th-75th quartile) follow-up period of 48.1 (21.8-77.9) months, 567 (28.4%) patients died, including 282 (14.1%) CVD deaths. Kaplan-Meier survival curves showed that all-cause and CVD cause-specific mortality increased significantly with elevated baseline FPG levels (Log-rank tests: both P-values <.001). However, with adjustment for potential confounding factors, baseline FPG levels were not significantly associated with all-cause and CVD cause-specific mortality. Nevertheless, a significant interaction between baseline FPG and low-density lipoprotein cholesterol (LDL-C) on all-cause mortality was found (P for interaction test: .013), and subgroup analyses further showed that all-cause mortality was significantly increased for baseline FPG ≥7.0mmol/L compared with the normal reference (FPG <5.6mmol/L) (hazard ratio 1.89, 95% confidence interval 1.11-3.23, P-value=.020) for patients with LDL-C ≥3.37mmol/L only, but not for those with lower LDL-C levels (<3.37mmol/L). The significant interaction effect between baseline FPG and LDL-C on all-cause mortality showed that, for PD patients with LDL-C ≥3.37mmol/L, higher FPG levels (≥7.0mmol/L) were significantly associated with an increased risk of all-cause mortality and need more intensive management of their FPG by clinicians in the future.

Weekly somapacitan had no adverse effects on glucose metabolism in adults with growth hormone deficiency

PurposeThe long-term effects of long-acting growth hormone (LAGH) analogues on glucose metabolism in adult growth hormone deficiency (AGHD) are not known. We investigated the impact of LAGH somapacitan, administered once-weekly, on glucose metabolism in patients with AGHD.MethodsIn post hoc-defined analyses, we compared the effects of somapacitan with daily growth hormone (GH) and placebo on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) in patients with AGHD across a unique data set from three phase 3 randomized controlled trials (REAL 1, REAL 2 and REAL Japan).ResultsNo new cases of diabetes mellitus were reported with somapacitan. Among GH-naïve patients (n = 120 somapacitan, n = 119 daily GH), higher changes from baseline in FPG, HOMA-IR and fasting insulin levels were observed with daily GH versus somapacitan at 34 weeks, but not at 86 weeks. HbA1c and HOMA-β did not differ between groups at either timepoint. Among treatment-naïve patients, sex, age, fasting insulin, glucose tolerance status and body mass index did not influence changes in glucose metabolism. In previously treated patients (REAL 1 extension: n = 51 somapacitan, n = 52 daily GH; REAL 2: n = 61 and n = 31, respectively; REAL Japan: n = 46 and n = 16, respectively), the difference in changes from baseline were not statistically significant between somapacitan and daily GH for any glucose metabolism parameters.ConclusionsSomapacitan, compared with daily GH, did not adversely affect glucose metabolism up to 86 weeks in a large cohort of treatment-naïve or previously treated patients with AGHD.Trial registrations (date of registration): NCT02229851 (2 September 2014), NCT02382939 (3 March 2015), NCT03075644 (7 March 2017).