bluuebunny/crossref_metadata_2025 huggingface dataset:
319-OR: Effects of Empagliflozin on Markers of Liver Steatosis and Fibrosis and Their Relation to Cardiorenal Outcomes in the EMPA-REG OUTCOME Trial
Authors: KAHL SABINE , OFSTAD ANNE PERNILLE , ZINMAN BERNARD , WANNER CHRISTOPH , SCHUELER ELKE , INZUCCHI SILVIO E. , RODEN MICHAEL
Published: June 2021

Treatment with empagliflozin (EMPA) improves cardiorenal outcomes, but also reduces liver fat content in individuals with both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Thus, we evaluated the effects of EMPA vs. placebo (PLAC) on NAFLD-related steatosis and fibrosis risks and the relation of fibrosis risk to cardiorenal outcomes in individuals with T2D in the randomized controlled trial EMPA-REG OUTCOME. The trial enrolled 7020 people with T2D and cardiovascular disease for treatment with 10 or 25 mg daily EMPA or PLAC. Post-hoc, we derived the Dallas Steatosis Index (DSI) and NAFLD fibrosis score (NFS) to assess the risks of steatosis and fibrosis from baseline to week 164 of treatment, respectively. Changes from baseline in DSI and NFS were examined by mixed model repeated measures analysis, and effects on cardiovascular and all-cause death, hospitalization for heart failure and nephropathy by Cox regression across fibrosis risk categories. At baseline, 72% of participants had high risk of steatosis (DSI probability of >50%; mean, 0.74±0.00 and 23% had high risk of advanced fibrosis (NFS >0.675; mean, 1.26±0.01. Overall DSI (logit) decreased with EMPA compared to PLAC at all timepoints (p<0.001; placebo-corrected change -0.13±0.03 at 164 weeks) and also in the subgroup at high steatosis risk. Despite comparable overall NFS over time in EMPA and PLAC groups, NFS was lower in the EMPA-treated advanced fibrosis subgroup at weeks 12, 28 and 108 (placebo-corrected changes -0.08±0.03, -0.11±0.03 and -0.11±0.04, all timepoints p<0.01 vs. PLAC). Of note, effects of EMPA on cardiorenal and mortality outcomes were consistent across high and low fibrosis risk groups.

In conclusion, EMPA may attenuate NAFLD-related steatosis as well as fibrosis progression specifically in individuals at risk of advanced fibrosis, and improves cardiorenal outcomes as well as all-cause mortality independent of fibrosis risk category.

Disclosure

S. Kahl: None. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. C. Wanner: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; Eli Lilly and Company. E. Schueler: None. S. E. Inzucchi: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Esperion, Merck & Co., Inc., Novo Nordisk. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.
323-OR: SGLT2 Inhibition Promotes Myocardial Ketone Utilization in the Normal and Failing Heart
Authors: GOEDEKE LEIGH , LEE JI EUN , MA YINA , HU XIAOYUE , ZHANG JIASHENG , DONG JIANYING , GALSGAARD KATRINE D. , GUERRERA NICOLE , HAEDERSDAL SOFIE , ZHANG XIAN-MAN , PERRY RACHEL J. , CLINE GARY , YOUNG LAWRENCE H. , SHULMAN GERALD I.
Published: June 2021

Recent clinical outcome studies demonstrate that SGLT2 inhibitors (i) significantly reduce major adverse cardiovascular events and heart failure in patients with and without type 2 diabetes; however, the mechanisms by which SGLT2i exert their cardiovascular benefits remain unclear. Here, we aimed to elucidate the acute effects of SGLT2i (dapagliflozin, dapa) on cardiac mitochondrial substrate oxidation. Using LC-MS/MS methodology combined with an infusion of [13C6]glucose and [13C4]βOHB, we assessed the ratio of cardiac mitochondrial pyruvate (VPDH) and βOHB (VβOHB) oxidation rates to rates of mitochondrial citrate synthase flux (VCS) in awake male Sprague Dawley (SD) rats. Metabolic studies were performed 4-6 h after oral dapa (1.5 mg/kg) or vehicle treatment in control rats and after induction of heart failure induced by permanent ligation of the left anterior descending coronary artery. Acute dapa treatment led to marked glycosuria with a 15% reduction in fasting plasma glucose concentrations and 50% increase in whole-body βOHB turnover and plasma βOHB concentrations (all P<0.05 vs. VEH). Dapa caused a 40-60% decrease in myocardial [14C]deoxyglucose uptake and pyruvate oxidation (VPDH/VCS) and a 60% increase in myocardial ketone oxidation (VβOHB/VCS) (all P<0.05 vs. VEH). Similar effects were observed in heart failure rats. Dapa treatment caused a 15% decrease in fasting plasma glucose concentrations, 50% increase in plasma βOHB levels and 60% increase in left ventricular VβOHB/VCS (all P<0.05 vs. VEH).

Conclusion: Collectively, these studies demonstrate that dapa shifts both the normal and failing heart to increased mitochondrial ketone oxidation, which may be mediated by increased hepatic ketogenesis and βOHB availability.

Disclosure

L. Goedeke: None. X. Zhang: None. R. J. Perry: None. G. Cline: None. L. H. Young: None. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company. J. Lee: None. Y. Ma: None. X. Hu: None. J. Zhang: n/a. J. Dong: None. K. D. Galsgaard: None. N. Guerrera: None. S. Haedersdal: None.

Funding

National Institutes of Health (R01DK113984, R01DK045735, K99HL150234); AstraZeneca
335-OR: Lipid-Induced Insulin Resistance in the Renal Cortex Is Associated with Plasma Membrane Sn-1,2-diacylglycerol Accumulation and PKCe Translocation
Authors: HUBBARD BRANDON T. , GASPAR RAFAEL C. , ZHANG DONGYAN , KAHN MARIO , NASIRI ALI , ZHANG XIAN-MAN , CLINE GARY , SHULMAN GERALD I.
Published: June 2021

While there is substantial evidence that the kidney is insulin responsive, it is unclear whether the organ becomes insulin resistant. Here, we investigate whether the kidney is susceptible to lipid-induced insulin resistance and, if so, whether insulin resistance may be mediated by increases in plasma membrane sn-1,2-diacylglycerol (DAG) content and activation of Protein Kinase Cε (PKCε). We studied 14 week old C57BL/6J mice fed either regular chow (RC) or a high fat diet (HFD) for three weeks. Infusion of [13C6]glucose under hyperinsulinemic-euglycemic clamp (HEC) conditions revealed HFD fed mice to have an ~40% reduction (P<0.01) in renal cortical mitochondrial pyruvate dehydrogenase flux relative to citrate synthase flux (VPDH/VCS) compared to RC mice. Next, we infused RC mice with a lipid emulsion (Intralipid® 20%) (RC+IL) during HEC. Despite matched plasma NEFAs at the clamp conclusion, renal cortical VPDH/VCS was significantly higher in RC+IL mice than in HFD mice (P<0.02). These findings suggest that reductions in insulin-stimulated mitochondrial VPDH/VCS observed in HFD mice are intrinsic to the kidney and cannot be attributed to alterations in fatty acid flux to the kidney. Consistent with our mitochondrial flux data, we found that feeding a HFD induced a defect in insulin signaling at the level of the insulin receptor (INSR) as evidenced by ~50% reductions in both insulin-stimulated INSRY1162 (P<0.05) and AKTS473 phosphorylation (P<0.001). HFD-induced reductions in insulin signaling were associated with an ~2-fold increase (P<0.01) in plasma membrane sn-1,2-DAG content, which was associated with an ~4-fold increase (P<0.05) in PKCε translocation.

Conclusion: HFD feeding induces insulin resistance in the renal cortex at the level of INSRY1162 phosphorylation. This defect in INSR signaling is associated with reduced insulin-stimulated pyruvate oxidation and may be mediated by a sn-1,2-DAG-PKCε-INSR mechanism.

Disclosure

B. T. Hubbard: None. R. C. Gaspar: None. D. Zhang: None. M. Kahn: None. A. Nasiri: Employee; Spouse/Partner; Medtronic. X. Zhang: None. G. Cline: None. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company.
336-OR: Mandarin Fish Ranavirus Viral Insulin/IGF-Like Peptide Inhibits Human IGF-1 Receptor
Authors: CHRUDINOVA MARTINA , GELFANOV VASILY , ZAKOVA LENKA , CUTONE JULIANNE , POWIS AMAYA , SEVGI KAAN , JIRACEK JIRI , DIMARCHI RICHARD , ALTINDIS EMRAH
Published: June 2021

Our recent studies published in PNAS and Molecular Metabolism showed for the very first time that viruses possess genes encoding viral insulin/IGF-1 like peptides (VILPs). These two studies provided several important insights on VILPs: 1. Identified VILPs in six different Iridoviridae viruses 2. Showed that chemically synthesized single chain (sc, IGF-1 like) and double chain (dc, insulin-like) VILPs can bind to human insulin and IGF-1 receptors and stimulate downstream signaling. 3. Demonstrated that VILPs can increase glucose uptake in vitro and in vivo. 4. Identified the unique tissue-specific effects of VILPs. 5. Found sequences of these viruses in the human gut and plasma virome.

In the present study, we focused on a novel, Mandarin Fish Ranavirus (MFRV) VILP and characterized both sc and dc forms for the first time. MFRV scVILP binds to human IGF1R with an affinity 100x higher than insulin, making it a VILP with the highest affinity to this receptor so far discovered. MFRV scVILP also activates IGF1R phosphorylation and post-receptor signaling. Interestingly, although MFRV scVILP is a weak agonist of IGF1R, it inhibits IGF-1 signaling at higher concentrations. When we treat cells with both IGF-1 and MFRV VILP, MFRV scVILP inhibits IGF-1 (10nM) stimulated IGF1R phosphorylation and activation of PI3K and MAPK pathways at high concentrations (> 250 nM). Surprisingly, the dc version of MFRV VILP neither bind nor stimulate IGF1R. This suggests that the C-chain of MFRV VILP is essential for both binding to IGF1R and the IGF-1 inhibitory effects.

Taken together, our results revealed that MFRV scVILP is a novel antagonist/inhibitor of IGF-1R. IGF1R signaling is overly activated in breast, prostate and colorectal cancers. Despite tremendous efforts to develop an effective inhibitor of IGF1R, these attempts failed. MFRV VILP has the potential to contribute development of new therapeutics in cancer therapy and to help us better understand ligand-receptor interactions and mechanisms of IGF1R inhibition.

Disclosure

M. Chrudinova: None. V. Gelfanov: Employee; Self; Novo Nordisk, Employee; Spouse/Partner; Eli Lilly and Company. L. Zakova: None. J. Cutone: None. A. Powis: None. K. Sevgi: None. J. Jiracek: None. R. Dimarchi: Employee; Self; Novo Nordisk. E. Altindis: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K01DK117967)
337-OR: Intensive Insulin Treatment in a Patient with Type A Insulin Resistance Syndrome Associated with a Novel Heterozygous Mutation of Trp1120Gly in the Insulin Receptor Gene
Authors: YANG YU , HUANG ZHIMIN , WEI GUOHONG , LI YUELI , DENG WANPING , LI YANBING
Published: June 2021

Background: Type A insulin resistance syndrome is a rare congenital severe insulin resistance syndrome resulting from mutations in the insulin receptor (IR) gene. We herein report a case treated with continuous subcutaneous insulin infusion (CSII) followed by insulin glargine and pioglitazone.

Clinical Case: A 16 year-old girl with BMI of 19.1 kg/m2, complained of primary amenorrhea and elevated glucose for 2 years. She was diagnosed with precocious puberty at the age of 7, and treated with letrozole and triptorelin successively for 6.5 years. Hyperinsulinemia was noted but not ameliorated with metformin treatment. All the treatment was suspended for 2 years before referring to our department. Plasma glucose during OGTT showed fasting glucose was 8.4 mmol/L, and 2-hour post-load was 23.5 mmol/L. HbA1c was 10.8%. Markedly increased fasting (245μU/mL) and post-load serum insulin (628μU/mL) were observed. Next generation sequencing revealed a novel heterozygous missense mutation of Trp1120Gly in the IR gene. The patient received CSII with 0.8U/kg as the starting daily total, and titrated the dosage according to SMBG, followed by insulin glargine and pioglitazone treatment. Her glucose was well controlled, insulin glargine was down to 8U/d at the end of 3 months. Her HbA1c dropped to 7.9%, along with fasting plasma glucose (4.6mmol/L) and serum insulin (95.44μU/mL), while 2-hour postprandial glucose and insulin were still high. Her menarche occurred after one cycle of ethinylestradiol and cyproterone combo tablets.

Conclusion: Improvement of glucose control with intensive insulin treatment was observed in a patient with type A insulin resistance syndrome. However, amelioration of insulin resistance was limited. No standard treatment was recommended for this rare syndrome. Thus, large-scale long-term studies assembled worldwide to optimize treatment strategy are needed.

Disclosure

Y. Yang: None. Z. Huang: None. G. Wei: None. Y. Li: None. W. Deng: None. Y. Li: None.

Funding

National Natural Science Foundation of China (82070918)
341-P: Effect of Pitolisant on Glucagon in Human Islets and People with Type 1 Diabetes
Authors: DEHN CLAYTON A. , FEIN MELANIE , HU JACK , YESILDAG BURCAK , MAXWELL ROBERT , HARP JOYCE B.
Published: June 2021

In 3D human islet microtissues from nondiabetic donors, pitolisant, a histamine 3 receptor antagonist, increased glucagon secretion >3-fold compared to vehicle control. However, the effect of pitolisant on glucagon was diminished in islets treated with cytokines, insulin, and low glucose to mimic T1D hypoglycemia. The purpose of this study was to determine if pitolisant can restore impaired glucagon secretion response to hypoglycemia in people with T1D. The study was a double-blind randomized placebo-controlled study of five adults (3 on pitolisant and 2 on placebo), 4 men, with long-duration T1D. Patients were domiciled overnight, at baseline and after 7 days of once daily oral pitolisant (36 mg) or matching placebo. Blood glucose levels were kept at 100-120 mg/dL overnight with regular insulin infusion and an insulin tolerance test (ITT) was conducted the following morning. Glucagon was measured by the Mercodia ELISA and glucose by a YSI Glucose Analyzer. Glucose was also assessed using a blinded Dexcom G6 CGM during the trial. Safety tolerability was assessed by standard methods. Mean change (95% CI) from baseline in peak glucagon (pg/ml) was 7.5 (-2.07-17.02) for the pitolisant group and 13.1 (2.08-24.09) for the placebo group. One patient on pitolisant and no patients on placebo returned to blood glucose >/=70 mg/dL during the 180-minute ITT. The pitolisant group required significantly less rescue D50 on-drug vs. at baseline (5 vs. 19 grams, p=0.05), while there was no difference in the placebo group (36 vs. 25 grams). In general, patients on pitolisant had numerically higher mean glucose on CGM during the on-drug period. There were no severe hypoglycemic events and no deaths. Pitolisant was well tolerated. We conclude that pitolisant does not increase glucagon secretion during hypoglycemia in people with T1D but may mitigate hypoglycemia by a glucagon-independent mechanism. The T1D islet microtissue model better predicts the clinical effects of pitolisant on glucagon secretion compared to healthy islets.

Disclosure

C. A. Dehn: None. M. Fein: None. J. Hu: None. B. Yesildag: None. R. Maxwell: Other Relationship; Self; Ferox Therapeutics LLC. J. B. Harp: Other Relationship; Self; Ferox Therapeutics.

Funding

Ferox Therapeutics; The Leona M. and Harry B. Helmsley Charitable Trust
354-P: Interstitial Fluid Glucose as a Measure of Hypoglycemia Burden in Elderly Subjects with Type 2 Diabetes Mellitus
Authors: TIAN KRISTY , ANG LI C. , BEE YONG MONG , GOH SU-YEN , TEH MING M.
Published: June 2021

Background: Elderly patients with type 2 diabetes mellitus (T2DM) are at high risk of severe hypoglycemia, but evidence addressing this problem is lacking.

Aims: To assess and compare the burden of exposure to low interstitial fluid glucose (IFG) in elderly subjects with tightly controlled T2DM on sulphonylurea (SU) or insulin therapy.

Methods: Outpatient T2DM subjects ≥65 years of age with HbA1c ≤7.5% were recruited to wear a Freestyle Libre-Pro sensor for 2 weeks. Collected data was analyzed for low IFG burden.

Results: A total of 65 subjects (35 male, 30 female), 72.0 ± 5.0 years old with diabetes duration of 21.4 ± 11.1 years and HbA1c of 6.8 ± 0.5% were recruited; 27 were insulin treated and 38 were SU treated. Patients on insulin had longer diabetes duration (25.4 ± 10.9 vs. 18.0 ± 10.4 years, p<0.05) and poorer kidney function (eGFR 58.6 ± 24.7 vs. 87.3 ± 48.0, p<0.05). Greater proportion of the insulin group performed regular capillary blood glucose (CBG) monitoring (74.1% vs. 29.7%). This group also had more monthly self reported hypoglycemic events (0.85 ± 1.70 vs. 0.14 ± 0.35, p<0.05) and a lower GOLD score (2.42 ± 1.72 vs. 3.73 ± 1.75, p<0.05). While there was no difference in mean number of low IFG events with glucose <72.0mg/dL between the 2 groups (0.92 ± 0.79 vs. 0.59 ± 0.48 events, p value >0.05), very low IFG events with glucose <50.0mg/dL occurred in higher proportions (52% vs. 23%, p<0.05), higher frequency (0.48 ± 0.70 vs. 0.16 ± 0.19 events/person, p <0.05) and for longer durations (1.56 ± 2.94 vs. 0.27 ± 0.43 hours/day, p<0.05) in the insulin group. 62.2% of the SU group and 63.0% of insulin group had at least 1 episode of very low IFG, but none of the SU group and only 2 in the insulin group reported hypoglycemic symptoms.

Conclusion: Low IFG was common among the studied population, with a greater burden in insulin treated patients. Majority were unable to detect events despite regular CBG monitoring suggesting the potential use of IFG in evaluating hypoglycemia burden.

Disclosure

K. Tian: None. L. C. Ang: None. Y. Bee: None. S. Goh: None. M. M. Teh: None.
357-P: Advanced Glycation End Products Associate with Vascular Stiffness in Diabetic, Prediabetic, and Normoglycemic Individuals
Authors: BIRUKOV ANNA , CUADRAT RAFAEL , POLEMITI ELLI , EICHELMANN FABIAN , SCHULZE MATTHIAS B.
Published: June 2021

Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. We hypothesized that advanced glycation end-products associate with vascular stiffness independent of glycemic status. Advanced glycation end-products were measured as skin autofluorescence, vascular stiffness was measured as pulse wave velocity, augmentation index and ankle-brachial index in 3,535 participants from the European Prospective Investigation into Cancer and Nutrition Potsdam cohort (median age 67 years, 60% women). A subset of 1,348 participants underwent an oral glucose tolerance test. Participants were sub-phenotyped into normoglycemic, prediabetes and diabetes groups. Skin autofluorescence associated with pulse wave velocity, augmentation index and ankle-brachial index, adjusted beta coefficients (95% CI) per unit skin autofluorescence increase: 0.38 (0.21; 0.55) for carotid-femoral pulse wave velocity, 0.25 (0.14; 0.37) for aortic pulse wave velocity, 1.00 (0.29; 1.70) for aortic augmentation index, 4.12 (2.24; 6.00) for brachial augmentation index and -0.04 (-0.05; -0.02) for ankle-brachial index. The associations were strongest in men, younger individuals and were consistent across all glycemic strata: for carotid-femoral pulse wave velocity 0.36 (0.12; 0.60) in normoglycemic, 0.33 (-0.01; 0.67) in prediabetes and 0.45 (0.09; 0.80) in diabetes groups; with similar estimates for aortic pulse wave velocity. Augmentation index was associated with skin autofluorescence only in normoglycemic and diabetes groups. Ankle-brachial index inversely associated with skin autofluorescence across all sex, age and glycemic strata. Our findings indicate that advanced glycation end-products are involved in vascular stiffening independent of glycemic status, age and other cardiometabolic risk factors.

Disclosure

A. Birukov: None. R. Cuadrat: None. E. Polemiti: None. F. Eichelmann: None. M. B. Schulze: None.

Funding

German Ministry of Education and Research; State of Brandenburg (82DZD00302)
367-P: Cardiovascular Risk Categories in Patients with Diabetes According to 2019 ESC/EASD Guidelines in Clinical Practice: Use of a Dedicated App (AWARE)
Authors: BERRA CESARE C. , MANFRINI ROBERTO , GHELARDI RENATA , BOLLATI PAOLA M. , BUCCIARELLI LOREDANA , MIRANI MARCO , MURATORI MILENA , FOLLI FRANCO ,   AWARE STUDY GROUP
Published: June 2021

The 2019 ESC-EASD guidelines provide recommendations for CV risk assessment and medical treatment in diabetic patients. Three CV risk categories were originally defined: 1) very high risk, 2) high risk and 3) moderate risk according to the presence of CVD, other target organ damage (proteinuria, renal impairment defined as eGFR ≥ 30 mL/min/1.73 m2, left ventricular hypertrophy, retinopathy), duration of disease, age, risk factors (hypertension, dyslipidemia, smoking, obesity). In very high risk CV category SGLT2-I and GLP1-RA were identify as treatment of choice. Based on these criteria, we developed the web APP “AWARE”, an application software which runs on a web server and is accessed via internet browser. From November 10th 2020 to January 10th 2021 we employed AWARE as a tool to assess CV risk of 650 type 2 diabetes patients in clinical practice. The APP was implemented with additional features such as HbA1c and therapy. Of the 650 subjects examined, 430 were very high risk (66%), 73 (11,2%) high risk, 5 (0,8%) at moderate risk while 145 patients (22%) didn’t match with any of these categories. We allocated these patients into an additional “undetermined risk” category. Median HbA1c in all subjects was 7.2±1.14 (7,3±1.15% in very high risk category, 7.2±1.15% in high risk category, 6,2±0.41% in moderate risk and 6.9±1.12% in “undetermined” risk). In the very high risk category CVD was present in 166 subject (38%), duration of disease>10 aa in 238 subjects (55%), proteinuria in 53 subjects (12%) (p=0.000 vs. all other categories). Either SGLT2-I or GLP1-RA were prescribed in 30% of patients in the very high risk category. The APP “AWARE” in useful to identify CV risk in diabetic. The classification according to the criteria of 2019 ESC/EASD guidelines does not includes 22% of patients in clinical practice. Around 70% of patients in the very high CV risk category are not treated with the optimal drug therapy suggested by the 2019 ESC/EASD guidelines.

Disclosure

C. C. Berra: None. R. Manfrini: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mundipharma International, Novo Nordisk, Sanofi. R. Ghelardi: None. P. M. Bollati: None. L. Bucciarelli: None. M. Mirani: None. M. Muratori: None. F. Folli: None. Aware study group: n/a.
373-P: Type 2 Diabetes, Chronic Kidney Disease, and Major Cardiovascular Events in Patients with Established Coronary Artery Disease
Authors: SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , MAECHLER MAXIMILIAN , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2021

Both type 2 diabetes (T2DM) and chronic kidney disease (CKD) confer a high risk of cardiovascular disease (CVD), and these conditions frequently coincide. The aim of this study was to investigate the single and joint effects of T2DM and CKD on major cardiovascular events (MACE) in a high-risk population of patients with established coronary artery disease (CAD).

We prospectively investigated 1460 patients with angiographically proven CAD over 10.4±4.8 years, of whom 454 (30.8%) had T2DM and 251 (17.1%) had CKD.

MACE occurred more frequently in T2DM patients than in nondiabetic subjects (40.4% vs. 28.7%, p<0.001) and in patients with CKD (eGFR < 60ml/min/1.73m2) than in those with an eGRF ≥60ml/min/1.73m2 (51.6% vs. 28.3%, p<0.001). When both, T2DM and CKD were considered, 863 subjects had neither T2DM nor CKD, 346 had T2DM but not CKD, 148 did not have diabetes but had CKD, and 103 had both T2DM and CKD. When compared with the incidence of MACE among patients with neither T2DM nor CKD (25.3%), MACE occurred more frequently in patients with T2DM who did not have CKD (35.8%; p<0.001) as well as in nondiabetic patients with CKD (47.6%; p<0.001) and occurred most frequently in patients with both, T2DM and CKD (57.4%; p<0.001), in whom the incidence of MACE was higher than in those with T2DM but not CKD (p<0.001) or those without T2DM but with CKD (p=0.025); the incidence of MACE was higher in nondiabetic CKD patients than in T2DM patients who did not have CKD (p=0.041). In Cox regression analysis, T2DM (HR=1.46 [1.20-1.78]; p<0.001) and CKD (HR=1.81 [1.45-2.27]; p<0.001) were mutually independent predictors of MACE after multivariate adjustment.

We conclude that T2DM and CKD are mutually independent risk factors for MACE in patients with established CAD. CAD patients with both CKD and T2DM are an extremely high risk for MACE.

Disclosure

L. Sprenger: None. C. H. Saely: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. M. Maechler: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
376-P: REWIND Data on Obesity and Cardiovascular (CV) Health: Waist-to-Hip Ratio (WHR) Independently Predicted CV Outcomes
Authors: FRANEK EDWARD , PAIS PREM , BASILE JAN N. , RAHA SOHINI , AHMAD NADIA , KAN HONG , KONIG MANIGE
Published: June 2021

Obesity is a major risk factor (RF) for health outcomes such as major adverse cardiovascular events (MACE) and cardiovascular disease (CVD)-related mortality. WHR is a validated measure of central adiposity and has been shown to predict CVD events. The aim of this post hoc analysis was to evaluate if WHR, adjusted for age and sex, was an independent RF for developing MACE-3 (non-fatal myocardial infarction (MI), non-fatal stroke, or CV death) and CVD-related mortality. Data from the REWIND trial placebo group (N=4952) were analyzed. All participants had type 2 diabetes, were aged 50 or older, and had either a previous CV event or CV RFs. During the median follow-up of 5.4 years, there were 663 patients with MACE-3 and 346 CVD-related deaths. A Cox proportional hazard model was used to investigate if WHR, adjusted for age and sex, was a significant RF for MACE-3 and CVD-related mortality, followed by testing additional baseline RFs (demographic, CVD history, and biochemical characteristics) using a stepwise variable selection method where WHR, age, and sex were forced into the model. BMI was tested similarly to WHR. WHR, but not BMI, was an independent risk factor for MACE-3 and CVD-related mortality. As expected, age and sex were significant RFs for both endpoints and were therefore adjusted in the model. Urinary albumin:creatinine ratio (UACR), non-HDL-C, and race (white) were significant RFs for MACE-3. UACR, LDL-C, history of MI, and race (American Indian/Alaska Native) were significant RFs for CVD-related mortality. In the resulting adjusted model, for every unit increase in WHR, there was an estimated 3.50-fold increase in MACE-3 risk (p=0.013) and 5.51-fold increase in CVD-related mortality risk (p=0.005). WHR was an independent predictor of MACE-3 and CVD-related mortality, indicating that central adiposity should be assessed and addressed in patients with or who have a high risk of CVD.

Disclosure

E. Franek: Advisory Panel; Self; Boehringer Ingelheim, Novo Nordisk, Speaker’s Bureau; Self; Boehringer Ingelheim. P. Pais: None. J. N. Basile: Other Relationship; Self; Medtronic, Research Support; Self; Eli Lilly and Company, ReCor. S. Raha: Employee; Self; Eli Lilly and Company. N. Ahmad: Employee; Self; Eli Lilly and Company. H. Kan: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Bristol-Myers Squibb Company, GlaxoSmithKline plc. M. Konig: Employee; Self; Eli Lilly and Company.
381-P: Type 2 Diabetes Significantly Modulates the Power of Lipoprotein(a) to Predict Cardiovascular Events and Mortality in Young Coronary Artery Disease Patients
Authors: MADER ARTHUR , MAECHLER MAXIMILIAN , LARCHER BARBARA , SPRENGER LUKAS , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , VONBANK ALEXANDER , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2021

Lipoprotein(a) [Lp(a)] is an important cardiovascular risk factor especially in young individuals. The power of Lp(a) to predict cardiovascular events in young coronary artery disease (CAD) patients with type 2 diabetes (T2DM) however is unclear and is addressed in the present study. Lp(a) was measured in a cohort of 731 patients with angiographically proven CAD who were aged <65 years. Vascular events were recorded over a mean follow-up of 6.6±3.2 years. At baseline, 216 patients had T2DM, and 515 did not have diabetes. During follow-up, 30.2% of our patients suffered cardiovascular events. Lp(a) proved to be a strong and independent predictor of vascular events in the total study cohort (standardized adjusted HR=1.30 [1.07-1.56]; p=0.007). In subgroup analyses by diabetes status, Lp(a) significantly predicted vascular events in nondiabetic patients (standardized adjusted HR= 1.39 [1.12-1.74]; p=0.003) but not in diabetic patients (standardized adjusted HR=0.93 [0.63-1.38]; p=0.731). An interaction term Lp(a)xT2DM was significant (p=0.002), indicating that T2DM significantly modulated the power of Lp(a) to predict cardiovascular events. We conclude that Lp(a) significantly modulates the power of Lp(a) to predict cardiovascular events in CAD patients <65 years.

Disclosure

A. Mader: None. C. H. Saely: None. M. Maechler: None. B. Larcher: None. L. Sprenger: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. A. Vonbank: None. H. Drexel: None.
388-P: GLP-1 Receptor Agonists Attenuates Secretion of Extracellular Matrix via Inhibiting HMGB1 Signaling in Rat Mesangial Cells
Authors: GU WENSHA , SHI MIN , ZHANG HONG
Published: June 2021

Background: GLP-1R agonists can exhibit a direct renoprotective effect in patients with diabetic nephropathy (DN) beyond the hypoglycemic effect, but the underlying mechanisms remain unknown. Recent studies have suggested that high mobility group box 1 (HMGB1) contributes to the development and progression of DN. In this study, we assessed whether GLP-1R agonists acts through HMGB1 and explored its downstream signaling pathways in DN.

Methods: Rat glomerular mesangial cells (GMCs) were divided into four groups: normal control (NG), normal control with 10 nmol/L exendin-4 treatment (GLP-1 analog) (NGE), high glucose (HG), and high glucose with 10 nmol/L exendin-4 treatment (HGE) groups. GMCs were transfected with GLP-1R-siRNA using Lipofectamine TM2000 and divided as HG, HGE, HGE + GLP-1R-siRNA, or HGE + scrambled siRNA. FN and type IV collagen (COL-IV) were evaluated by enzyme-linked immunosorbent assay (ELISA). GLP-1R, HMGB1, TGF-β1, phosphorylated and total extracellular signal-regulated kinases (ERK), c-Jun NH2-terminal kinases (JNK), p38 mitogen-activated protein kinases (p38MAPK), and NF-κB p65 were measured by western blot analysis.

Results: FN and COL-IV were higher in the HG group than NG group (P<0.05). Compared with NG group, the level of GLP-1R was decreased, HMGB1 and TGF-β1 were increased in the HG group (P<0.05). Additionally, NF-κB p65, the phosphorylation levels of ERK, JNK, and p38MAPK were all significantly elevated in the HG group (P<0.05). However, all these effects were reversed by Exendin-4 treatment (P<0.05), except phosphorylated p38MAPK (P>0.05). Moreover, the protective effects of Exendin-4 were abolished by GLP-1R knockdown (P<0.05).

Conclusion: These results suggest that GLP-1 receptor agonists attenuates the ECM secretion of GMCs induced by high glucose. The potential mechanism involves it binding to and activating GLP-1R, which prevents ECM production by inhibiting HMGB1 and its signaling pathways.

Disclosure

W. Gu: None. M. Shi: None. H. Zhang: None.

Funding

National Natural Science Foundation of China (81200595, 81400807, 81700723)
391-P: The Nrf2 Activator Increases TFAM and Suppresses STING in Human Renal Proximal Tubular Cells
Authors: BESSHO RYOICHI , TAKIYAMA TAKAO , PROMSUWAN SURATSAWADEE , KITSUNAI HIROYA , SAWAMOTO KAZUKI , TAKEDA YASUTAKA , TAKIYAMA YUMI
Published: June 2021

Recent study has demonstrated the Nrf2 (NF-E2-related factor 2) activator bardoxolone methyl improved renal function in diabetic kidney disease (DKD). On the other hand, mitochondrial transcription factor A (TFAM) activation inhibits mitochondrial DNA (mtDNA) release into the cytoplasm and suppresses stimulator of interferon genes (STING)-mediated inflammation in renal proximal tubular cells. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is recognized as activators of Nrf2. In this study, we investigated the effects of SFN on TFAM and STING expression and its mitochondrial protective and anti-inflammatory effects. Because mitochondrial damage caused by fatty acids bound to albumin is involved in pathogenesis of DKD due to increased albumin reabsorption, we treated human renal proximal tubular cells (Lonza) with palmitic acid (PA, 200µM). Total RNA, DNA and protein were extracted and analyzed by qRT-PCR and western blotting. To quantify the mitochondrial DNA released into the cytoplasm, DNA was extracted from cytoplasmic and nuclear fractions. SFN (10µM) induced Nrf2 downstream target gene, NAD(P)H:quinone oxidoreductase 1 (NQO-1) mRNA expression to 359% (p<0.05). SFN alone increased TFAM mRNA expression to 132% (p<0.05) and suppressed STING mRNA expression by 26% (p<0.05). Whereas, PA had no effect on TFAM mRNA expression but increased STING mRNA expression to 135% (p<0.05). SFN suppressed PA-induced STING mRNA expression by 34% (p<0.05) and STING protein expression by 48%. PA increased cytoplasmic mtDNA to 237% and SFN decreased PA-induced cytoplasmic mtDNA release by 41%. PA increased IL-6 mRNA expression to 139% (p<0.05) and MCP-1 mRNA expression to 138% (p<0.05). SFN suppressed PA-induced IL-6 mRNA expression by 33% (p<0.05) and MCP-1 mRNA expression by 47% (p<0.05). Together, the Nrf2 activators may have renoprotective effects through mitochondrial protection and anti-inflammatory effect by activating TFAM and inhibiting STING.

Disclosure

R. Bessho: None. T. Takiyama: None. S. Promsuwan: None. H. Kitsunai: None. K. Sawamoto: Other Relationship; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Ono Pharmaceutical Co., Ltd., Roche Diagnostics K. K., Taisho Pharmaceutical Co., Ltd. Y. Takeda: None. Y. Takiyama: Other Relationship; Self; Gilead Sciences, Inc., Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Mochida Pharmaceutical Co., Ltd., Roche Diabetes Care, Taisho Pharmaceutical Co., Ltd.
392-P: ROCK2-Mediated Podocyte Dysfunction in Diabetic Nephropathy
Authors: MATOBA KEIICHIRO , TAKEDA YUSUKE , AKAMINE TOMOYO , NAGAI YOSUKE , UKICHI RIKAKO , KANAZAWA YASUSHI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI
Published: June 2021

The small GTPase RhoA and its downstream effector, Rho-kinase (ROCK), are implicated in a variety of cellular functions (e.g., cell adhesion, migration) via effect on cytoskeletal reorganization. We and others have illuminated ROCK as an important pathogenic regulator of diabetic kidney disease. Renal ROCK activity is elevated in both type 1 and type 2 diabetic murine models, as well as in diabetic patients. ROCK has two isoforms, ROCK1 and ROCK2. ROCK1 has been shown to regulate mitochondrial fission and epithelial-to-mesenchymal transition in the setting of diabetic kidney disease: however, the role of renal ROCK2 remain unclear. In the present study, we have demonstrated the upregulation of ROCK2 in glomerular podocytes obtained from 3 established models of diabetic kidney disease, (i.e., streptozotocin injection, db/db, and high-fat diet treatment), and diabetic patients. In an attempt to elucidate the roles of podocyte ROCK2, we generated podocyte-specific ROCK2 knockout mice (PR2KO) by breeding ROCK2 flox mice with Podocin-Cre mice. We found that podocyte-restricted ROCK2 deletion did not lead to any defects in the kidney development and functions. Of note, PR2KO were protected against albuminuria and glomerular sclerosis in streptozotocin-induced diabetic mice. In addition, renoprotective actions of podocyte ROCK2 deletion were also observed in type 2 diabetic db/db mice and high-fat diet-fed animals. Mechanistically, RNA-Seq analysis in ROCK2-null podocytes revealed the recovery of fatty acid utilization. When considered alongside our previous observations, the current work highlights the importance of ROCK2 in diabetic podocytopathy.

Disclosure

K. Matoba: Research Support; Self; Eli Lilly Japan K. K. Y. Takeda: None. T. Akamine: None. Y. Nagai: None. R. Ukichi: None. Y. Kanazawa: None. K. Utsunomiya: None. R. Nishimura: Speaker’s Bureau; Self; Abbott Japan Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K. K., Kissei Pharmaceutical Co., Ltd., Medtronic, MSD Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding

Japan Society for the Promotion of Science (20K08645, 18K15985); Suzuken Memorial Foundation; Takeda Science Foundation; Yokoyama Foundation for Clinical Pharmacology; MSD Life Science Foundation; Ichiro Kanehara Foundation; Japan Diabetes Foundation; Ueh
393-P: Combination Treatment with Lisinopril and Empagliflozin Improves Urine and Histological Markers of Diabetic Kidney Disease in Female Renin-AAV UNx db/db Mice
Authors: ØSTERGAARD METTE V. , CHRISTENSEN MICHAEL , SECHER THOMAS , SKYTTE JACOB L. , ROOSTALU URMAS , SALINAS CASPER G. , SEMBACH FREDERIKKE E. , FINK LISBETH N. , VRANG NIELS
Published: June 2021

Introduction: Emerging treatments of diabetic kidney disease (DKD) include SGLT2 inhibitors and GLP-1 receptor agonists that are nephroprotective beyond their blood glucose lowering effects. To confirm the translatability of a mouse model for drug discovery in DKD, we tested the efficacy of an ACE inhibitor and a SGLT2 inhibitor in the reninAAV UNx db/db mouse model.

Methods: Female db/db mice were injected with a renin-encoding adeno-associated virus construct (reninAAV) to induce hypertension and uninephrectomized (UNx). At 12 weeks of age, dosing with vehicle, lisinopril, empagliflozin, or the combination (combo) was initiated. Plasma and urine markers were measured after 12 weeks of dosing and terminal kidney samples were collected for 3D light sheet microscopy and 2D histology.

Results: In reninAAV UNx db/db mice, treatment with empagliflozin and combo reduced fed BG and HbA1c compared to vehicle. Treatment with lisinopril and combo reduced urine ACR and KIM1-to-creatinine compared to vehicle, while treatment with empagliflozin alone worsened urine ACR. Glomerular hypertrophy as assessed by 3D imaging was reduced in combo treated reninAAV UNx db/db mice compared to vehicle, while treatment with empagliflozin alone worsened glomerular hypertrophy. The total number of glomeruli per kidney was unaffected by treatments. Compared to vehicle treatment, lisinopril and combo treatment reduced the fraction of score 3+4 glomeruli, and glomerulosclerosis index (GSI) was reduced by with lisinopril and combo treatment. Treatment with empagliflozin alone worsened GSI. Morphometric analyses showed that lisinopril and combo treatment reduced kidney CD11b and KIM1 load.

Conclusion: Responses to the combination treatment with lisinopril and empagliflozin showed improvement of urine and histological markers of DKD. Together, these data confirm the translatability of the reninAAV UNx db/db mouse model of DKD.

Disclosure

M. V. Østergaard: None. M. Christensen: None. T. Secher: Employee; Self; Gubra, Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Self; Gubra, Stock/Shareholder; Spouse/Partner; Novo Nordisk. J. L. Skytte: None. U. Roostalu: Employee; Self; Gubra. C. G. Salinas: Employee; Self; Gubra, Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Spouse/Partner; Novo Nordisk. F. E. Sembach: None. L. N. Fink: Employee; Self; Gubra, Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra, Employee; Self; Gubra, Stock/Shareholder; Self; Gubra.
402-P: Liraglutide Might Have Synergistic Renal Protection Effect with SGLT2 Inhibitors in Rapidly Progressive Diabetic Kidney Disease
Authors: KASHIMA KOJI , SHIMIZU HIROYUKI , YAMADA MASANOBU
Published: June 2021

Objective: SGLT2 inhibitor (SGLT2i) and GLP-1 receptor agonist (GLP-1RA) should be considered for patients with type 2 diabetes (T2D) with CKD. But very few data are available whether synergistic effects of both drugs exist. We assessed annual eGFR decline rate by adding SGLT2i in patients with T2D on GLP-1RA therapy.

Methods: A total of 75 patients with T2D with CKD stage 3-4, treated by SGLT2i (empagliflozin 65%) were analyzed. The duration of diabetes at the time of recruitment were as follows: stage 3a (n=29); 11.9±5.4 yrs, stage 3b (n=28); 19.9±12.1 yrs, and stage 4 (n=18); 13.8±8.5 yrs. Macroalbuminuria existed in 49% (37/75). Average age was 70.3±12.2 yrs old. GLP-1RA (Liraglutide: n=36) was initially or additionally used in 41%, 64% and 44% respectively for glucose management, considering for ASCVD. Individual eGFR decline rate (slope) was calculated from the data for 46±20 months before using SGLT2i and 31±9 months after adding it. The effects on slopes by SGLT-2i, GLP-1RA combination therapies (GLP-1RA initiated at different timing) were compared with those without GLP-1RA therapy.

Results: 1) i) Baseline on GLP-1RA initiation therapy -5.2±5.3 improved to -2.2±1.4 (P<0.05) after SGLT2i added. (n=11) ii) Slopes -5.0±3.5 improved to -1.2±4.5 (P<0.03) with simultaneous intensification by SGLT2i + GLP-1RA. (n=13) iii) Slopes -14.6±18.0 improved to -5.4±5.5 (P<0.05) by intensification by GLP-RA, then improved to -2.6±3.3 (P<0.05) with SGLT2i added. (n=14) In this rapidly declining group, macroalbuminuria highly existed in 71% (10/14), and nephrosis existed in 36% (5/14), but nephrosis all came into remission through this therapy. 2) SGLT2i monotherapy (n=37): Slopes -4.1±3.0 improved to -1.2±3.1 ml/min/1.73m2/year (P<0.001) after SGLT2i added. On this background, macroalbuminuria less existed (46%), and nephrosis existed none.

Conclusion: Liraglutide might have synergistic renal protection effects with SGLT2i in rapidly progressive DKD.

Disclosure

K. Kashima: None. H. Shimizu: None. M. Yamada: None.
411-P: Fibroblast Growth Factor 23 and Diabetic Kidney Disease Phenotypes in Type 2 Diabetes
Authors: GAROFOLO MONIA , PELOSINI CATERINA , LUCCHESI DANIELA , FALCETTA PIERPAOLO , SESSA MARIA RITA , PRATO STEFANO DEL , PENNO GIUSEPPE
Published: June 2021

Fibroblast growth factor 23 (FGF23) targets tubular epithelial cells to promote phosphaturia and it has been associated with adverse outcomes in chronic kidney disease (CKD). Emerging data suggest that FGF23 plays a specific role in type 2 diabetes (T2D). We evaluated intact FGF23 (iFGF23) levels (plasma EDTA; chemiluminescence immunoassay) in 182 T2D subjects with no-DKD (n = 46), with albuminuria alone (ACR ≥30 mg/g; DKD stages 1-2, n = 48), with eGFR <60 ml/min/1.73m2 alone (Alb-DKD; n = 42) and with both albuminuria and eGFR <60 (Alb+DKD; n = 46). There was no difference in ACR between DKD stages 1-2 and Alb+DKD (97 [IQR 49-329] and 268 [62-736] mg/g); eGFR (CKD-EPI formula based on creatinine [eGFRcreat = 49 [45-54] and 45 [35-52] ml/min/1.73m2] or based on creatinine and cystatin-C) did not differ between Alb-DKD and Alb+DKD. Age, DD, HbA1c, triglycerides, uric acid and fibrinogen increased across DKD groups, while HDL cholesterol decreased, with no other significant difference in clinical and laboratory parameters. BP-lowering agents, RAS blockers and lipid-lowering drugs were slightly more frequent in albuminuric groups. Alb+DKD had the highest levels of inflammatory biomarkers: uric acid, hs-CRP and fibrinogen. In the whole cohort, iFGF23 was significantly and directly correlated with these 3 biomarkers. iFGF23 increased steeply (p<0.0001) across DKD groups (no DKD: 48.2 [IQR 37.3-61.5] pg/ml; DKD stages 1-2: 53.0 [42.5-61.4]; Alb-DKD: 60.4 [45.1-73.4] and Alb+DKD 76.6 [60.1-96.3]), with iFGF23 of Alb+DKD higher as compared to no-DKD (p<0.0001), DKD stages 1-2 (p<0.0001), and also Alb-DKD (p=0.008). In the whole cohort, iFGF23 was mildly associated with ACR (r = 0.260; p=0.001) and more strongly inversely related with eGFRcreat (r = -0.483, p<0.0001). Our results suggest that, for the same degree of eGFR reduction, higher iFGF23 levels in Alb+DKD as compared to Alb-DKD might be expression of more advanced renal damage and/or of an overwhelming inflammation.

Disclosure

M. Garofolo: Consultant; Self; Eli Lilly and Company. C. Pelosini: None. D. Lucchesi: None. P. Falcetta: None. M. Sessa: None. S. Del prato: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Sanofi. G. Penno: Advisory Panel; Self; Eli Lilly and Company.
42-LB: Medication Adherence in Young Adults with Youth-Onset Type 2 Diabetes: The iCount Study
Authors: TRIEF PAULA M. , USCHNER DIANE , TUNG MELINDA , DREWS KIMBERLY , KALICHMAN SETH , ANDERSON BARBARA , BULGER JANE D. , WEINSTOCK RUTH S.
Published: June 2021

Background: Medication adherence is poor in young adults (YAs) with youth-onset type 2 diabetes (T2D). Little is known about intrapersonal factors that may relate to adherence.

Aims: To assess associations of intrapersonal factors to medication adherence in Treatment Options for Adolescents and Youth (TODAY2) YAs.

Methods: Validated measures (attitudes, beliefs, self-efficacy, distress, depression, anxiety) and insulin use surveys, were completed at a TODAY2 visit. Adherence to oral hypoglycemia agents (OHAs) was assessed with 3 monthly unannounced phone pill counts. Those taking ≥ 80% of pills/insulin classified “high-adherent;” < 80% of pills/insulin, “low-adherent.” If taking none, reasons were queried and adjudicated (no need vs. low-adherent). Logistic regressions assessed factors associated with OHA/insulin adherence controlling for gender, race/ethnicity, education, duration, healthcare coverage, and HbA1c.

Results: Of 381 YAs in iCount (mean age 26 yrs, 68% female, 20% non-Hispanic white, 38% non-Hispanic Black, 36% Hispanic, 64.9% <$25k income, mean HbA1c 9.4%), 224 were taking OHAs. As 12 lacked adherence scores, 212 were in OHA analyses; 70.0% were low-adherent to OHAs. Negative beliefs about medicines were associated with low OHA adherence in univariate, but not multivariate analyses. No measured intrapersonal factor was associated with OHA adherence. Of 192 in insulin analyses, 37.0% were low-adherent to insulin. Low insulin adherence was associated with less belief in seriousness of T2D (p=0.036), more concern that medications are overused (p=0.005) and diabetes distress (p=0.020). Insulin adherence did not relate to other diabetes attitudes or beliefs, depressive symptoms or anxiety. Limitations: small N with high depressive/anxiety symptoms; self-reported insulin use.

Conclusion: Poor medication adherence is common in YAs with youth-onset T2D. More needs to be learned about factors associated with adherence to develop tailored, effective interventions.

Disclosure

P. M. Trief: None. D. Uschner: None. M. Tung: None. K. Drews: None. S. Kalichman: None. B. Anderson: None. J. D. Bulger: None. R. S. Weinstock: Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1RO1DK110456-01A1; U01DK61230)