Abstract: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40–99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope −3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (−4.7 vs. −2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.

Abstract: Introduction: The difference between bedtime and morning glucose levels (BeAM value) is a clinically relevant measure that can guide clinicians regarding insulin titrations. As chronic kidney disease (CKD) develops, changes in insulin sensitivity and kinetics and limitations to available medications may contribute to over-basalization, insufficient prandial control, and large BeAM. We hypothesized that CKD and less time in range (TIR) derived from continuous glucose monitoring (CGM) are associated with large BeAM in T2DM. Methods: This was a prospective observational cohort study of 1people with T2DM treated with insulin or sulfonylurea, 81 participants with CKD (eGFR & lt;60 mL/min/1.73 m2) , and 24 controls with eGFR ≥60 frequency matched on age, duration of diabetes, HbA1c, and glucose-lowering medications. Each participant wore a CGM for two 6-day periods. BeAM was calculated as the difference between mean bedtime sensor glucose values and mean morning sensor values, with large BeAM defined as ≥30 mg/dL glucose drop from bedtime to morning. Results: Participants had a mean age of 68 years, diabetes duration years and HbA1c 7.7%. CKD and controls had a mean eGFR 38 and 83 mL/min/1.73 m2 respectively. Median (IQR) BeAM was 29 (9-52) mg/dL for participants with CKD and (-4-31) mg/dL for controls (p = 0.11) . Forty participants with CKD (49%) and 7 controls (29%) had a large BeAM. Those with a large BeAM had less TIR (58 v 68%) , higher HbA1c (8.0 vs. 7.5%) , and higher glucose management indicator (GMI, 7.5 vs. 7.2%) compared to those with BeAM & lt;30 mg/dL (each p & lt;0.05, adjusting for age, sex, and race) . Coefficient of variation, diabetes duration, and insulin dose (total or basal) did not correlate with BeAM. Conclusions: Large BeAM was common among participants with long-standing T2DM and CKD and was associated with less TIR and higher GMI. These data suggest that there is opportunity for improvement in daytime and prandial diabetes management among patients with CKD. Disclosure L.Mayeda: None. L.Zelnick: None. S.Trikudanathan: Research Support; Bionic pancreas, Bionic pancreas , Insulet Corporation, Insulet Corporation. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. I.De boer: Advisory Panel; AstraZeneca, Bayer AG, Cyclerion Therapeutics, Inc., George Clinical, Goldfinch Bio, Inc., Other Relationship; American Society of Nephrology, Research Support; Dexcom, Inc. Funding American Diabetes Association (4-15-CKD-20) ; National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088762, R01087726)

Abstract: Background: Baseline risk variables and visit-to-visit variability (VV) of systolic blood pressure (SBP) , HbA1c, serum creatinine, and uric acid (UA) are potential risk markers of kidney function decline in type 1 diabetes. Methods: Post-hoc analysis of the PERL study (NCT02017171) - a double-blind randomized placebo-controlled clinical trial investigating allopurinol’s effect on iohexol-derived glomerular filtration rate (iGFR) in type 1 diabetes with elevated UA. Primary outcome was iGFR change over three years. Linear regression with backwards selection of baseline clinical variables was performed to identify an optimized model forecasting iGFR change. VV of SBP, HbA1c, serum creatinine, and UA were calculated as standard deviations of the residuals in individual linear regression models (LV) and coefficients of variation (CV) using all available measurements in the run-in period; thereafter assessed by linear regression, with iGFR change as the dependent variable. Adjustment included sex, baseline age, diabetes duration, BMI, HbA1c, SBP, kidney function (iGFR or eGFR, as appropriate) , urine albumin excretion rate (UAER) , smoking, and renin-angiotensin system inhibitor use. Results: 422 participants completed the trial, 4were included in this analysis. In the optimized baseline risk marker model, race other (including but not limited to Hawaiian/Pacific Islander) than White, Black, or Asian, higher HbA1c, UAER, and heart rate, and lower iGFR were associated with faster iGFR decline; Hispanic/Latino ethnicity was not. Assessing VV, higher LV and CV of SBP was associated with faster iGFR decline (adjusted LV β: -0.79, p=0.01; CV β: -0.79, p=0.04) ; VVs of HbA1c, creatinine, and UA were not. Conclusions: We identified several risk markers of faster iGFR decline in a high-risk population of individuals with type 1 diabetes. In addition to previously described associations, higher SBP VV was a risk marker for faster kidney function decline. Disclosure V.Rotbain curovic: None. S.Polsky: Advisory Panel; Medtronic, Other Relationship; diaTribe, Research Support; Dexcom, Inc., Eli Lilly and Company, Leona M. and Harry B. Helmsley Charitable Trust, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi-Aventis U.S. R.Pop-busui: Advisory Panel; Averitas Pharma, Inc., Boehringer Ingelheim International GmbH, Nevro Corp., Novo Nordisk, Reata Pharmaceuticals, Inc., Regenacy Pharmaceuticals, Inc. R.J.Sigal: Advisory Panel; Novo Nordisk Canada Inc., Research Support; Novo Nordisk Canada Inc. K.R.Tuttle: Advisory Panel; Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Consultant; AstraZeneca, Eli Lilly and Company, Research Support; Bayer AG, Goldfinch Bio, Inc., Novo Nordisk, Travere. G.E.Umpierrez: Research Support; AstraZeneca, Dexcom, Inc., Novo Nordisk. A.Wallia: Advisory Panel; Eli Lilly and Company, Research Support; Novo Nordisk, UnitedHealth Group. S.Rosas: Advisory Panel; AstraZeneca, Teladoc Health, Other Relationship; Bayer AG, Research Support; AstraZeneca, Bayer AG. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. The perl study group: n/a. N.Roy: None. T.W.Hansen: Stock/Shareholder; Novo Nordisk A/S. L.Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. I.De boer: Advisory Panel; AstraZeneca, Bayer AG, Cyclerion Therapeutics, Inc., George Clinical, Goldfinch Bio, Inc., Other Relationship; American Society of Nephrology, Research Support; Dexcom, Inc. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. I.Lingvay: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Mannkind, TARGET PharmaSolutions; Valeritas;; Altimmune; DataRevive; Click; Medscape Duke CRI; Janssen Pharma; Bayer; Intercept, Novo Nordisk, Sanofi, Zealand Pharma A/S, Consultant; Novo Nordisk, Research Support; NovoNordisk; Mylan; Merck, Sanofi. J.B.Mcgill: Advisory Panel; Gilead Sciences, Inc., Lilly Diabetes, MannKind Corporation, Novo Nordisk A/S, Provention Bio, Inc., Salix Pharmaceuticals, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; Dexcom, Inc., Novo Nordisk. Funding Supported by grants from the NIDDK (R03-DK-094484, R34-DK-097808, UC4-DK-101108, P30-DK-036836, and P30-DK-020572) , the JDRF (17-2012-377) , the National Center for Advancing Translational Sciences (UL1-TR-002494, UL1-TR- 001422, UL1-TR-002556, UL1-TR-002319, and UL1-TR- 001105) , and the National Institute on Aging (Claude Pepper Center grant number, P30-AG-024824)

Abstract: The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.

Abstract: In chronic kidney disease, glycated albumin and fructosamine have been postulated to be better biomarkers of glycemic control than HbA1c. We evaluated the accuracy, variability, and covariate bias of three biomarkers (HbA1c, glycated albumin, and fructosamine) compared with continuous glucose monitoring (CGM)–derived measurement of glycemia across estimated glomerular filtration rate (eGFR) in type 2 diabetes. RESEARCH DESIGN AND METHODS A prospective cohort study was conducted of 104 participants with type 2 diabetes, 80 with eGFR & lt;60 mL/min/1.73 m2 (not treated with dialysis) and 24 frequency-matched control subjects with eGFR ≥60 mL/min/1.73 m2. Participants wore a blinded CGM for two 6-day periods separated by 2 weeks, with blood and urine collected at the end of each CGM period. HbA1c, glycated albumin, and fructosamine were measured by high-performance liquid chromatographic, enzymatic, and colorimetric nitroblue tetrazolium methods, respectively. RESULTS Within-person biomarker values were strongly correlated between the two CGM periods (r = 0.92–0.95), although no marker fully captured the within-person variability of mean CGM glucose. All markers were similarly correlated with mean CGM glucose (r = 0.71–77). Compared with mean CGM glucose, glycated albumin and fructosamine were significantly biased by age, BMI, serum iron concentration, transferrin saturation, and albuminuria; HbA1c was underestimated in those with albuminuria. CONCLUSIONS Glycated albumin and fructosamine were not less variable than HbA1c at a given mean CGM glucose level, with several additional sources of bias. These results support measuring HbA1c to monitor trends in glycemia among patients with eGFR & lt;60 mL/min/1.73 m2. Direct measurements of glucose are necessary to capture short-term variability.

Abstract: Introduction: Glycemic control for dialysis patients with diabetes mellitus (DM) is challenging due to limitations of HbA1c, risk of hypoglycemia, and fewer options for glucose-lowering agents. We sought to comprehensively describe glycemic patterns among dialysis patients using continuous glucose monitoring (CGM). Methods: The Blood Sugar Sensing On Maintenance Dialysis (BLOSSOM) study is a prospective community-based cohort of people treated with dialysis, with or without DM, designed to assess the prevalence, causes, and consequences of dysglycemia. Each participant wore a Dexcom G6 CGM for 10 days. This interim analysis examined the first 153 BLOSSOM dialysis participants. Results: Dialysis participants had a mean (SD) age of 61 (14) years, 132 (86%) underwent hemodialysis, and 21 (14%) were treated with peritoneal dialysis (PD). Among 90 dialysis participants with DM, mean (SD) glucose management indicator (GMI) was 7.9% (1.2%), time in range (TIR) (70-180 mg/dL) was 50% (29%) and 27 (30%) participants achieved TIR ≥70%. Mean (SD) time high ( & gt;180 mg/dL), very high ( & gt;250 mg/dL), low ( & lt;70 mg/dL) and very low ( & lt;54 mg/dL) was 49% (29%), 21% (23%), 2% (11%) and 1% (11%), respectively. Of 63 dialysis participants without DM, mean (SD) GMI was 6.2% (0.4%), and time in normal range (70-140 mg/dL) 75% (18%). Mean (SD) time low and very low were 2% (8%) and 0% (3%), with low and very low sensor glucose values seen in 38 (60%) and 23 (37%) participants, respectively. PD patients without known DM (n=9) had a mean (SD) GMI of 6.6% (0.3%) and spent mean (SD) 54% (21%) of time in normal range. Conclusions: In this community-based sample of maintenance dialysis patients, uncontrolled hyperglycemia was highly prevalent among patients with DM. PD patients without DM were in normal range less than half of the time. Hypoglycemia was seen in patients with and without DM. Our findings warrant additional investigation into causes and consequences of glycemic patterns in patients on dialysis. Disclosure L.Mayeda: None. L.Zelnick: None. S.Trikudanathan: Research Support; Insulet Corporation, Bionic pancreas. I.B.Hirsch: Consultant; Abbott Diabetes, Lifecare, Inc., Hagar, Research Support; Beta Bionics, Inc., Insulet Corporation, Dexcom, Inc. S.Watnick: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126373)

Abstract: Objective: To determine the prevalence of sodium-glucose contransporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP1RA) use among adults with type 2 diabetes (T2D) in the United States. Methods: We studied adults with T2D and eGFR ≥30mL/min/1.73m2 who participated in the National Health and Nutrition Examination Survey (NHANES) , focusing on the 2017-2020 examination cycle. We tested prevalence of SGLT2i and GLP1RA use among subgroups based on demographic variables and relevant comorbidities, including chronic kidney disease (CKD) , congestive heart failure (CHF) , and atherosclerotic cardiovascular disease (ASCVD) . We compared use of SGLT2i and GLP1RA to other glucose-lowering medications and assessed trends from prior NHANES cycles. Results: Among 1,375 participants studied in 2017-2020, mean age was 60 years, 46% were women, 13% self-identified as non-Hispanic Black, 10% self-identified as Mexican American, 37% had CKD, 8.5% had CHF, and 23% had ASCVD. The prevalence of SGLT2i and GLP1RA use was 5.8% and 4.4%, respectively. SGLT2i were used by 7.2% of adults with CKD or CHF, and GLP1RA were used by 3.5% of adults with ASCVD. Differences in SGLT2i or GLP1RA use were observed by age, race, ethnicity, and health insurance status. Biguanides, sulfonylureas, DPP-4 inhibitors, and insulin were used more frequently than SGLT2i or GLP1RA. Overall, prevalence of SGLT2i but not GLP1RA use increased significantly from 2013-2014 to 2017-2020. Conclusions: SGLT2i and GLP1RA use is low among adults with T2D, including among those with strong indications. Enhanced implementation of these agents is crucial to improving kidney and cardiovascular outcomes and mitigating health disparities in T2D. Disclosure C.Limonte: None. Y.Hall: None. S.Trikudanathan: Research Support; Bionic pancreas, Bionic pancreas , Insulet Corporation, Insulet Corporation. K.R.Tuttle: Advisory Panel; Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Consultant; AstraZeneca, Eli Lilly and Company, Research Support; Bayer AG, Goldfinch Bio, Inc., Novo Nordisk, Travere. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. I.De boer: Advisory Panel; AstraZeneca, Bayer AG, Cyclerion Therapeutics, Inc., George Clinical, Goldfinch Bio, Inc., Other Relationship; American Society of Nephrology, Research Support; Dexcom, Inc. L.Zelnick: None. Funding This work was supported by an unrestricted fund from the Northwest Kidney Centers. CPL was funded by NIDDK grant T32DK007467 and the American Kidney Fund Clinical Scientist in Nephrology grant program. Additional funding was provided by R01DK126373, R01DK125084, R01DK088762.

Abstract: Rapid loss of estimated glomerular filtration rate (eGFR) within its normal range has been proposed as a strong predictor of future kidney disease. We investigated this association of eGFR slope early in the course of type 1 diabetes with long-term incidence of kidney and cardiovascular complications. RESEARCH DESIGN AND METHODS The annual percentage change in eGFR (slope) was calculated during the Diabetes Control and Complications Trial (DCCT) for each of 1,441 participants over a mean of 6.5 years and dichotomized by the presence or absence of early rapid eGFR loss (slope ≤−3% per year) as the exposure of interest. Outcomes were incident reduced eGFR (eGFR & lt;60 mL/min/1.73 m2), composite cardiovascular events, or major adverse cardiovascular events (MACE) during the subsequent 24 years post-DCCT closeout follow-up. RESULTS At DCCT closeout (the baseline for this analysis), diabetes duration was 12 ± 4.8 years, most participants (85.9%) had normoalbuminuria, mean eGFR was 117.0 ± 13.4 mL/min/1.73 m2, and 149 (10.4%) had experienced early rapid eGFR loss over the preceding trial phase. Over the 24-year subsequent follow-up, there were 187 reduced eGFR (6.3 per 1,000 person-years) and 113 MACE (3.6 per 1,000 person-years) events. Early rapid eGFR loss was associated with risk of reduced eGFR (hazard ratio [HR] 1.81, 95% CI 1.18–2.79, P = 0.0064), but not after adjustment for baseline eGFR level (HR 0.94, 95% CI 0.53–1.66, P = 0.84). There was no association with composite cardiovascular events or MACE. CONCLUSIONS In people with type 1 diabetes primarily with normal eGFR and normoalbuminuria, the preceding slope of eGFR confers no additional association with kidney or cardiovascular outcomes beyond knowledge of an individual’s current level.