Lifestyle modification program, LIFE is LIGHT, in patients with type 2 diabetes mellitus and obesity: Results from a 48‐week, multicenter, non‐randomized, parallel‐group, open‐label study

Abstract Background Obesity is a potential risk factor for development of type 2 diabetes mellitus (T2DM). To achieve long‐term weight reduction in patients with T2DM and obesity using comprehensive lifestyle management program (LMP). Materials and methods This 48‐week interventional, multicenter, parallel‐group, open‐label study included patients aged ≥18 years with T2DM and a body mass index (BMI) of 27–40 kg/m2. The primary objective was to demonstrate a clinically significant weight reduction (≥5%) from baseline in intensive lifestyle modification (ILM) and standard treatment (ST) groups. Results The ILM group (N = 100) received recommendations for dietary and physical activity, and behavioral counseling. The ST group (N = 30) was managed in accordance with routine T2DM clinical practice. The patients in ST group were older (60.6 ± 8.9 vs. 54.6 ± 10.2 years in ILM group); overall more than 60% were women. At Week 48, the mean reduction in body weight was 5.8% (95% confidence interval [CI]: −6.9, −4.6) and 1.2% (95% CI: −2.6, 0.2) (p < 0.001) in the ILM and ST group, respectively. At Week 48, a weight loss of ≥5% was achieved by 50% of patients in the ILM group versus 13.3% in the ST group (p = 0.002). The decreases in BMI, waist‐to‐hip ratio and glycated hemoglobin (HbA1c) was significantly greater in the ILM versus ST group with between‐group differences of −1.63 (p ≤ 0.001), −0.03 (р ≤ 0.001) and −0.69% (p = 0.002), respectively. Conclusion A clinically significant weight reduction (≥5%) was demonstrated in patients with obesity and T2DM with use of a comprehensive LMP, along with improvements in BMI, waist‐to‐hip ratio, and HbA1c.


| INTRODUCTION
Obesity and type 2 diabetes mellitus (T2DM), the two major lifestyle disorders have a profound impact on healthcare expenditure globally due to their increasing prevalence. Obesity increases the risk of developing T2DM by 80%-85% 1 ; and by 2025 around 300 million people will be affected by obesity-related diabetes. 2 In Russia, findings from the NATION study demonstrated increased T2DM prevalence with increasing body mass index (BMI) and obesity; in the group with a BMI less than 25 kg/m 2 the prevalence of T2DM was 1.1%, which increased markedly to 12.0% in persons with obesity. 3 The prevention and treatment of obesity includes several strategies such as lifestyle management (diet and physical activity), behavioral and psychological therapies, pharmaceutical interventions and bariatric surgery. 4 Furthermore, guidelines recommend such strategies as part of diabetes self-management education and support. Bariatric surgery has also been recommended for adults with T2DM with a BMI ≥ 40.0 kg/m 2 (BMI ≥ 37.5 kg/m 2 in people of Asian ancestry). 5 Studies have demonstrated that a significantly meaningful weight loss of 5% can result in the reduction of diabetes-related complications, thereby improving cardiovascular (CV) outcomes. [6][7][8] Intensive lifestyle interventions that focus on weight management in patients with T2DM have resulted in weight loss as well as improved glycemic control and reduced risk of CV disease, as evidenced in the Action for Health in Diabetes (Look AHEAD) trial (follow-up of 13.5 years). 6,7 Furthermore, findings from the Diabetes Remission Clinical Trial (DiRECT) study revealed that intensive weight management for 12 months within a primary care setting resulted in remission of diabetes and discontinuation of antidiabetic drugs in almost 50% of participants. 8 Despite the knowledge on the benefits of weight loss for managing T2DM effectively, implementing and maintaining lifestyle management interventions can be a challenge for patients due to various reasons including a lack of proactive discussions between healthcare providers and patients. 9,10 This leads to unwillingness of the patients to change their habits and lifestyle, especially when they do not feel sick, or they lack the tools to assist with a longterm change of obesity-related parameters. 11,12 On the other hand, the use of sulphonylureas and insulin for the treatment of T2DM can result in weight gain, which is a big challenge in individuals with obesity and may result in delaying treatment intensification, leading to clinical inertia. This emphasizes the need for individualization and intensive lifestyle intervention in patients with T2DM and obesity. 13 Over the past few decades, experience with various lifestyle modification programs in patients with T2DM and obesity across different countries such as the Diabetes Prevention Program (DPP), Look AHEAD and Practice-based Opportunities for Weight Reduction (POWER) (USA); Malmö (Sweden); Da Qing (China); Diabetes Prevention Study (Finland and India) and a study in the Japanese population has been promising. [14][15][16][17][18][19][20][21] Although the findings from these programs were important, most of them were controlled studies. On the other hand, the 12-week multidisciplinary program, Weight Achievement and Intensive Treatment (Why WAIT) was developed for use in routine clinical practice by the Joslin Diabetes Center (Boston, MA, USA) in patients with diabetes and obesity. It was a structured lifestyle intervention program, which included intensive and interactive medication adjustments, a structured modified dietary regimen, graded-balanced and individualized exercise intervention, cognitive behavioral support and group education. The program demonstrated a marked weight loss, leading to a reduction in glycated hemoglobin (HbA1c) and blood pressure (BP) in patients with T2DM. [22][23][24] However, in Russia, there is a lack of evidence supporting the benefits of such lifestyle interventional programs.
The current study LIFE is LIGHT is a 48-week multidisciplinary program, taking inspiration from the Why WAIT. The aim of the study was to achieve long-term weight loss in patients with T2DM and obesity using a comprehensive and holistic lifestyle change approach, thereby improving glycemic control and lipid metabolism and reducing BP levels alongside decreasing the hospitalization rate. The study included a unique program of weight management, specifically designed for patients with T2DM, with five components: planned diet modification, balanced and personalized physical exercises, short-term behavioral counseling, medical assistance, and group education. The program of active weight loss included group sessions with a team consisting of a nutritional specialist, physical therapist, clinical psychologist, and endocrinologist.

| Planned diet modification
Patients with T2DM (overweight/obese and not receiving insulin) were on a moderately hypocaloric diet with a caloric deficit of GALSTYAN ET AL.
-369 500-1000 calories per day, but not less than 1500 kcal/day (men) and 1200 kcal/day (women). Patients were recommended to exclude or limit the consumption of animal fats and carbohydrates with high a glycemic index as much as possible, consume proteins and starches in an amount that was half of their usual intake and include foods rich in mono-and polyunsaturated fatty acids in their diet. Healthy carbohydrates included vegetables, wholegrain products, low-fat dairy products and fruits. Food substitutes were not used in the study.

| Balanced and personalized physical exercises
Patients were also recommended to increase their aerobic physical activity (walking, сycling, swimming, and skiing) to 40-60 min/day.

| Short-term behavioral counseling
The components of the behavioral counseling were goal setting, selfmonitoring, control of stimulus, attributive style modification, stress management, and relapse prevention.

| Medical assistance
The endocrinologist assessed the adherence of patients to this diet plan and physical activity by using a self-monitoring diary that the patients filled out daily for 48 weeks.

| Group education
Education classes were conducted weekly in the first 12 weeks and were followed up with monitoring once every 4 weeks for the next 36 weeks, with a total observation period of 48 weeks. Education was compliant with the principles provided in the "Standards of Specialized Diabetes Care in the Russian Federation." 25 During the first 12 weeks, the status of patients in the ILM group was monitored weekly (the allowed window for visits was ±1 day).
After the first 13 weeks, body weight and metabolic parameters were evaluated on monthly basis. The patients in the ST group were examined for all criteria at the beginning of the study by physicians at Weeks 12,24,36,and 48 in order to collect data on primary and secondary endpoints.

| Study sample
Men and women aged ≥18 years with a confirmed diagnosis of T2DM with a BMI between 27 and 40 kg/m 2 were enrolled in the study. Written informed consent from the participant was required before any assessment was performed, along with signed informed consent from an ophthalmologist and cardiologist regarding the inclusion of the patient in the study. Pregnant or nursing (lactating) women; patients with type 1 diabetes, proliferative retinopathy, hemorrhage and disinsertion of retina, or renal impairment (serum creatinine > 1.5 mg/dL, creatinine clearance < 40 ml/min and/or proteinuria) and people with chronic alcoholism or acute alcoholic intoxication were not included into the study. Alcoholism was assessed by the investigator inquiring patients about daily amount of alcohol intake, as well as by using the medical history of the patient. Inability to perform the physical exercises due to orthopedic or CV disorders was a specific exclusion criterion for the ILM group.

| Study objectives
The primary objective of the study was to demonstrate that an intensive lifestyle change program for patients with T2DM and obesity could lead to clinically significant weight reduction (≥5%); Other secondary objectives included the investigation of anthropometric parameters (waist circumference, waist-to-hip ratio, and BMI) in both the ILM and ST groups.

| Study assessments
The metabolic and functional status of the participants was evaluated by estimation of parameters such as BMI and body weight, waist the Novartis Hypoglycemia Perspectives Questionnaire and the assessment of the perceived exertion rate with the Borg Scale. 26 The questionnaire included seven aspects of QoL: concern of symptoms related to blood glucose reduction, emotional response to the event, behavior to prevent hypoglycemia, assessment of likelihood of hypoglycemia in the future, anxiety regarding hypoglycemia, anxiety related to control of hypoglycemia, and self-diagnosis of hypoglycemia for symptoms.

| Sample size
Sample size was calculated based on observed weight changes in the "Why WAIT" program. The average weight loss observed at the end of 1 year was 8%. Given that the baseline criteria and translation of the program could be different when executing it in Russia, an achievable change in weight of 5% was assumed. A sample size (with a possible dropout of 20%) of 100 patients in the ILM group and 30 patients in the ST group was required to provide 80% power to detect a significant difference (significance level, α = 0.05) between values in the two groups.

| Statistical analysis
The patients' disposition, demographic data, study parameters and their changes were summarized using descriptive statistics. The Activities. The analysis of the primary endpoint-decrease in body weight of ≥5% at 48 weeks was performed using multivariate logistic regression by calculating the odds ratio (OR) with the corresponding 95% confidence interval (CI). Confounding factors such as age, gender, baseline BMI, disease duration, and the baseline HbA1c were taken into account in the regression model.
The efficacy parameters at all planned time points were compared between groups using the generalized estimating equations method taking into account the correlation between the repeated measurements.

| Ethical considerations
The study was conducted in accordance with Good Clinical Practice and the ethical principles of the Declaration of Helsinki. An independent Ethics Committee or Institutional Review Board approved all study protocols and amendments. Informed consent forms were designed in the Russian language and were signed before including patients in the study.

| Enrollment and retention
Of the 130 patients enrolled in the study, 100 were included in the ILM group while the remaining 30 were included in the ST group. In the ILM group, 90 (90%) patients completed the study while 29 (96.7%) in the ST group completed the study in accordance with the protocol (Figure 1).

| Baseline demographics and patient characteristics
Patient demographics and baseline characteristics are presented in Table 1. The proportion of women across the ILM (69.0%) and the ST (63.3%) groups were higher than the proportions of men. The mean ± SD age of patients in the ILM group was 54.6 ± 10.2 years whereas patients in the ST group were slightly older with a mean ± SD age of 60.6 ± 8.9 years. The majority of patients were

| Primary efficacy parameters
Compared with baseline, patients in the ILM group lost 5.8% (95% CI:   (Figure 4). 27 The percentage changes in body weight from baseline to Week 12,24,36, and 48 and the corresponding between group comparisons are presented in Table 2.

| HbA1c and FBG
The mean change in HbA1c from baseline at the end of 48 weeks was significantly greater in the ILM group than in the ST group. The difference in the mean ± SE changes in HbA1c values between the groups was −0.69 ± 0.22% (95% CI: −1.12, −0.25; p = 0.002) ( Table 2). The reduction in the levels of HbA1c is depicted in Figure 5. 27 No statistically significant difference in the FBG level was observed between the groups during the study.

| Glucose-lowering drugs
Even though "LIFE is LIGHT" is an interventional program, the use of drug therapy was in accordance with routine clinical practice and for the indications listed in drug labels. All the drug prescriptions were at the discretion of the physician and not subjected to the protocol related interventions of the program. However, it is worth mentioning that comprehensive lifestyle modifications, behavioral counseling, and educational support could contribute to the structure T A B L E 2 Changes in the secondary efficacy parameters from baseline to Weeks 12,24,36, and 48 of the study period of medications used among patients in the intensive (ILM) group before and after the program ( Figure 6). Thus, patients who met the primary endpoint of the study were less likely to use drugs associated with weight gain (decrease by one-third in use). The difference was due to both an increase (from 4% to 10%) in the use of weight loss promoting therapy and the reduced need for antidiabetes drugs (doubling from 4% to 8% of subjects with no glucose-lowering therapy). In addition, the structure of oral antidiabetes drugs was similar in the ILM and ST groups because drugs were prescribed according to current treatment guidelines.

| BP and lipid profile
The SBP decreased, by a mean ± SE by 7.4 ± 1.56 mmHg (95% CI: Patients in the ST group did not report hypoglycemic events within a year prior to the study or during the study. In the ILM group, one patient was hospitalized due to a decrease in the blood glucose level; one patient required emergency medical help twice; three patients needed help from another person several times; and one patient lost consciousness twice.  (HbA1c < 6.5%) and can lead to discontinuation of antihyperglycemic drugs. 8 The improvements in glycemia induced by weight loss are most likely to be seen early in the natural progression of T2DM when insulin resistance due to obesity has caused reversible β-cell dysfunction but insulin secretory capacity remains relatively preserved. 30,31 Although fewer patients experienced hypoglycemia at the end of the study period, the hypoglycemic conditions were evident during the program. Considering this, it is recommended to make substantial efforts while designing lifestyle intervention programs to prevent hypoglycemic events and choose antidiabetes drugs, which do not induce hypoglycemia.

| DISCUSSION
The components of the intensive lifestyle intervention program in the current study contributed to good QoL in the study participants, as evaluated by the results of hypoglycemia questionnaire and Borg Scale. As compared to baseline, there was a decrease in the proportion of patients experiencing hypoglycemia at the end of the study period. In addition, the mean values of the assessment of physical activity among patients in the ILM group were approximately the same after the first training and at the end of the program.
These findings reflect that self-managed behaviors, relationships between patients and providers, and education programs to motivate lifestyle changes help to improve QoL in patients with T2DM. 32 The components of ILM such as balanced diet, physical activity, medical assistance, behavioral counseling, and group education have demonstrated an overall improvement in metabolic parameters such as HbA1c, BP, sustained reduction in body weight with minimal hypoglycemic events as well as good QoL in the study participants.

GALSTYAN ET AL.
Obesity is an established risk factor for several noncommunicable diseases such as CV disease, T2DM, hypertension and coronary heart disease, and even certain cancers. 33 It is the basis for the development of insulin resistance and results in carbohydrate metabolism compensation, which is associated with CV risk factors. 13 Thus, T2DM treatment should focus on early lifestyle intervention alongside pharmacotherapy in order to reduce the risk of diabetes-related complications. Targeting body weight is a reliable way to contribute to optimal HbA1c levels, and is a viable and cost-effective measure for the optimal management of T2DM in routine clinical practice.
There were a few limitations to this study. One of such limitations is the lack of randomization that may induce selection bias. Another limitation was the relatively small sample size of the study population and may lead to higher variability in the observed mean values and bias.
In conclusion, the study demonstrated a clinically significant weight loss of ≥5% in patients with T2DM and obesity along with a positive impact on BMI, waist-to-hip ratio and HbA1c by the use of a proposed comprehensive LMP. The LIFE is LIGHT study highlights that a pragmatic approach of dietary modifications, physical activity, and behavioral counseling results in clinically significant weight loss and improved QoL.

ACKNOWLEDGMENTS
The study was sponsored by Novartis. Article processing charges for this study was funded by Novartis. All named authors meet the In-