Baseline characteristics of participants in the LANDMARC trial: A 3‐year, pan‐india, prospective, longitudinal study to assess management and real‐world outcomes of diabetes mellitus

Abstract Introduction Longitudinal data on progression, complications, and management of type 2 diabetes mellitus (T2DM) across India are scarce. LANDMARC (CTRI/2017/05/008452), the first pan‐India, longitudinal, prospective, observational study, aims to understand the management and real‐world outcomes of T2DM over 3 years. Methods Adults (≥25 to ≤60 years old at T2DM diagnosis; diabetes duration ≥2 years at enrollment; controlled/uncontrolled on ≥2 anti‐diabetic agents) were enrolled. Baseline characteristics were analyzed using descriptive statistics. Results Of the 6279 recruited participants, 6236 were eligible for baseline assessment (56.6% [n/N = 3528/6236] men; mean ± SD age: 52.1 ± 9.2 years, diabetes duration: 8.6 ± 5.6 years). mean ± SD HbA1c, fasting plasma glucose, and postprandial glucose values were 64 ± 17 mmol/mol (8.1 ± 1.6%), 142.8 ± 50.4 mg/dl, and 205.7 ± 72.3 mg/dl, respectively. Only 25.1% (n/N = 1122/6236) participants had controlled glycemia (HbA1c < 53 mmol/mol, <7%). Macrovascular and microvascular complications were prevalent in 2.3% (n/N = 145/6236) and 14.5% (n/N = 902/6236) participants, respectively. Among those with complications, non‐fatal myocardial infarction (n/N = 74/145, 51.0%) and neuropathy (n/N = 737/902, 81.7%) were the most reported macrovascular and microvascular complication, respectively. Hypertension (n/N = 2566/3281, 78.2%) and dyslipidemia (n/N = 1635/3281, 49.8%) were the most reported cardiovascular risks. Majority (74.5%; n/N = 4643/6236) were taking oral anti‐diabetic drugs (OADs) only, while 24.4% (n/N = 1522/6236) participants were taking OADs+insulin. Biguanides (n/N = 5796/6236, 92.9%) and sulfonylureas (n/N = 4757/6236, 76.3%) were the most reported OADs. Basal (n/N = 837/6236, 13.4%) and premix (n/N = 684/6236, 11.0%) insulins were the most reported insulins. Conclusions Baseline data from LANDMARC help understand the clinical/medical profile of study participants and underscore the extent of suboptimal glycemic control and prevalence of associated complications in a vast majority of Indians with T2DM.


| INTRODUC TI ON
A sharp increase in type 2 diabetes mellitus (T2DM) cases is predicted globally in the years to come. In 2019, an estimated 463 million adults worldwide (aged 20-79 years) had diabetes; this number is expected to increase to 700 million by 2045. 1 In Southeast Asia, in 2019, there were ~87.6 million adults (aged 20-79 years) with diabetes, imparting a regional prevalence of 8.8%. This number is projected to increase to 153 million by 2045. 2,3 India, in 2019, had over 77 million cases of diabetes, which was the second highest in the world after China (116.4 million cases). 4 Diabetes, a complex long-standing disease, demands unending medical care and self-management knowledge to avert or reduce acute and chronic complications. 5 However, several issues related to sociocultural beliefs, people's attitude, physician barriers, treatment inertia, access to an adequate healthcare system, and financial constraints hinder optimal management of diabetes. 6  participants (those with diabetes: 19,453 participants) aged 15-49 years from all states and territories of India. 7 Consequentially, there is marked diabetes-related morbidity and mortality. In 2019, Southeast Asia had ~1.2 million diabetes-related deaths, and ~1 million of these diabetes-related deaths were in India (age group:

20-79 years). 3,8
Real-world data on the current continuum of diabetes care can provide valuable insights required for designing efficient management strategies and assessing healthcare system performance in India. Although the incidence and prevalence of diabetes has and is being studied judiciously through cross-sectional studies, [9][10][11][12][13] longitudinal data on understanding the development of diabetic complications over a period of time and their regional occurrences and outcomes are scarce or non-existent in India.
The LongitudinAl Nationwide stuDy on Management And Realworld outComes of diabetes (LANDMARC) is being conducted to investigate the incidence of macrovascular and microvascular complications, assess glycemic control, and evaluate treatment adaptation over a period of 3 years in participants with T2DM across India.
The aim of the present analysis was to describe the baseline data of participants enrolled in the LANDMARC study.

| PARTICIPANTS AND ME THODOLOGY
The details of the design and methodology of the LANDMARC study have been published earlier 14 and are briefly summarized in following sections.

| Study design and participants
LANDMARC is the first national, multicenter, longitudinal, prospective, observational real-world study to investigate a large cohort of people with T2DM across India over a period of 3 years. Adults ≥25 years and ≤60 years of age at the time of diagnosis, having T2DM for a duration of ≥2 years and controlled/uncontrolled on ≥2 anti-diabetic agents, were recruited. People with known type 1 diabetes mellitus and secondary diabetes (e.g., gestational diabetes and fibrocalculus pancreatic diabetes) having limited life expectancy due to terminal diseases, (n/N = 4757/6236, 76.3%) were the most reported OADs. Basal (n/N = 837/6236, 13.4%) and premix (n/N = 684/6236, 11.0%) insulins were the most reported insulins.
Conclusions: Baseline data from LANDMARC help understand the clinical/medical profile of study participants and underscore the extent of suboptimal glycemic control and prevalence of associated complications in a vast majority of Indians with T2DM.

K E Y W O R D S
baseline characteristics, diabetes, diabetes management, diabetic complications, India

What's new
• People with long-standing diabetes are at an increased risk of diabetes complications and cardiovascular events.
In India, progression of diabetes and its complications over a long time has not been studied extensively.

• The LongitudinAl Nationwide stuDy on Management
And Real-world outComes of diabetes (LANDMARC) study has recruited 6279 people with type 2 diabetes across India and will prospectively gather data on disease control, treatment, concomitant complications and risks in these participants over 3 years.
• LANDMARC baseline data represent the real-world snapshot of a type 2 diabetic profile and underscore poor glycemic control and a considerable burden of complications prevalent in India.

Previous presentation
Part of the data in this article was presented at 79th and those on an investigational drug or those who had participated in a clinical trial in the previous 3 months, were excluded.
The study was approved by the Ethics Committee of the participating sites. The protocol complies with the Declaration of Helsinki, the principles laid by the 18th World Medical Assembly (Helsinki, 1964) and all subsequent amendments. The study is also aligned with the guidelines for Good Epidemiology Practice (US & European) and the local regulations, ethics committees (institutional review board/independent ethics committee), and applicable authorities.
All participants provided signed informed consent before study participation and data collection/ documentation.

| Selection of investigators
Investigators (general practitioners, endocrinologists, and diabetologists) willing to participate in the study were selected based on requisite qualification and availability of resources to conduct this study. Approximately 450 sites were planned to represent India across regions (East, West, North, and South), urban/semi-urban practices, clinic/hospital bases, and government/corporate hospitals/nursing homes.
Data are being collected in electronic-case report forms (e-CRF).
The data collected at baseline visit include the following: informed consent, eligibility criteria check, demographic characteristics, anthropometry, diabetes medical history, information related to known diabetes complications (myocardial infarction, stroke, peripheral vascular disease, neuropathy, nephropathy, retinopathy, acute coronary syndrome, heart failure, and unstable angina), and known cardiovascular (CV) risks (hypertension, dyslipidemia, and albuminuria).

| Statistical analysis
Categorical data are presented as counts and percentages. Number of observations available (n), mean ± standard deviation (SD), median, and minimum and maximum values have been reported, when appropriate. The statistical test was conducted at a 5% significance level.
The minimum sample size required for this study was 4387 with a 2sided 99% confidence interval, assuming that the percentage of participants with composite incidence of non-fatal myocardial infarction, stroke, and CV death after 3 years would be 3%. It was calculated that the inclusion of approximately 6300 participants will allow estimating this percentage with a precision of at least 1%, after considering that ~30% of the participants will drop out from the study before the end of the 3 years. The eligible population includes all participants who met the inclusion/exclusion criteria for the study.

| RE SULTS
The LANDMARC study included 382 sites across India (num-
Abbreviations: HbA1c, glycated hemoglobin; N, number of participants analyzed; n, number of participants with non-missing results at the visit; SD, standard deviation; T2DM, type 2 diabetes mellitus.
Macrovascular complications were present in 6.3% (n/N = 57/902) participants having microvascular complications and in 3.8% (n/N = 126/3281) participants having CV risk factors (Table S9 and S10   (Table S3). The prevalence of CV risks was the lowest in North India (n/N = 687/1686, 40.7%; Table S3). Proportions of participants with CV risks were almost similar across all HbA1c categories. (Table 2) Table S12). The proportion of participants with CV risks increased consistently with increase in age and was the highest in older participants (age ≥ 66 years: n/N = 297/429, 69.2%; Table S8).

| DISCUSS ION
This pan-India, real-world, longitudinal study aims to assess glycemic control and development of macro-and microvascular complications for a period of 3 years and explore the treatment adaptation trends in a vast sample of adults with T2DM. This article presents the demographics and clinical/medical profile of study participants at the study entry.
At baseline, only 25.1% of the study population had optimal glycemic control (HbA1c < 53 mmol/mol; <7%). This result is similar to 26.0% of participants from India had HbA1c < 53 mmol/mol or <7%) 16 and wave-7 (2016, 25.2% of participants had HbA1c 53 mmol/mol or <7%). 17 This result is also similar to that of a report from North Kerala (28.3%, HbA1c < 53 mmol/mol or <7%) 18 and to that of a recent national diabetes registry program conducted across 200 diabetes clinics/centers in India (23.4%). 19 Further, the 1st phase of the multicentric Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study conducted in 480 participants with selfdeclared diabetes reports a slightly higher (31.0%) proportion of participants with glycemic control. 20 These studies cumulatively indicate substantial and persistent prevalence of suboptimal glycemic control for over a decade in India.
In this study, duration of diabetes, intensification of treatment, and prevalence of diabetes-related complications seemed to be linearly related. Participants with shorter duration of diabetes were mainly on only OADs, whereas those with long-standing diabetes were on combination therapies (mainly OADs and insulin). This is consistent with the results of the TIGHT study. 15 In real-world settings, the guarded step-wise approach followed to manage diabetes results in a substantial burden of the uncontrolled disease.

| CON CLUS IONS
Analysis of baseline data from LANDMARC helps understand the clinical/medical profile of study participants and underscores the extent to which suboptimal glycemic control and associated complications are prevalent in India. There is therefore a felt need for diabetes awareness and education, supported by community-based healthcare interventions for early diagnosis as well as assessment and treatment of diabetes, its complications, and associated comorbidities. This is the entry-stage data from the LANDMARC study, and further longitudinal information will add to our understanding on the management and real-world outcomes of T2DM in India.

AUTH O R CO NTR I B UTI O N S
AKD, SKM, and CT were involved in the study concept and design.
DC was involved in study concept and design, data analyses, and drafting the study report. All the authors participated in the interpretation of data and the writing, reviewing, and editing of the manuscript and had final responsibility for approving the published version of the manuscript. AKD is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

DATA AVA I L A B I L I T Y S TAT E M E N T
Qualified researchers may request access to person-level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Person-level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at https://www.clini calst udyda tareq uest.com.

S U PP O RTI N G I N FO R M ATI O N
Additional supporting information may be found online in the Supporting Information section.