HbA1c Subgroups Research Articles

Glycemic Outcomes in Baseline Hemoglobin A1C Subgroups in the International Diabetes Closed-Loop Trial.

Using a closed-loop system significantly improves time in range (TIR) 70-180 mg/dL in patients with type 1 diabetes (T1D). In a 6-month RCT, 112 subjects were randomly assigned to closed-loop control (Tandem Control-IQ) after obtaining 2 weeks of baseline Continuous glucose monitoring (CGM) data from sensor-augmented pump therapy. We compared glycemic outcomes from baseline to end of study among subgroups classified by baseline HbA1c levels. All HbA1c subgroups showed an improvement in TIR due to reduction of both hyperglycemia and hypoglycemia. Those with HbA1c <6.5% improved mostly by reducing nocturnal hypoglycemia due to the automated basal insulin adjustments. Those with HbA1c ≥8.5% improved mostly by reducing daytime and nocturnal hyperglycemia due to both automated basal insulin adjustments and correction boluses during the day. There does not appear to be any reason to exclude individuals with T1D from automated insulin delivery based on their HbA1c. Clinical Trial Identifier: NCT03563313.

The effect of short-term intensive insulin therapy on inflammatory cytokines in patients with newly diagnosed type 2 diabetes.

BackgroundDiabetes mellitus was a chronic low‐grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short‐term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII).MethodsThirty‐three newly diagnosed type 2 diabetic patients were enrolled between September 2020 to December 2020. Expression of 40 inflammatory cytokines of the patients were tested with RayBiotech antibody array before and after 1 week of intensive insulin therapy of CSII. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to explore the signaling pathway involved in the therapy.ResultsFive inflammatory cytokines were downregulated significantly after 1 week of CSII therapy. They were interleukin‐6 receptor (IL‐6R), regulated upon activation normal T‐cell expressed and secreted (RANTES), intercellular adhesion molecule‐1 (ICAM‐1), tissue inhibitor of metalloproteinase‐1 (TIMP‐1), and platelet‐derived growth factor type BB (PDGF‐BB) (p < 0.05 and foldchange <0.83). Among patients with baseline glycated hemoglobin (HbA1c) < 10%, three proinflammatory cytokines were decreased significantly after therapy: IL‐6R, RANTES, and ICAM‐1. As for the patients with baseline HbA1c ≥ 10%, eight inflammatory cytokines were inhibited significantly after the treatment, including ICAM‐1, IL‐6R, RANTES, TIMP‐1, TIMP‐2, macrophage inflammatory protein‐1 beta (MIP‐1β), PDGF‐BB, and tumor necrosis factor receptor type II (TNF RII). No matter which subgroup of baseline HbA1c level was considered, the decreased cytokines after CSII therapy were significantly involved in TNF signaling pathway. Nuclear factor‐kappa B (NF‐κB) signaling pathway was mainly enriched in patients with baseline HbA1c ≥ 10%.ConclusionsA panel of 40 inflammatory cytokines, measured by protein microarray, were evaluated for 1 week of CSII treatment in newly diagnosed type 2 diabetic patients. After treatment, many proinflammatory cytokines decreased. In the higher baseline HbA1c subgroup, more proinflammatory cytokines improved. No matter which subgroup of HbA1c level was considered, IL‐6R, RANTES, and ICAM‐1, which were involved in TNF signaling pathway, decreased significantly after CSII therapy. This was the first report showing that the cytokines of IL‐6R, TIMP‐2, PDGF‐BB, and TNF RII decreased after the CSII therapy.

Association of Baseline HbA1c With Cardiovascular and Renal Outcomes: Analyses From DECLARE-TIMI 58.

Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models. In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06-1.19], 1.08 [1.04-1.13], and 1.17 [1.11-1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05). Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c <7%.

Efficacy and Safety of Once-Weekly Semaglutide 2.0 mg vs 1.0 mg by Baseline HbA1c and BMI: SUSTAIN FORTE Subgroup Analyses

Once-weekly subcutaneous semaglutide 2.0 mg showed superior efficacy with similar safety vs 1.0 mg in 961 participants with type 2 diabetes (HbA1c 8.0-10.0%) after 40 weeks in SUSTAIN FORTE. We assessed the effect of semaglutide 2.0 mg vs 1.0 mg on HbA1c and body weight (BW) in prespecified baseline (BL) HbA1c (<9.0%, ≥9.0%) and BMI (<35, ≥35 kg/m2) subgroups. Mean BL HbA1c was 8.9% and BMI 34.6 kg/m2. For HbA1c and BW, estimated treatment differences favored semaglutide 2.0 mg vs 1.0 mg across all BL HbA1c and BMI subgroups. Treatment-by-subgroup interactions were nonsignificant (HbA1c, p=0.55 and p=0.41; BW, p=0.40 and p=0.13; Figures A-D). Greater mean HbA1c reductions were observed for both doses in the higher vs lower BL HbA1c subgroup (Figure A). Conversely, greater mean BW reductions were observed for both doses in the lower vs higher BL HbA1c subgroup (Figure C). Similar mean HbA1c reductions were observed across BL BMI subgroups (Figure B), while greater mean BW reductions were observed for both doses in the higher vs lower BL BMI subgroup (Figure D). Overall, the incidence of adverse events was similar for both doses and across BL HbA1c and BMI subgroups with no new safety concerns identified. In line with the results in the overall population, semaglutide 2.0 mg provided consistently greater reductions in HbA1c and BW vs 1.0 mg across BL HbA1c and BMI subgroups.

Aspirin and pre-eclampsia prevention in women with pre-existing diabetes: a retrospective study.

Aspirin is routinely prescribed in high-risk pregnancies to prevent pre-eclampsia; however, there is a paucity of data in women with pre-existing diabetes. To assess the efficacy and safety of aspirin in women with pre-existing diabetes in preventing pre-eclampsia. A retrospective review of women with pre-existing diabetes who attended antenatal clinics in a tertiary referral hospital between 2013 and 2019 was conducted. Cases were those receiving aspirin prior to 16 weeks, with pre-eclampsia as the primary outcome. The relationship between early pregnancy glycaemic control and pre-eclampsia was also assessed. Of the 164 women included in the study, 45 received aspirin. There were no differences in pre-eclampsia (odds ratio (OR) 0.9 (0.3-3.0), P = 0.924) or any other measure of placental insufficiency (OR 1.7 (0.7-4.3), P = 0.243) between the aspirin and control groups after adjusting for baseline differences. Aspirin therapy was associated with an increased risk of postpartum haemorrhage (PPH) (OR 3.1 (1.1-9.1), P = 0.041). The incidence of pre-eclampsia increased stepwise according to early pregnancy HbA1c subgroups of ≤6.0% (n = 47), 6.1-7.5% (n = 57) and > 7.5% (n = 39), with rates of 0, 12.3 and 20.5% (P = 0.007) respectively. The aspirin group had a higher baseline risk of pre-eclampsia and placental insufficiency, therefore the absence of difference between the groups favoured the efficacy of aspirin. PPH was highlighted as a potential complication of therapy, and early pregnancy HbA1c as a novel risk stratification tool for pre-eclampsia in women with pre-existing diabetes.

Glycaemic efficacy of an expanded dose range of dulaglutide according to baseline glycated haemoglobin (HbA1c) subgroup: Post hoc analysis of AWARD-11.

The AWARD‐11 trial demonstrated the safety and efficacy of dulaglutide 3.0 and 4.5 mg compared to dulaglutide 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. This post hoc analysis examined the change from baseline in glycated haemoglobin (HbA1c) and proportions of patients achieving HbA1c <7% at weeks 36 and 52 with dulaglutide 1.5 mg, 3.0 mg or 4.5 mg across clinically relevant baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%). Mean reductions in HbA1c were observed across all baseline HbA1c subgroups at 36 weeks (range of HbA1c change: 1.5 mg: −1.0% to −2.2%; 3.0 mg: −1.2% to −2.5%; and 4.5 mg: −1.2% to −3.2%). More patients randomized to 3.0 mg or 4.5 mg (vs. 1.5 mg) achieved HbA1c <7% at 36 weeks regardless of baseline HbA1c; the difference in proportions was greater at higher baseline HbA1c (P‐interaction = 0.096). Similar patterns in glycaemic improvement and proportions achieving HbA1c <7% were observed at 52 weeks. Hypoglycaemia and gastrointestinal adverse events were similar among the HbA1c subgroups. Glycaemic control was improved with dulaglutide dose escalation from 1.5 mg to 3.0 mg or 4.5 mg across baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%).

Effect of dulaglutide 3.0 and 4.5mg on weight in patients with type 2 diabetes: Exploratory analyses of AWARD-11.

AimTo evaluate the impact of dulaglutide 3.0 and 4.5 mg versus 1.5 mg on body weight in patients with type 2 diabetes (T2D) based on exploratory analyses of the AWARD‐11 trial.Materials and MethodsPatients were randomized to once‐weekly dulaglutide 1.5 (n = 612), 3.0 (n = 616) or 4.5 mg (n = 614) for 52 weeks. The primary objective was superiority of dulaglutide 3.0 and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary and exploratory assessments included weight reduction in the overall trial population and baseline body mass index (BMI) and HbA1c subgroups.ResultsAt baseline, patients had a mean age of 57.1 years, HbA1c 8.6% (70 mmol/mol), weight 95.7 kg and BMI 34.2 kg/m2. At 36 weeks, dulaglutide 3.0 and 4.5 mg were superior to 1.5 mg for weight change from baseline (1.5 mg, −3.1 kg; 3.0 mg, −4.0 kg [P = .001]; 4.5 mg, −4.7 kg [P < .001]). Higher dulaglutide doses were associated with numerically greater weight reduction compared with 1.5 mg in each baseline BMI and HbA1c subgroup. Absolute weight reduction increased with increasing BMI category, but percentage weight loss was similar between subgroups. Weight reductions with dulaglutide were greater in patients with lower versus higher baseline HbA1c.ConclusionsIn patients with T2D, inadequately controlled by metformin, incremental weight loss was observed with dulaglutide 1.5, 3.0 and 4.5 mg doses regardless of baseline BMI or HbA1c. Although absolute weight loss was numerically greater in patients with higher baseline BMI, percentage of weight loss was similar between BMI subgroups.

The retinopathy-derived HbA1c threshold of 6.5% for type 2 diabetes also captures the risk of diabetic nephropathy in NHANES.

To determine if an HbA1c diagnostic threshold of less than 6.5% (<48 mmol/mol) could be identified based on a urinary albumin-creatinine ratio (UACR) of 30 mg/g or higher in subjects not known to have diabetes. A UACR was measured for 20 158 participants in the 2011-2018 nationally representative cross-sectional National Health and Nutrition Examination Surveys (NHANES; cycles 7-10 inclusive). There was a significant trend for an increasing risk with a UACR of 30 mg/g or higher across increasing HbA1c categories (P < .0001). This trend was mainly attributable to the high prevalence of raised UACR in the 7.0% or higher HbA1c subgroup of subjects not previously diagnosed with diabetes. None of the odds ratios in the lower HbA1c subgroups versus the HbA1c subgroup of less than 5.0% reached significance. There were racial/ethnic differences in UACR risk (P < .0001), with White and Black subjects exhibiting little increased risk (vs. HbA1c <5.0%) until they reached an HbA1c of 7.0%, while Asian and Hispanic subjects showed some increased, but non-significant, risks at lower HbA1c levels. Maximizing the area under receiver operating characteristic curves from logistic regressions predicted an ideal HbA1c threshold of 5.8%, but there was little variation in area from 5.5% to 7.0%. A clinically useful diagnostic threshold below 6.5% for HbA1c for elevated UACR risk was not identified, with an increased risk only obvious at an HbA1c of 7.0% or higher. Thus, the retinopathy-derived HbA1c threshold of 6.5% also captures the risk of diabetic nephropathy in NHANES.

665-P: Efficacy and Safety of Once-Weekly Semaglutide 2.0 mg vs. 1.0 mg by Baseline HbA1c and BMI: SUSTAIN FORTE Subgroup Analyses

Once-weekly subcutaneous semaglutide 2.0 mg showed superior efficacy with similar safety vs. 1.0 mg in 961 participants with type 2 diabetes (HbA1c 8.0-10.0%) after 40 weeks in SUSTAIN FORTE. We assessed the effect of semaglutide 2.0 mg vs. 1.0 mg on HbA1c and body weight (BW) in prespecified baseline (BL) HbA1c (<9.0%, ≥9.0%) and BMI (<35, ≥35 kg/m2) subgroups.Mean BL HbA1c was 8.9% and BMI 34.6 kg/m2. For HbA1c and BW, estimated treatment differences favored semaglutide 2.0 mg vs. 1.0 mg across all BL HbA1c and BMI subgroups. Treatment-by-subgroup interactions were nonsignificant (HbA1c, p=0.55 and p=0.41; BW, p=0.40 and p=0.13; Figure A-D). Greater mean HbA1c reductions were observed for both doses in the higher vs. lower BL HbA1c subgroup (Figure A). Conversely, greater mean BW reductions were observed for both doses in the lower vs. higher BL HbA1c subgroup (Figure C). Similar mean HbA1c reductions were observed across BL BMI subgroups (Figure B), while greater mean BW reductions were observed for both doses in the higher vs. lower BL BMI subgroup Figure D). Overall, the incidence of adverse events was similar for both doses and across BL HbA1c and BMI subgroups with no new safety concerns identified.In line with the results in the overall population, semaglutide 2.0 mg provided consistently greater reductions in HbA1c and BW vs. 1.0 mg across BL HbA1c and BMI subgroups.View largeDownload slideView largeDownload slide DisclosureJ. B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Fortress Biotch, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego Inc., Stability Health, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Research Support; Self; NovaTarg Therapeutics, Novo Nordisk, Sanofi, Tolerion, Inc., vTv Therapeutics, Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. P. Auerbach: Employee; Self; Novo Nordisk A/S. H. S. Bajaj: Other Relationship; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Kowa Pharmaceuticals America, Inc., Merck & Co., Inc., Sanofi, Tricida, Inc. Y. Fukushima: None. I. Lingvay: Advisory Panel; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Consultant; Self; TARGET PharmaSolutions, Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Zealand Pharma A/S, Research Support; Self; Mylan N. V., Sanofi. S. Macura: Employee; Self; Novo Nordisk A/S. A. L. Søndergaard: Stock/Shareholder; Self; Novo Nordisk A/S, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Tankova: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Sanofi, Wörwag Pharma, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Pharma Ltd., Sandoz International GmbH, Sanofi, Servier Laboratories. N. Tentolouris: None.FundingNovo Nordisk A/S

The Added and Interpretative Value of CGM-Derived Parameters in Type 1 Diabetes Depends on the Level of Glycemic Control

ObjectiveIn type 1 diabetes mellitus (T1DM) management, continuous glucose monitoring (CGM)-derived parameters can provide additional insights, with time in range (TIR) and other parameters reflecting glycemic control and variability being put forward. This study aimed to examine the added and interpretative value of the CGM-derived indices TIR and coefficient of variation (CV%) in T1DM patients stratified according to their level of glycemic control by means of HbA1C. MethodsT1DM patients with a minimum disease duration of 10 years and without known macrovascular disease were enrolled. Patients were equipped with a blinded CGM device for 7 days. TIR and time spent in hypoglycemia and hyperglycemia were determined, and CV% was used as a parameter for glycemic variability. Pearson (r) and Spearman correlations (rs) and a regression analysis were used to examine associations. ResultsNinety-five patients (age: 45 ± 10 years; HbA1C level: 7.7% ± 0.8% [61 ± 7 mmol/mol]) were included (mean blood glucose [MBG]: 159 ± 31 mg/dL; TIR: 55.8% ± 14.9%; CV%: 43.5% ± 7.8%) and labeled as having good (HbA1C level ≤7% [≤53 mmol/mol]; n = 20), moderate (7%-8%; n = 44), or poor (>8% [>64 mmol/mol]; n = 31) glycemic control. HbA1C was significantly associated with MBG (rs = 0.48, P < .001) and time spent in hyperglycemia (total: rs = 0.52; level 2: r = 0.46; P < .001) but not with time spent in hypoglycemia and CV%, even after an analysis of the HbA1C subgroups. Similarly, TIR was negatively associated with HbA1C (r = −0.53; P < .001), MBG (rs = −0.81; P < .001), and time spent in hyperglycemia (total: rs = −0.90; level 2: rs = −0.84; P < .001) but not with time in hypoglycemia. The subgroup analyses, however, showed that TIR was associated with shorter time spent in level-2 hypoglycemia in patients with good (rs = −0.60; P = .007) and moderate (rs = −0.25; P = .047) glycemic control. In contrast, CV% was strongly positively associated with time in hypoglycemia (total: rs = 0.78; level 2: rs = 0.76; P < .001) but not with TIR or time in hyperglycemia in the entire cohort, although the subgroup analyses showed that TIR was negatively associated with CV% in patients with good glycemic control (r = −0.81, P < .001) and positively associated in patients with poor glycemic control (r = +0.47; P < .01). ConclusionThe CGM-derived metrics TIR and CV% are related to clinically important situations, TIR being strongly dependent on hyperglycemia and CV% being reflective of hypoglycemic risk. However, the interpretation and applicability of TIR and CV% and their relationship depends on the level of glycemic control of the individual patient, with CV% generally adding less clinically relevant information in those with poor control. This illustrates the need for further research and evaluation of composite measures of glycemic control in T1DM.

Diabetes mellitus, HBA1C, and in vivo Alzheimer’s disease pathologies

AbstractBackgroundAlthough previous studies have reported associations of diabetes mellitus (DM) with cognitive impairment or dementia, the exact pathophysiological links underlying the associations remain incompletely understood. In this context, we aimed to investigate the associations of DM or glycated hemoglobin (HbA1c) with in vivo Alzheimer’s disease (AD) pathologies such as cerebral beta‐amyloid protein (Aβ) deposition and tau deposition.MethodTotal 136 participants (71 cognitively normal, 31 mild cognitive impairment, and 34 AD dementia) from the Korean Brain Aging Study for Early Diagnosis &amp; Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study, were included for this analysis. All participants underwent comprehensive clinical and neuropsychological assessment, 11C labelled Pittsburgh Compound B (PiB) positron emission tomography (PET), 11F AV‐1451 PET, magnetic resonance imaging, apolipoprotein E genotyping, and HbA1c measurement.ResultNeither the presence of DM nor HbA1c level was associated with global Aβ deposition after controlling for age, sex, education, vascular risk score (except DM), apolipoprotein e4 positivity, and clinical diagnosis. In contrast, higher HbA1c was significantly associated with lower AD‐signature region tau deposition and the presence of DM showed a trend level association with decreased tau deposition. Additionally, we found significant Aβ deposition x HbA1c (or the presence of DM) interaction effect on tau deposition. While higher Aβ deposition was significantly related to increased tau deposition in lower HbA1c (or DM negative) subgroup, there was no such relationship between Aβ and tau deposition in higher HbA1c (or DM positive) one. Sensitivity analyses including only cognitively normal individuals also showed similar results.ConclusionOur results indicate that DM or higher blood glucose may not contribute to cognitive impairment or dementia via AD‐specific pathologies, especially amyloid deposition. Therefore, other non‐AD pathophysiological contributions including vascular pathologies should be considered. Although being very cautious, high blood glucose may relate to delayed brain tau deposition.

Clinical Management and Pump Parameter Adjustment of the Control-IQ Closed-Loop Control System: Results from a 6-Month, Multicenter, Randomized Clinical Trial.

Background: Data are limited on the need for and benefits of pump setting optimization with automated insulin delivery. We examined clinical management of a closed-loop control (CLC) system and its relationship to glycemic outcomes. Materials and Methods: We analyzed personal parameter adjustments in 168 participants in a 6-month multicenter trial of CLC with Control-IQ versus sensor-augmented pump (SAP) therapy. Preset parameters (BR = basal rates, CF = correction factors, CR = carbohydrate ratios) were optimized at randomization, 2 and 13 weeks, for safety issues, participant concerns, or initiation by participants' usual diabetes care team. Time in range (TIR 70-180 mg/dL) was compared in the week before and after parameter changes. Results: In 607 encounters for parameter changes, there were fewer adjustments for CLC than SAP (3.4 vs. 4.1/participant). Adjustments involved BR (CLC 69%, SAP 80%), CR (CLC 68%, SAP 50%), CF (CLC 44%, SAP 41%), and overnight parameters (CLC 62%, SAP 75%). TIR before and after adjustments was 71.2% and 71.3% for CLC and 61.0% and 62.9% for SAP. The highest baseline HbA1c CLC subgroup had the largest TIR improvement (51.2% vs. 57.7%). When a CR was made more aggressive in the CLC group, postprandial time >180 mg/dL was 43.1% before the change and 36.0% after the change. The median postprandial time <70 mg/dL before making CR less aggressive was 1.8%, and after the change was 0.7%. Conclusions: No difference in TIR was detected with parameter changes overall, but they may have an effect in higher HbA1c subgroups or following user-directed boluses, suggesting that changes may matter more in suboptimal control or during discrete periods of the day. Clinical Trials Registration number: NCT03563313.

62 - Once-Weekly Semaglutide Reduces HbA1c and Body Weight Across Baseline HbA1c Subgroups in the SUSTAIN 1–5 and 7–10 Clinical Trials

This posthoc analysis assessed change in HbA1c and body weight with once-weekly (OW) semaglutide in the phase 3 SUSTAIN 1–5 and 7–10 trials by baseline HbA1c subgroup.

Predictions of diabetes complications and mortality using hba1c variability: a 10-year observational cohort study.

Emerging evidence suggests that HbA1c variability, in addition to HbA1c itself, can be used as a predictor for mortality. The present study aims to examine the predictive power of mean HbA1c and HbA1c variability measures for diabetic complications as well as mortality. The retrospective observational study analyzed diabetic patients who were prescribed insulin at outpatient clinics of the Prince of Wales Hospital and Shatin Hospital, Hong Kong, from 1 January to 31 December, 2009. Standard deviation (SD), root mean square (RMS), and coefficient of variation were used as measures of HbA1c variability. The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes were diabetes-related complications. The study cohort consists of 3424 patients, including 3137 patients with at least three HbA1c measurements. The low mean HbA1c subgroup had significantly shorter time-to-death for all-cause mortality (P < 0.001) but not cardiovascular mortality (P = 0.920). The high Hba1c subgroup showed shorter time-to-death for all-cause (P < 0.001) and cardiovascular mortality (P < 0.001). Mean Hba1c and Hba1c variability predicted all-cause as well as cardiovascular-specific mortality. In terms of secondary outcomes, mean HbA1c and HbA1c variability significantly predicted diabetic ketoacidosis/hyperosmolar hyperglycemic state/diabetic coma, neurological, ophthalmological, and renal complications. A significant association between dichotomized HbA1c variability and hypoglycemia frequency was found (P < 0.0001). High HbA1c variability is associated with increased risk of all-cause and cardiovascular mortality, as well as diabetic complications. The association between hypoglycemic frequency, HbA1c variability, and mortality suggests that intermittent hypoglycemia resulting in poorer outcomes in diabetic patients.

387-P: Glycemic Outcomes in Baseline Hemoglobin A1c Subgroups in the International Diabetes Closed-Loop (IDCL) Trial

Using a closed loop system significantly improves time in range (TIR) in patients with type 1 diabetes (T1D). In a 6-month RCT, 112 subjects were assigned to closed-loop control (Tandem Control-IQ) after obtaining two weeks of baseline CGM data from sensor-augmented pump therapy. We compared glycemic outcomes from baseline to end of study among subgroups classified by baseline HbA1C level. Participants’ mean age was 33±16 (range 14-71 yrs) and mean baseline HbA1C was 7.4±1.0 (range 5.4% to 10.6%). All HbA1c subgroups showed an improvement in TIR due to reduction of both hyperglycemia and hypoglycemia (Table). Those with HbA1c &amp;lt;6.5% improved mostly by reducing nocturnal (MN to 6 AM) hypoglycemia. Those with HbA1c ≥8.5% improved mostly by reducing daytime and nocturnal hyperglycemia. Participants with lower HbA1c at baseline reduced their overnight hypoglycemia the most, likely due to the system’s automated basal insulin adjustment. For those with higher HbA1c at baseline, increased TIR came mostly from hyperglycemia reduction, likely due to automated basal insulin adjustment in day and night. These participants likely also benefitted from hourly automatic correction boluses during the day. All HbA1c subgroups benefitted from automated insulin delivery. Disclosure L. Ekhlaspour: None. D. Raghinaru: None. J. Lum: None. S.A. Brown: Research Support; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care, Tandem Diabetes Care, Tolerion, Inc. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Medtronic. Research Support; Self; Beta Bionics, Inc., Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UC4108483); University of Virginia; Tandem Diabetes Care

The Benefit of Insulin Degludec/Liraglutide (IDegLira) Compared With Basal-Bolus Insulin Therapy is Consistent Across Participant Subgroups With Type 2 Diabetes in the DUAL VII Randomized Trial.

Insulin degludec/liraglutide (IDegLira) results in glycated hemoglobin (HbA1c) levels comparable with basal-bolus (BB) therapy. Here, we assessed the effect of once-daily IDegLira compared with BB (once-daily insulin glargine 100 U/mL and insulin aspart ≤4 times/day) across subgroups with varying characteristics. DUAL VII trial participants (type 2 diabetes [T2D], HbA1c 53-86 mmol/mol [7.0%-10.0%]) were subgrouped post hoc based on the following baseline characteristics: HbA1c (≤58.5, >58.5 to ≤69.4, and >69.4 mmol/mol; ≤7.5%, >7.5 to ≤8.5%, and >8.5%), body mass index (<30, ≥30 to <35, and ≥35 kg/m2), age (18 to <65 and ≥65 years), duration of diabetes (≥0 to 10 and ≥10 years), total pretrial daily basal insulin dose (20 to <30, ≥30 to <40, and ≥40 to ≤50 U), and fasting plasma glucose (<7.2 mmol/L/<130 mg/dL and ≥7.2 mmol/L/≥130 mg/dL). Compared with BB, and in all subgroups, IDegLira treatment consistently gave similar HbA1c reductions, less severe or blood glucose-confirmed hypoglycemia, lower end-of-trial (EOT) total daily insulin dose, and weight loss. In all subgroups, mean EOT HbA1c was ≤53 mmol/mol (≤7.0%). The greatest HbA1c reduction occurred in the highest baseline HbA1c subgroup. Overall, mean EOT daily insulin dose was 0.43 to 0.52 U/kg with IDegLira and 0.74 to 1.07 U/kg with BB. More participants achieved the triple composite endpoint (HbA1c <53 mmol/mol [<7.0%] without weight gain or hypoglycemia) with IDegLira vs BB across the baseline HbA1c subgroups (≤58.5 mmol/mol [44.6% vs 7.0%], >58.5 to ≤69.4 mmol/mol [41.1% vs 8.3%], and >69.4 mmol/mol [23.8% vs 3.4%]). These results support initiating IDegLira in patients with varying baseline characteristics and uncontrolled T2D on basal insulin. NCT02420262.

Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous once-weekly semaglutide: A patient-level, pooled analysis of the SUSTAIN 1-5 trials.

AimTo evaluate the impact of relevant patient‐level characteristics on the efficacy and safety of subcutaneous, once‐weekly semaglutide in subjects with type 2 diabetes.Materials and MethodsExploratory post hoc analyses of pooled SUSTAIN 1‐5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c < 7.0% [53 mmol/mol]), without weight gain or severe/blood glucose‐confirmed symptomatic hypoglycaemia at week 30 with semaglutide (0.5/1.0 mg) across clinically relevant patient subgroups: baseline HbA1c (≤7.5%, >7.5%‐8.0%, >8.0%‐8.5%, >8.5%‐9.0% and > 9.0%), background medications, diabetes duration and pancreatic beta‐cell function.ResultsMean HbA1c (% point) reductions increased from lowest to highest HbA1c subgroups (−0.9%, −1.2%,‐1.5%, −1.7% and −2.3% [effect of subgroup within treatment: P = 0.247] for semaglutide 0.5 mg, and −1.1%, −1.4%, −1.9%, −2.1% and −2.7% [P = 0.045] for semaglutide 1.0 mg), with mean HbA1c ranges at week 30 of 6.3%‐7.3% and 6.1%‐6.9%, respectively. The corresponding BW reductions generally decreased with increasing baseline HbA1c (−4.4, −3.9, −3.9, −3.3 and −2.9 kg [P = 0.004], and −6.4, −5.9, −5.2, −4.5 and −4.8 kg [P < 0.001], respectively). HbA1c and BW reductions were consistently greater for semaglutide 1.0 mg versus 0.5 mg across background medication, diabetes duration and pancreatic beta‐cell function subgroups. Adverse events with semaglutide were consistent with the glucagon‐like peptide‐1 receptor agonist class, with gastrointestinal events the most common.ConclusionsSemaglutide was consistently efficacious across the continuum of diabetes care in a broad spectrum of patient subgroups with a range of clinical characteristics.

Comparison of the Effectiveness and Safety of Vildagliptin Add-On to Metformin Versus Other Oral Dual Antidiabetes Agents in Patients with Type 2 Diabetes: The China Prospective Diabetes Study.

IntroductionThe efficacy and safety of vildagliptin alone or with metformin is well established by randomized trials, but it is unknown whether it can be extrapolated to the real-world setting in Chinese patients with type 2 diabetes mellitus (T2DM). This study aimed to assess the effectiveness and safety of vildagliptin add-on to metformin versus dual oral antidiabetes drug (OAD), non-vildagliptin combination therapies in real-world Chinese patients with T2DM.MethodsThe China Prospective Diabetes Study was a post-marketing, prospective, multicenter, observational, real-world study conducted in 52 centers. Patients inadequately controlled with OAD monotherapy and who initiated vildagliptin add-on to metformin (VM cohort) or two OADs other than vildagliptin (comparator cohort) were included for the present analysis. The composite primary endpoint was glycated hemoglobin (HbA1c) < 7% and without tolerability events (hypoglycemia, weight gain ≥ 3%, or discontinuation due to gastrointestinal events) at 12 months. Secondary endpoints included change in HbA1c from baseline, subgroup analysis, and tolerability. Propensity score matching analysis was performed to adjust for baseline covariates imbalance (body mass index (BMI) and HbA1c).ResultsA total of 604 patients received VM and 670 received comparator therapy. Patients who received VM were younger, more obese, and had a higher baseline HbA1c and a shorter duration of T2DM. After propensity score matching, there were 530 patients per cohort. After 12-month treatment, the success rates of the composite primary endpoint were 50.9% and 33.0% in the VM and comparator cohorts, respectively (P < 0.001; odds ratio = 2.10, 95% confidence interval (CI) 1.64–2.70). Furthermore, the success rates of the composite endpoint were higher with VM across geographic area, BMI, and baseline HbA1c subgroups. Fewer tolerability events occurred in the VM cohort versus the comparator cohort (8.3% vs. 16.2%, P < 0.001; relative risk = 0.51, 95% CI 0.36–0.72).ConclusionCompared with dual OAD non-vildagliptin combination therapies, vildagliptin add-on to metformin is effective and safe to achieve glycemic control in Chinese patients with T2DM.FundingNovartis.Electronic supplementary materialThe online version of this article (10.1007/s13300-019-0645-z) contains supplementary material, which is available to authorized users.

1023-P: Do Baseline Characteristics Impact Efficacy of Efpeglenatide QW in Uncontrolled Type 2 Diabetes?

Once-weekly (QW), subcutaneous efpeglenatide (EFPEG) is a long-acting GLP-1 RA for T2D management. In EXCEED 203 (NCT02057172), EFPEG QW significantly reduced HbA1c vs. placebo (PBO) for early T2D (naïve/metformin monotherapy). This post hoc subanalysis explored the efficacy of EFPEG QW (pooled low [1 and 2 mg] or high dose [3 and 4 mg]) vs. PBO stratified by baseline characteristics: HbA1c (&amp;lt;8%; 8‒9%; &amp;gt;9%), BMI (&amp;lt;30; ≥30 kg/m2), FPG, T2D duration, and age (&amp;lt;median; ≥median). Change in HbA1c, FPG, and BMI from baseline to Week 13 was compared within and across baseline characteristic subgroups. Within subgroups, HbA1c and FPG reductions were significantly greater for patients with higher HbA1c at baseline with high-dose EFPEG (p≤0.0015) according to HbA1c and FPG subgroups; low-dose EFPEG followed the same trend in most cases. HbA1c and FPG reduction were similar for BMI, T2D duration, and age subgroups; BMI outcomes did not significantly differ within subgroups. There were numerically greater LS mean reductions in HbA1c and FPG from baseline vs. PBO, which were significant for high-dose EFPEG, for all subgroups (except HbA1c &amp;gt;9% for FPG; Table); reductions were greater with high-dose vs. low-dose EFPEG. For BMI, there was a trend for reductions vs. PBO with high-dose EFPEG (Table). In conclusion, high-dose EFPEG demonstrated significant reductions in HbA1c vs. PBO for all baseline characteristic subgroups. Disclosure G.E. Dailey: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US. Speaker's Bureau; Self; Sanofi US. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Melior Pharmaceuticals, Inc., Bukwang Pharm. Co., Ltd., Merck &amp; Co., Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. C. Morales: Other Relationship; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi. U. Wendisch: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Lexicon Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Stock/Shareholder; Self; Novartis AG, Novo Nordisk A/S. M.E. Trautmann: Consultant; Self; CeQur Corporation, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Oramed Pharmaceuticals, ProSciento, Servier. Stock/Shareholder; Self; Lilly Diabetes. M. Hompesch: Stock/Shareholder; Self; ProSciento. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. J. Kang: Employee; Self; Hanmi Pharm. Co., Ltd. C.H. Sorli: Employee; Self; Sanofi. I. Ogbaa: Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. Other Relationship; Self; Sanofi. J.A. Stewart: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc. Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. Funding Hanmi Pharmaceutical, Co., Ltd.; Sanofi

Positive Relationship of Platelet Volume Indices with HbA1c in Unselected Type-2 Diabetes Mellitus Patients.

The aim of this study is to investigate the relationship of several platelet volume indices with glycated hemoglobin (HbA1c) in a large cohort of type 2 diabetes mellitus (T2DM) patients. This is a retrospective study conducted on 1,729 T2DM patients. The database was based on the laboratory information system of the Department of Clinical Laboratory Medicine of the First Affiliated Hospital of Shaoyang University from May 2017 to February 2018. These patients were divided into two subgroups depending on their platelet volume indices and HbA1c levels. Mean platelet volume (MPV), platelet distribution width (PDW) and platelet-large cell ratio (P-LCR) were positively correlated with HbA1c levels (all p < 0.01), but not the thrombocytocrit (PCT). The platelet, MPV, PDW, P-LCR, and glucose levels were significantly higher in the higher HbA1c subgroup (≥ 6.5%) than that in lower subgroup (< 6.5%) (p < 0.01). The platelet, MPV, P-LCR, PCT, HbA1c, and glucose levels were significantly higher in higher PDW subgroup (≥ 17 fL) than that in lower subgroup (< 17 fL) (p < 0.01). In the higher MPV subgroup (≥ 12 fL), the platelet, PDW, P-LCR, PCT, HbA1c, and glucose levels were significantly higher than that in lower subgroup (< 12 fL) (p < 0.01). These platelet volume indices were positively correlated with HbA1c in T2DM patients, which might provide potential new parameters to monitor glucose control.