Abstract
Introduction
Diabetic ketoacidosis (DKA) is a potentially life-threatening diabetic complication. Despite the high prevalence of DKA and the substantial associated healthcare burden, limited research on strategies to improve outcomes currently exists.
Thiamine (vitamin B1) is a cofactor of pyruvate dehydrogenase, which plays a key role in aerobic glucose metabolism. Thiamine deficiency is common in patients with DKA, resulting in a shift to anaerobic metabolism and hyperlactatemia, which can prolong and complicate recovery. Therefore, we hypothesise that thiamine administration will improve aerobic metabolism and lead to faster resolution of acidemia in patients with DKA.
Methods and analysis
In this single centre, double-blind, randomised, placebo-controlled, parallel group interventional trial, 100 patients admitted to the hospital with DKA will be randomised to receive either intravenous thiamine (200 mg in 50 mL 0.9% saline) or placebo (0.9% saline identical in appearance and volume) two times per day for 2 days. The primary outcome will be the change in bicarbonate level over 24 hours as compared between the two treatment groups. Additional secondary outcomes include the change over time in anion gap, lactate levels, oxygen consumption by circulating mononuclear cells, intensive care unit and hospital length-of-stay and hospital resource usage when comparing the two study arms.
Ethics and dissemination
This trial was approved by the Committee on Clinical Investigations, the institutional review board of Beth Israel Deaconess Medical Center (protocol number 2018P000475). Findings will be disseminated through peer-reviewed publications and professional conference presentations.
Trial registration number
NCT03717896; clinicaltrials.gov.
Keywords: Randomized Controlled Trial, DIABETES & ENDOCRINOLOGY, INTENSIVE & CRITICAL CARE
STRENGTHS AND LIMITATIONS OF THIS STUDY.
This article describes a single-centre, randomised, blinded clinical trial of thiamine versus placebo in diabetic ketoacidosis (DKA), a prevalent and life-threatening disease with few clinical trials examining therapeutic options in this group of patients.
The primary outcome for the trial is a change in the bicarbonate level between enrolment and 24 hours after enrolment, measuring resolution of acidosis, a goal in treating DKA.
This trial is not powered to assess patient-centred outcomes such as length of stay and mortality and these will be evaluated as secondary outcomes.
Although this trial is not able to measure baseline thiamine levels in real time, it will be able to determine whether baseline thiamine deficiency leads to a differential treatment effect.
Introduction
The Thiamine as Adjunctive Therapy for Diabetic Ketoacidosis (DKAT) trial was developed to assess the clinical efficacy of intravenous thiamine for reversal of acidosis and improvement of cellular oxygen consumption in patients admitted to the hospital with diabetic ketoacidosis (DKA). DKA is a potentially life-threatening disorder that may expose survivors to significant morbidity and is characterised by severe hypovolemia, hyperglycaemia, ketonemia and metabolic acidemia.1 2 The healthcare burden of DKA treatment is substantial, often requiring intensive care unit (ICU) admission, with estimates of annual cost for patients with DKA consistently increasing and exceeding $6 billion in the USA alone.3 Despite this burden of DKA on public health, there is limited research on strategies to improve outcomes.
Thiamine (vitamin B1) is a cofactor of pyruvate dehydrogenase (PDH), playing a key role in aerobic glucose metabolism. The activity of PDH is reduced in thiamine deficient states, resulting in a shift to anaerobic glucose metabolism.4 Thiamine is often depleted in patients with diabetes.5–7 Indeed, thiamine deficiency occurs in as many as 39% of patients with DKA, and thiamine deficiency is associated with elevated lactate.8
In this randomised, double-blinded, placebo-controlled trial, we hypothesise that treating DKA patients with intravenous thiamine will lead to faster resolution of acidemia through improvement in aerobic metabolism. Herein, we describe the protocol and proposed statistical analysis plan (SAP) for the DKAT trial, which was designed by the trial lead investigators and statisticians. All analyses specified in this SAP have been defined prospectively. The complete study protocol can be found on clinicaltrials.gov; it was posted on 24 October 2018. The first enrolment was on 21 November 2018.
Methods and analysis
Trial design
The DKAT trial is a single centre, double-blind, randomised, placebo-controlled, parallel group interventional trial. Patients admitted to the hospital with DKA who are enrolled in the study will be randomised to receive either intravenous thiamine (200 mg in 50 mL 0.9% saline) two times per day for 2 days or placebo (0.9% saline identical in appearance and volume) on the same schedule. The primary hypothesis is that administration of thiamine will aid in the reversal of acidosis measured by the primary outcome of change in bicarbonate over 24 hours as compared with placebo (figure 1).
Figure 1.
Diagram of trial design. ICU, intensive care unit.
Informed written consent will be obtained prior to enrolment from all participants or their legally authorised representatives. A sample informed consent form is included in the online supplemental material. Participants and their legally authorised representatives will be made aware that participation is strictly voluntary and that consent can be withdrawn at any time.
bmjopen-2023-077586supp001.pdf (231.1KB, pdf)
Patient population
Patients will be enrolled from Beth Israel Deaconess Medical Center, a tertiary academic centre located in Boston, Massachusetts. Patients will be enrolled within 6 hours of meeting the inclusion criteria at the enrolling hospital.
Inclusion criteria
Adult (≥18 years).
Bicarbonate (HCO3) ≤15 mEq/L.
Anion gap >12 mEq/L.
pH ≤7.24 (if already obtained by clinical team).
Urine ketones (qualitative) or serum ketones (β-hydroxybutyric acid) >3 mmol/L.
Enrolment within 6 hours of presentation.
Exclusion criteria
Current thiamine supplementation ≥6 mg/day (ie, more than a multivitamin).
Competing causes of severe acidosis, including seizure, carbon monoxide poisoning, cyanide toxicity, cardiac arrest and liver dysfunction (specifically defined as known cirrhosis).
Known allergy to thiamine.
Competing indication for thiamine administration as judged by the clinical team (eg, significant alcohol use).
Research-protected populations (pregnant, prisoners).
Patient enrolled previously in same study.
Code status of do not resuscitate/do not intubate or comfort measures only.
Randomisation and blinding
Participants will be randomised in a 1:1 ratio to either 200 mg thiamine or placebo using permuted block randomisation of size 2 or 4 via the use of SAS V.9.4 software. The block sizes are randomly assigned. Participants will be stratified according to severity of DKA as defined by bicarbonate level. Patients with a bicarbonate level <10 mEq/L will be stratified to the severe DKA group and those with a bicarbonate level ≥10 to the moderate DKA group. Stratification will help ensure balanced randomisation between groups. The master list of group assignments will be maintained in the pharmacy area. A sealed envelope with group assignment will be placed in each patient’s chart for the unexpected and rare need to unblind the study. All study personnel (participants, care providers, investigators and outcomes assessors), with the exception of the research pharmacist, will be blinded to the intervention.
Intervention
Trial participants will be randomised to receive intravenous thiamine 200 mg diluted in 50 mL 0.9% saline every 12 hours or placebo (50 mL 0.9% saline every 12 hours) for 48 hours. Thiamine is colourless and odourless and, therefore, cannot be distinguished by clinicians from placebo.
Data collection and monitoring plan
All data will be collected by local study staff and recorded using a Research Electronic Data Capture (REDCap), a HIPAA-compliant electronic data capture tool hosted at Beth Israel Deaconess Medical Center.9 10 Data entry will be monitored for accuracy by a data manager on a weekly basis. Using a combination of automated edit checks on REDCap (eg, to identify missing data, values out of range) and manual review of datapoints, discrepancies will be identified. These discrepancies will be tracked and followed until resolution using the query feature on REDCap. To reinforce the monitoring, weekly email summaries of salient queries will be sent out to the study staff, and input from the clinical team will be actively solicited for any data entry issues that come up that require medical knowledge to accurately address. Additionally, to ensure a high quality of data, a system of double data entry will be put into place for key variables, where two separate data entry staff independently enter values, and REDCap functionality is used to trace and correct discrepancies between the two entered values.
Safety and monitoring
The independent Data Safety Monitoring Board (DSMB) is composed of three physicians experienced in clinical research and specialising in Pediatric Critical Care/Endocrinology (Michael Agus, MD), Pulmonology/Critical Care (Jakob McSparron MD) and Emergency Medicine (Matthew Wong, MD MPH) as well as an independent biostatistician (Ariel Mueller, MA). Members will review the accruing data to ensure that study conduct and enrolment are adequate and that there are no serious safety concerns. They will assess all adverse events as well as monitor the overall conduct of the study. The DSMB will meet approximately once per year to ensure adequate monitoring of the trial. Additional meetings can be called as deemed necessary by the Chair or other members. There are no prespecified stopping rules for futility or efficacy.
If a serious imbalance of adverse events is perceived, the DSMB can request unblinding of data for review. In case of an emergency need for unblinding of a subject, the principal investigator or a designee will contact the research pharmacy. The research pharmacy is unblinded and can provide treatment assignments for that subject.
Blood collection
Blood samples will be collected at 0, 6, 12, 18, 24 and up to 72 hours or prior to hospital discharge, whichever comes first. Samples for bicarbonate and lactic acid will be sent to on-site clinical laboratories for immediate analysis. Samples taken at 0, 24 and 72 hours or prior to discharge will be centrifuged at 3000 × g for 10 min to separate serum, plasma and isolation of peripheral blood mononuclear cells (PBMCs). PBMCs will be isolated from fresh whole blood using a density gradient separation method (Ficoll-Paque premium, GE Healthcare Bio-Science, Piscataway, New Jersey). PDH activity and quantity will then be measured after disruption of the mitochondrial membrane via an immunocapture and microplate-based assay as previously described.11 PDH-specific activity will be calculated as PDH activity/ln(PDH quantity). Cellular oxygen consumption will be measured in PBMCs from a subset of the patients based on personnel and equipment availability. The complete mitochondrial respiration profile will be measured using an XFe96 Extracellular Flux Analyzer and the XF Cell Mito Stress Test Kit (Seahorse Bioscience, North Billerica, Massachusetts). The XF Cell Mito Stress Test uses modulators of respiration that targets components of the electron transport chain in the mitochondria to reveal key parameters of metabolic function. Three sequential injections of oligomycin, carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone and a mix of rotenone and antimycin A inhibit specific complexes of the electron transport chain to provide isolated measurements of basal respiration, ATP production, maximal respiration and non-mitochondrial respiration, respectively. Proton leak and spare respiratory capacity are then calculated using these parameters.12 Serum and plasma samples will be aliquoted into light-protected cryotubes, frozen at −80°C, and stored in a secure and temperature-controlled facility.
Patient and public involvement
No patients have been or will be involved in the design, recruitment or conduct of the study. Patients or their representatives will assess the burden of the intervention at the time of randomisation through the informed consent process.
Outcomes
Primary outcome
The primary outcome is the difference in the change of bicarbonate levels over 24 hours between the thiamine and placebo groups. The change in bicarbonate levels corresponds to the resolution of acidosis. In this trial, we are measuring change in bicarbonate levels over time by measuring levels at 0, 6, 12, 18 and 24 hours.
Secondary outcomes
Primary secondary outcomes
Anion gap
The difference in change over time of the anion gap (calculated as the difference between sodium and the sum of chloride and bicarbonate) between the thiamine and placebo groups. The anion gap will be measured at 0, 6, 12, 18 and 24 hours after study drug administration.
Lactate
The difference in change over time of lactate between the thiamine and placebo groups. Serial lactate levels will be measured at 0, 6, 12, 18 and 24 hours after study drug administration.
Oxygen consumption by circulating mononuclear cells
Oxygen consumption by circulating mononuclear cells is an index of whole body oxidative glucose metabolism. It also reflects whole body thiamine status due to the critical cofactor role of thiamine in oxidative metabolism. Mononuclear cell oxygen consumption will be assessed by the investigators when the patient is admitted into the study and again after 24 hours to determine there is a difference between the two groups.
ICU length of stay
ICU length of stay (LOS) will be defined as the number of days in which the patient is in the ICU for at least 6 hours of that calendar day.
Hospital LOS
Hospital LOS will be defined as the number of days in which the patient is a hospital inpatient for at least 6 hours of that calendar day.
Hospital resource usage
Total DKA-related cost for hospital resource usage will be assessed from hospital records by collecting all relevant Current Procedural Terminology codes from the patient billing information and using the in-network cost for inpatient services at https://www.fairhealthconsumer.org/ using the zip code of the treating hospital.
Other secondary outcomes
Sequential Organ Failure Assessment Score
The difference in the change in Sequential Organ Failure Assessment (SOFA) Score over 24 hours between the thiamine and placebo groups. The SOFA score will be defined using a modification in which the arterial oxygen saturation/fraction of inspired oxygen (SaO2/FiO2) ratio is substituted for the partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2 ratio) as has been previously described.13 14 This modified score will be used to account for participants without an arterial catheter
C-peptide levels
We will measure serial C-peptide levels at the time of study drug administration and at 72 hours or before discharge. This will be an exploratory outcome to see whether thiamine treatment is effective in preserving β-cell function.15 16 This outcome will be analysed separately for patients with diabetes type 1 and type 2.
Duration of insulin therapy
The duration of insulin therapy is calculated by examining the hospital clinical information systems for all records of intravenous insulin infusion beginning at the time of enrolment. The start and the stop time-stamps of medication infusion are used to calculate a duration of infusion, and these durations are summed across all instances of intravenous infusion to arrive at a total duration of insulin therapy in minutes. This variable is reported in hours (minutes ≤30 are rounded down to the nearest hour, minutes >30 are rounded up to the nearest hour).
Cognitive function
As an exploratory outcome, we will measure cognitive function using the Hopkins Verbal Learning Test (measures verbal learning and memory),17 Brief Visual Spatial Memory Test (measures visuospatial memory),18 Trail Making Test A and B (measurement of cognitive function utilising connection of dots by correct order),19 WAIS-IV Digit Span (measures working memory),20 Test of Verbal Fluency and Animal Naming (measures phonemic and semantic verbal fluency)21 and the Test of Premorbid Functioning (estimates premorbid intellectual function).22 The tests will be administered by trained research assistants at the patient’s bedside 72–96 hours after enrolment or prior to discharge (whichever comes first). Due to changes over the lifespan in cognition, any analyses involving these tests will control for age as a continuous variable.
Safety outcomes
Patient records will be reviewed daily from the time of enrolment for 72 hours for adverse outcomes that could potentially be related to the intervention. Anticipated adverse events include rash and/or serious allergic reaction. However, we also will collect any other serious and unexpected adverse events. Any adverse event that is thought to be related or possibly related to the study drug (defined as at least 50% chance that the adverse event is related to the study drug as assessed by a physician on the research team) will be reported to the institutional review board (IRB) shortly following the event per local protocol. In addition, unexpected serious adverse events related to the study drug will undergo expedited reporting to the DSMB within 7 days of the coordinating centre becoming aware of the event.
Sample size
The analysis method for the primary endpoint will be linear mixed-effects modelling (LMM). This type of modelling is used in longitudinal or repeated measures studies to take into account the correlation of within-subject measurements. In this study, each subject is expected to have five bicarbonate measurements, one at 0, 6, 12, 18 and 24 hours, which are correlated. Based on preliminary data from a pilot study, which had three consistent time points, we observed that patients with DKA had a mean of 8.9 mEq/L at time 0, 18 mEq/L at 12 hours and 20 mEq/L at 24 hours. We took a conservative position to assume that the potential effect size (the mean difference of bicarbonate between the two groups) will be 20%. That is, we assumed that the mean bicarbonate level at the three different time points was 8.9 mEq/L, 21.6 mEq/L and 22.5 mEq/L. We then simulated the longitudinal data with the assumption that the variance–covariance structure of the bicarbonate data followed a compound-symmetry structure with between-subject variance of 3.8. The linear-mixed effects model was used on the simulated data to obtain the estimated F statistic, numerator and denominator df. From these estimates, the non-centrality parameter was computed and used to obtain the power. With 80 subjects with type-I error of 0.05, we have a power of 99% to detect the stated difference over 0, 12 hours and 24 hours. The addition of two more time points with similar between-subject variance will increase our power. We plan to enrol 100 subjects (50 thiamine and 50 placebo) to allow for a small drop-out rate (less than 20%; due to reasons such as subject withdrawal, hospital discharge or death prior to outcomes of interest, potentially missing data due to patient clinical care (eg, having testing done, having access issues for blood draws, etc) and to ensure adequate power for the preplanned key analysis of thiamine-deficient patients.
Statistical analysis
Analysis principles
Analyses will be conducted on a modified intention-to-treat basis: all participants receiving at least the first dose of the study medication will be analysed according to the group to which they were assigned, regardless of treatment compliance after the first dose. The analyses of primary and secondary outcomes will control for the stratified randomisation. Prespecified subgroup analyses (by baseline thiamine level and by diabetes type) will be conducted regardless of whether a statistically significant treatment effect on the primary outcome is observed in the overall sample. Covariates included in each analysis are specified in the sections below.
No formal adjustments for multiplicity of testing will be applied, but the outcome will be ordered by degree of importance (ie, primary vs secondary) and significant test results will be interpreted in light of the multiple comparisons made. All tests will be two sided and the nominal level of statistical significance (α) will be 5%. All CIs will have 95% coverage.
Trial profile
The flow of patients through the trial will be shown using a Consolidated Standards of Reporting Trials diagram.23 This will include the number of screened patients who met study inclusion criteria, the number of patients who were included, and exclusion reasons for non-included patients.
Baseline characteristics
A description of the baseline characteristics will be presented overall and by treatment group (table 1). Categorical variables will be summarised by frequencies and percentages. Percentages will be calculated according to the number of patients for whom data are available. Continuous variables will be summarised using means±SD or medians and IQR. Basic demographic data for all patients screened will be included. Descriptive statistics will be used to summarise the study population.
Table 1.
Baseline characteristics of patients.
| Characteristics | Overall | Thiamine | Placebo |
|
Demographics
Age Sex Race BMI |
|||
|
Diabetes history
Type I/type II/unknown Ketoacidosis history History of insulin use Current insulin pump use |
|||
|
Past medical history
Coronary artery disease Malignancy Congestive heart failure Chronic obstructive pulmonary disease Dementia/Alzheimers Diabetes Alcohol use disorder HIV/AIDS Liver disease Renal disease Stroke/transient ischaemic attack Tobacco use Organ or bone marrow transplant |
|||
|
Vital signs
Temperature Heart rate Systolic blood pressure Diastolic blood pressure Respiratory rate Oxygen saturation Glasgow Coma Scale |
|||
|
Laboratory values
Glucose Serum ketones Urine ketones present pH Bicarbonate PaCO2 Base excess Anion gap Lactate Albumin Sodium Potassium Chloride Creatinine WBC |
|||
|
Therapies
Insulin infusion rate IV fluid type IV fluid volume* |
|||
|
SOFA Score
Baseline SOFA Score |
*Volume of intravenous fluids received in the 6 hours prior to enrolment.
.BMI, body mass index; SOFA, Sequential Organ Failure Assessment; WBC, white cell count.
Compliance with the administration of study drug
The cumulative dose of study drug received (mg) and overall compliance, defined as the number of doses given divided by the number of expected doses, will be summarised by treatment group. These variables will be presented as mean±SD or median (IQR) based on the distribution of the data, assessed visually using histograms and statistically using a Shapiro-Wilk test.
Protocol deviations
Protocol deviations will be summarised by treatment group as the number and proportion of deviations by type. Any withdrawals of consent resulting in permanent discontinuation of the study drug will also be summarised in this fashion. Timing of withdrawals will be reported. Significant protocol modifications will be reported to the IRB and DSMB in the appropriate timeframe and updated on clinicaltrials.gov.
Concomitant therapies
If the clinical team decides to provide a participant with thiamine outside of the study protocol, the study drug will be discontinued by the study team and the thiamine will be given open label by the clinical team (non-study supply). The number and proportion of patients receiving open-label thiamine during the study protocol will be described.
Analysis of primary outcome
To calculate the primary outcome of difference in bicarbonate levels over 24 hours, serial measurements of bicarbonate will be collected at baseline (immediately prior to study drug), 6, 12, 18 and 24 hours following enrolment. An LMM will be used to obtain the estimated mean difference in these outcomes between the two groups (placebo and thiamine) over the first 24 hours. In this model, the dependent variable will be the outcome, and the independent variables of interest are the randomised group (placebo and thiamine), each time point, the interaction between group and time, and severity at enrolment (represented by randomisation strata). The interaction will allow us to obtain the estimated mean difference in outcomes between the two groups at each time point. We will also evaluate baseline demographic and clinical characteristics in the placebo and thiamine groups to ensure that relevant demographics or clinical variables were adequately balanced during randomisation. The clinical protocol at the institution where the study is taking place recommends administration of lactated Ringers solution in the setting of DKA, and we, therefore, do not anticipate administration of large amounts of 0.9% saline. As administration of 0.9% saline can affect bicarbonate levels, we will collect the total amount of 0.9% saline administered over the first 24 hours to ensure that the groups are balanced. In the unlikely event, such variables are unbalanced, we will explore including the unbalanced variables into this model as a sensitivity analysis.
To account for within-subject correlation, we will explore the following variance–covariance structures: independence, compound-symmetry, auto-regressive with lags, toeplitz and unstructured. The variance–covariance structure will be incorporated into the estimation of the mean structure of the LMM. The selection of the variance–covariance structure will be based on the Akaike Information Criterion from each model. We will use a restricted maximum likelihood estimation method for the estimation.
Analysis of secondary outcomes
The following outcomes will be summarised using mean (SD) or median (IQR), and linear regression controlling for severity at enrolment (represented by randomisation strata) will be performed to assess the differences between treatment groups
ICU LOS.
Hospital LOS.
Hospital resource utilisation.
SOFA score.
Cognitive function.
The following outcomes with serial measurements will be analysed with a LMM in a similar fashion as described above for the primary endpoint:
Anion gap.
Lactate levels.
Oxygen consumption by peripheral mononuclear cells.
C-peptide levels, restricted to patients with type 1 diabetes.
C-peptide levels, restricted to patients with type 2 diabetes.
Duration of insulin therapy will be compared between groups using the Kaplan-Meier log-rank test and Cox proportional hazards model controlling for stratification group. The outcome variable is duration of insulin therapy in hours and the predictor is the allocated treatment.
Analysis of adverse events
Rates of serious expected and unexpected adverse events will be reported by group assignment. Proportions of patients with adverse events will be compared between the treatment groups using Fisher’s exact test.
Analysis of subgroups
The analysis will include the following predefined subgroup analyses:
By baseline thiamine level: we will perform a preplanned subanalysis of the primary outcome of bicarbonate levels in thiamine-deficient (defined as plasma thiamine levels ≤7) subjects. We will also perform a secondary analysis adding an interaction term for thiamine deficiency into the primary analysis to assess whether there is a statistically significant difference in the relationship between treatment and outcome between the thiamine-deficient and the non-thiamine-deficient groups. We anticipate that this subgroup will consist of approximately 40% of the total population but will have a stronger treatment effect. We did not stratify randomisation according to baseline thiamine as there is currently no point-of-care test to measure thiamine levels at this time. We will use the same analytic approaches in the deficient group as were performed for the entire cohort.
By diabetes type: we will perform a preplanned subanalysis of the primary outcome of bicarbonate levels in subgroups of patients defined by diabetes type 1 or type 2. We will also perform a secondary analysis adding an interaction term for diabetes type into the primary analysis to assess whether there is a statistically significant difference in the relationship between treatment and outcome between the subgroups defined by diabetes type.
Missing data
If missingness for any key variable (ie, those used in the primary outcome analysis) is >5% but <15%, we will consider performing multiple imputation with chained equations.
Trial progress
This manuscript describes the SAP for the DKAT trial. The SAP is published prior to unblinding of the study and provides transparency in decisions with respect to statistical analysis. The DKAT trial has now enrolled more than 80% of its intended population with recruitment expected to continue through May 2024.
Ethics and dissemination
Study progress and safety will be monitored by an independent DSMB as described above. This study was approved by the Committee on Clinical Investigations, the IRB for the Beth Israel Deaconess Medical Center.
We plan to present the results of this at one or more major scientific conferences and to publish them in a peer-reviewed scientific journal. Patient-level data will be available to the DKAT trial investigator team and to other academic investigators on request as adjudicated by the DKAT investigator team and per resources available at the time of the requests.
Authorship of the manuscript will be granted to individuals who contribute substantially to the design, conduct, interpretation and reporting of the trial.
Supplementary Material
Footnotes
Contributors: All authors made substantial contributions to the concept and design of the manuscript. JV and SM equally contributed to the initial draft of the manuscript, after which all authors (NB, KB, AM, XL, LN, MS, LB, MWD, AG) provided important intellectual content and contributed to the revision of the manuscript. AG and LB contributed to the design of the statistical analysis plan. All authors read and approved the final manuscript.
Funding: This work was supported by the National Institution of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number (grant number R01DK112886). MWD is supported, in part, by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grant number K24HL127101). NB, MS and JV are supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grant number T32HL155020). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Competing interests: None declared.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review: Not commissioned; externally peer-reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Ethics statements
Patient consent for publication
Not applicable.
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