The LongitudinAl Nationwide stuDy on Management And Real‐world outComes of diabetes in India over 3 years (LANDMARC trial)

Abstract Introduction LANDMARC (CTRI/2017/05/008452), a prospective, observational real‐world study, evaluated the occurrence of diabetes complications, glycemic control and treatment patterns in people with type 2 diabetes mellitus (T2DM) from pan‐India regions over a period of 3 years. Methods Participants with T2DM (≥25 to ≤60 years old at diagnosis, diabetes duration ≥2 years at the time of enrollment, with/without glycemic control and on ≥2 antidiabetic therapies) were included. The proportion of participants with macrovascular and microvascular complications, glycemic control and time to treatment adaptation over 36 months were assessed. Results Of the 6234 participants enrolled, 5273 completed 3 years follow‐up. At the end of 3‐years, 205 (3.3%) and 1121 (18.0%) participants reported macrovascular and microvascular complications, respectively. Nonfatal myocardial infarction (40.0%) and neuropathy (82.0%) were the most common complications. At baseline and 3‐years, 25.1% (1119/4466) and 36.6% (1356/3700) of participants had HbA1c <7%, respectively. At 3‐years, population with macrovascular and microvascular complications had higher proportion of participants with uncontrolled glycemia (78.2% [79/101] and 70.3% [463/659], respectively) than those without complications (61.6% [1839/2985]). Over 3‐years, majority (67.7%–73.9%) of the participants were taking only OADs (biguanides [92.2%], sulfonylureas [77.2%] and DPP‐IV inhibitors [62.4%]). Addition of insulin was preferred in participants who were only on OADs at baseline, and insulin use gradually increased from 25.5% to 36.7% at the end of 3 years. Conclusion These 3‐year trends highlight the burden of uncontrolled glycemia and cumulative diabetes‐related complications, emphasizing the importance of optimizing diabetes management in India.


| INTRODUC TI ON
The constantly rising burden of type 2 diabetes mellitus (T2DM) in India has had a catastrophic impact on the healthcare system primarily due to the development of diabetes-associated complications and subsequent morbidity and mortality. The chronic nature of the disease course is the key attributable factor for the rising incidence of diabetes-related complications in this patient population. 1 Diagnosis of diabetes at an early stage of the disease course is low in India, and more than 50% of diabetes cases are undiagnosed across the countries from South-East Asia region. 2 Furthermore, poor glycemic control and subsequent development of complications emphasize the need for optimal diabetes management strategies in India. [3][4][5] For comprehensive understanding of the Indian scenario, there is a need for real-world evidence in terms of longitudinal data regarding the glycemic control achieved, the occurrence of diabetes-related complications during disease progression, and treatment strategies implemented in the Indian diabetic population. The LongitudinAl Nationwide stuDy on Management And Real-world outComes of diabetes in India (LANDMARC) initiated in 2017 was a novel national, prospective, observational real-world study carried out in people with T2DM from pan-India regions to determine the occurrence of diabetes complications, glycemic control and treatment patterns in the routine clinical practice over a period of 3 years. Trends observed in the interim analysis of baseline, 1-year and 2-year data have previously been published, [6][7][8][9][10][11][12] and this article will explore comprehensive trends observed over a 3-year period.

| ME THODS
Details of the design and methodology of the LANDMARC study were published earlier 13 and are briefly summarized here.

| Studydesignandethics
The LANDMARC study (Trial Registration No (CTRI/2017/05/ 008452) was a prospective, multicenter, observational real-world study investigating a large cohort of people with T2DM across pan-India sites over a period of 3 years (April 2017-July 2021).
The trial protocol was approved by the relevant Ethics Committee or institutional review board at the study sites. The protocol complies with the Declaration of Helsinki and all subsequent amendments. All participants provided signed informed consent before study participation.

| Studyparticipants
This study included participants of either sex, aged 25-60 years at the time of diagnosis of T2DM, with T2DM for at least 2 years at the time of enrolment, with or without glycemic control and on two or more antihyperglycemic therapies. Other details of inclusion and exclusion criteria were summarized in our previous publications. 13

| Datacollection
Information related to study end-points was collected prospectively every six months up to the end of the study at 36 months. The study design was planned to mirror the real-life management of participants with T2DM; therefore, no assessments were mandated, and the available data were recorded in electronic case report forms (eCRFs). Data quality control was performed by qualified designated personnel. Any adverse drug reaction related to any Sanofi product (clinical signs, laboratory values or other) was reported and followed up until the clinical recovery was complete and laboratory results (if clinically significant) had returned to normal or until progression had been stabilized.

| Studyend-points
Study end-points assessed were subdivided into three subsections: complications, glycemic control and management.

Funding information Sanofi
Addition of insulin was preferred in participants who were only on OADs at baseline, and insulin use gradually increased from 25.5% to 36.7% at the end of 3 years. • proportion of participants controlled (HbA1c <7%)/uncontrolled (HbA1c ≥ 7%) at 12, 24 and 36 months, and the occurrence of microvascular and macrovascular complications in these two groups at the end of 36 months; • comparison of change in glycemic assessments at 36 months between participants with and without complications at baseline; • comparison of the glycemic control and outcomes at 36 months in participants with and without complications at baseline.
C Management end-points were to assess time to treatment adaptation from baseline to 12, 24 and 36 months (any dose change/ addition/deletion/drug intensification/titration for OADs, insulin or other injectable antidiabetic agents).

| Samplesizecalculation
The minimum sample size required for this study was 4387 with a two-sided 99% confidence interval, assuming that the percentage of participants with the composite incidence of nonfatal MI, stroke and cardiovascular death after 3 years would be 3%. Hence, the inclusion of approximately 6300 participants would allow estimating this percentage with a precision of at least 1%, after considering that approximately 30% of the participants will drop out from the study before the end of the third year. 13

| Statisticalanalysis
Data analyses were done using SAS version 9.4 or higher. The normality of data was assessed using Kolmogorov-Smirnov test. A descriptive analysis was used to present categorical data as numbers and percentages and numerical data as mean and standard deviation (for normally distributed data sets) or median and range (for skewed data sets). Comparative analysis between two groups was performed using an independent sample t-test (continuous variables).
McNemar's test was used for comparative analysis between paired sample data. A p-value <.05 was considered statistically significant.

| Demographicsandbaselinecharacteristics
Of the 6279 participants recruited, 6234 fulfilled eligibility criteria and enrolled in the study. A total of 12 participants of this eligible population who had critical protocol deviation were excluded from the evaluable population (N = 6222). Overall, 5273 participants completed 3 years in this study, and 961 participants discontinued the study ( Figure 1); the reasons for discontinuation are summarized in Table S1. The key reasons for discontinuation were participants lost to follow-up (41.0%), site withdrawal from the study (17.6%) and withdrawal due to the pandemic (14.5%).
There were a total of 53 deaths (5.5%), out of which 37 (3.9%) were cardiovascular deaths, and the remaining 16 deaths were due to unknown causes. Details of demographics and baseline characteristics are presented in Table S2. At baseline, the mean (SD) age of the participants was 52.1 (9.2) years with more than half (57.0%) of the population belonging to the age group 50-65 years and more than half of the participants being men (56.6%). The mean (SD) BMI was 27.2 (4.6) kg/m 2 , and majority of participants were obese (66.8%). At baseline, the median (range) duration of diabetes was 7.1 (4.3-11.1) years, and one-third of participants were insulin naïve (75.2%).  Table 1). Among 37 cardiovascular deaths, the majority were sudden deaths (n = 24), followed by fatal MI (n = 10), coronary artery procedure (n = 2) and stroke (n = 1).

| Complications
3.2.2 | Composite of nonfatal MI/nonfatal stroke/ hospitalization for unstable angina/cardiovascular death over 36 months The population showed an increasing trend over the visits in the incidence of these complications, from 1.6% at baseline, to 1.9% at 12-months, to 2.2% at 24-months. The cumulative incidence at the end of 36 months was 2.3% ( Table 2).

| Participants with other
cardiovascular events (hospitalization due to ACS, urgent revascularization procedures, HF or unstable angina) at the end of 6-, 12-, 24-and 36-months A total of five (0.08%) participants required urgent revascularization procedures during the study period (one participant at the end of 12-months and four participants by the end of 24-months). During the study period, eight (0.1%) participants required hospitalization for cardiovascular events (eight events); five of these participants were hospitalized for ACS (one, three and one at 6, 24 and 36 months, respectively), two for unstable angina (at 12 and 24 months) and one for HF (at 24 months) ( Table S3).

| Composite renal and retinal microvascular outcome
The cumulative incidence of renal and retinal complications showed an increasing trend over the follow-up visits from 2.5% at baseline to 3.1% at 12-months follow-up, which further increased to 3.9% at 24-months follow-up and to 4.1% at the end of 36-months follow-up (  Among participants with microvascular complications at baseline, there was no significant difference in proportion of participants reaching HbA1c <7% at the end of 36 months (2.4%-2.2%) ( Figure 3C) while among participants without microvascular complications at baseline, there was a significant increase in the proportion of participants reaching HbA1c <7% at the end of 36 months (from 15.6% to 19.6%; p < .0001) ( Figure 3D).

Improvement in glycemic parameters in the insulin subgroup
was significantly better compared with the insulin naïve subgroup (p < .0001) ( Table S4).

| Shift in oral and injectable antidiabetic drugs
The proportion of participants taking injectable glucose-lowering

| Change in dose of OADs categories
At 12-, 24-and 36-months visit, dose modifications such as increase/ decrease in dose, addition or discontinuation of an OAD occurred mostly in <0.5% of the participants in each drug count category.
Most of the dose modifications were done at around 6 months (Table S5).

| Change in dose of insulin categories
The mean (SD) change from baseline in total daily dose of basal in-  Note: Data shown as n (%). Percentages are based on number of study participants using at least one OAD within each subgroup in evaluable population.

F I G U R E 4
Comparison of the use of oral and injectable glucose-lowering drugs at baseline and 36-months. AGIs, alphaglucosidase inhibitors; DPP-4i, dipeptidyl peptidase-4 inhibitors; GLP-1A, glucagonlike peptide 1 analogue; SGLT2i, sodiumglucose cotransporter 2 inhibitors.  At the end of 3-years, there was an increase in the cumulative incidence of composite renal and retinal microvascular outcomes The gradual trend of improvement in the glycemic control observed over 3 years in the present real-world study is around 36% and is similar to that reported in the previous literature from India, wherein the proportion of people achieving glycemic control ranges between 23.4% and 31.0%. 1,26 This comprehensively portrays the current real-life burden of uncontrolled diabetes among the Indian population. Reports from a real-world study from India (the TIGHT study) are in accordance with this observation, wherein a high burden (76.6%) of poor glycemic control was recorded. 3,4,26,27 According to global as well as national guidelines, achieving and maintaining optimal glycemic targets over a long duration is the fundamental goal of the management of diabetes. 23,28 In addition, a patient-centric approach is also important, wherein all the metabolic factors are considered while the treatment decision is being taken.
These include cardiovascular risks, weight management, improvements in quality of life, patient preference and treatment affordability. 23 The present study findings also highlight the therapy patterns among participants with T2DM across Indian healthcare settings.
Almost all participants were on OADs with biguanides, sulfonylureas and DPP-IV inhibitors being the most commonly used OADs. There and DPP-4 inhibitors were commonly prescribed for people with a disease duration of more than 5 years. 29 In addition, the therapy trend observed in another cross-sectional study from India was in concordance with the LANDMARC study. 30 The key strength of this study is the longitudinal design, the pan-

ACK N O WLE D G E M ENTS
The authors would like to thank the study investigators and study participants as well as their families/caregivers who were involved in this study. Medical writing support was provided by Tejal Vedak of Sqarona Medical Communications LLP, Mumbai and paid by Sanofi.
Editorial support was also provided by Anahita Gouri and Vaibhav Ltd and Tech Observer Pvt. Ltd for site management and coordination support, and Zifo R&D Solutions for data management services.

FU N D I N GI N FO R M ATI O N
This study was funded by Sanofi.

DATA AVA I L A B I L I T Y S TAT E M E N T
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