Efficacy of a Diabetes Specific Nutritional Supplement (DSNS) on Glycemic Response in Prediabetic Adults: A Two-Armed, Open-Labelled Randomized Controlled Study

Abstract

It is well known that Diabetes Specific Nutritional Supplements (DSNSs) are linked to improved glycemic control in individuals with diabetes. However, data on efficacy of DSNSs in prediabetics is limited. This was a two-armed, open-labelled, randomized controlled six-week study on 199 prediabetics [30 - 65 years; Glycosylated Hemoglobin (HbA1c) 5.7% - 6.4% and/or Fasting Blood Glucose (FBG) 100-125 mg/dl]. Two parallel phases were conducted: Acute Blood Glucose Response (ABGR) and Intervention phase. Prediabetic participants were randomized into test (n = 100) and control (n = 99). The primary objective was to assess the ABGR of DSNS versus an isocaloric snack, measured by incremental Area under the Curve (iAUC). Test and control received 60 g of DSNS and 56 g of isocaloric snack (cornflakes) respectively, both in 250 ml double-toned milk on visit days 1, 15, 29 and 43. Postprandial Blood Glucose (PPG) was estimated at 30, 60, 90, 120, 150 and 180 minutes. During the 4 weeks intervention phase, the test group received DSNS with lifestyle counselling (DSNS + LC) and was compared with the control receiving lifestyle counselling alone (LC alone). Impact was studied on FBG, HbA1C, anthropometry, body composition, blood pressure, nutrient intake, and physical activity. The impact of DSNS was also studied using CGM between two 14-day phases: CGM1 baseline (days 1 - 14) and CGM2 endline (days 28 - 42). DSNS showed significantly lower PPG versus isocaloric snack at 30 (p < 0.0001), 60 (p < 0.0001), 90 (p < 0.0001), 120 (p < 0.05) and 150 (p < 0.05) minutes on all visit days. iAUC for 0 - 180 minutes was significantly lower (p < 0.0001) for DSNS as compared to control for all visit days. Post 4-week intervention, both DSNS + LC and LC alone reported significant reductions in FBG, BMI, waist circumference, and BP versus baseline. DSNS + LC reported a significant reduction in weight from baseline. Significantly higher intakes of protein, calcium, iron, vitamin B₁₂, and chromium were reported by DSNS + LC versus LC alone. No other significant changes were reported between groups. It may be concluded that DSNS may be considered as a snack for prediabetic or hyperglycemic individuals requiring nutritional support for improved glycemic control.

Keywords

Diabetes Specific Nutritional Supplement, Prediabetes, Acute Blood Glucose Response, Incremental Area under Curve, Lifestyle Counselling

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1. Introduction

Prediabetes is characterized as an intermediary stage with glycemic parameters above normal but below the diabetes threshold [1]-[4]. According to the American Diabetes Association, prediabetes is diagnosed with impaired glucose tolerance (2 hours after 75 g oral glucose load: 140 - 199 mg/dL)/or glycosylated hemoglobin (HbA1C: 5.7% - 6.4%) or fasting blood glucose (FBG: 100 - 125 mg/dL) [3] [5].

Globally, 10.5% of the adult population has diabetes, with another half unaware that they are living with the condition. This number is projected to rise to 643 million by 2030 [6]. The global prevalence of Impaired Fasting Glucose (IFG) in 2021 was 5.8% and is projected to rise to 6.5% in 2045 [7]. The prevalence of diabetes in India is 11.4% and prediabetes is 15.3% [8]. About 24.5% of the population is diagnosed with impaired fasting glucose with a conversion rate of 5% - 10% of developing diabetes. Besides being a precursor for Type 2 Diabetes Mellitus (T2DM), prediabetes is a strong predictor of cardiovascular disease, including hypertension and hyperlipidemia, renal disease, retinopathy, neuropathy, and all-cause mortality.

Lifestyle modifications and anti-diabetic drug treatment are general methods used for treatment of diabetes. However, lifestyle modifications including diet and physical activity form the first line of treatment for reducing the incidence of diabetes, prediabetes, and improving impaired glucose tolerance by 27% - 58%. Pharmacological treatment (mainly metformin) has also shown beneficial results in reversing hyperglycemia. Evidence has shown that lifestyle modification that includes weight loss and exercise had a larger benefit than metformin in prediabetics. Over the years, studies have shown that dietary modifications and increased physical activity slow down the progression of individuals with prediabetes. However, compliance with lifestyle modifications for a longer period of time can be a crucial problem, especially in developing countries.

Lifestyle Counselling (LC) is an integral part of Medical Nutrition Therapy (MNT) for prevention and management of diabetes and prediabetes, with goals of promoting and supporting healthy eating patterns, maintaining the pleasure of eating, improving sleep quality, and providing the individuals with the necessary support for healthy lifestyle. Indian diets are generally characterized as high in saturated fat, trans fat, and refined carbohydrates. Evidence from a recent systematic review has shown that Diabetes Specific Nutritional Supplement (DSNS) as a meal/snack replacement led to reduced glycemic and insulin excursions when compared to standard formulas and other foods. These also showed improvements in lipid profile and cardiometabolic indicators.

DSNSs are usually low in carbohydrates, high in Monounsaturated Fatty Acids (MUFA), protein, fiber, and rich in micronutrients, thus have low Glycemic Index (GI), which renders them suitable for individuals with diabetes or prediabetes, at risk of hyperglycemia. The DSNSs are mostly rich in micronutrients and could subtly shift the daily nutrient intake to the recommended levels aiding in glycemic control. The majority of the studies on prediabetics were focused on single or a limited combination of nutrients with limited data on multiple micronutrient-fortified supplements.

There is enough evidence reporting that DSNS significantly improved glycemic control, and reduced HbA1c, body weight, and waist circumference, among overweight and obese diabetic participants. Studies have shown that DSNSs reduce post-prandial elevation in diabetic subjects as measured by incremental Area under Curve (iAUC). The Area under the Curve (AUC) is the geometric mean value to quantify the total increased blood glucose after consuming any food over time. It is recognized as an important measure to understand acute blood glucose responses after consuming a food or meal in diabetic research. Evidence has shown that iAUC curve is lower for high fiber or low carbohydrate meals as compared to standard meals indicating lower blood glucose elevation, suggesting it to be used as an important measure in assessing efficacy of DSNSs. However, studies on efficacy of DSNSs on health status of prediabetic individuals are limited. The primary objective of the present study was to assess the ABGR of a DSNS versus an isocaloric snack, as measured by iAUC in prediabetic adults. Secondary objectives included studying the efficacy of DSNS + LC versus LC alone post four weeks on FBG, anthropometry, body composition, blood pressure, nutrient intake, physical activity, and continuous glucose monitoring indicators.

2. Methodology

This was a two-armed, open-labelled, randomized, controlled six-week, single-center study conducted among 199 prediabetic participants. The study was conducted according to the principles and requirements of the Declaration of Helsinki and was consistent with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidance on Good Clinical Practice (2019) and Indian Council of Medical Research ethical guidelines. The study was reviewed and approved by the Institutional Ethics Committee of the study site. All participants provided written informed consent. The study was explained in detail along with potential benefits and risks to them and their families. The study was registered at Clinical Trials Registry India with registration number CTRI/2023/02/049511. The flow chart for study design is shown in Figure 1.

Figure 1. Flow chart of study design. N = total number of participants, n = number of participants in each group. DSNS: Diabetes Specific Nutritional Supplement; LC: Lifestyle Counselling; CGM: Continuous Glucose Monitoring; iAUC: incremental Area under Curve; ITT: Intention to Treat Analysis; PP: Per Protocol.

2.1. Study Design and Participants

Prediabetic participants (n = 200), both males and females (non-pregnant/non-lactating), between 30 - 65 years of age were recruited in the study. Prediabetes was diagnosed on HbA1C ≥ 5.7% to ≤6.4% and/or fasting blood glucose between 100 - 125 mg/dl. The participants who were not receiving any anti-diabetic medication and willing to consent were recruited in the study. Participants who had BMI < 18.0 and >32.5 kg/m², or had any acute infections, eating disorders, or were taking any medication that could have profoundly affected blood glucose, were habitual substance abuse (alcohol, smoking, tobacco) consumers or had any known history of kidney or liver diseases in past 3 months were excluded at the screening.

The sample size was calculated considering an average 10% change in iAUC as outcome, 80% power and an alpha of 0.05 and with a dropout rate of 10%, making a total sample size to be 126 (n = 63 in each arm of the study). In total, 1286 participants were screened, out of which 992 did not meet the inclusion/exclusion criteria. Considering dropouts, two hundred participants were finally recruited after receiving consent for the study. They were randomized into test and control groups according to a schedule generated using SAS® statistical software (Version: 9.4; SAS Institute Inc., USA). One participant from the control group dropped out after randomization. Thus, a total of 199 participants [test (n = 100) and control (n = 99)] participated in this parallel phase study (Figure 1). The study was conducted in two parallel phases for 6 weeks: Acute Blood Glucose Response (ABGR) and Intervention phase including Continuous Glucose Monitoring (CGM). The same participants were involved in both phases (Figure 1).

2.2. Study Product

The test DSNS is a low GI nutrition supplement (Horlicks Diabetes Plus provided by Hindustan Unilever Limited). It is a dual fiber blend (Nutriose® and Fibersol®) formulation containing 22% soluble fiber and with a high MUFA composition (70% of total fatty acids delivering ~18% of energy). It delivers 13 vitamins and 7 minerals (≥15% RDA) along with the three macronutrients and fiber (refer Table S1 for nutrient Composition of DSNS). The carbohydrate delivers 40%, fiber 12%, protein 23% and fat 25% of total energy. This formula has been designed in line with the ICMR-INDIAB 2021 recommendations for Type 2 Diabetes (T2D) remission and prevention of progression to T2D in prediabetic and Normal Glucose Tolerance (NGT) individuals.

2.3. Acute Blood Glucose Response (ABGR) Phase

ABGR phase was conducted on four visit days during the study. During each visit, participants reported at the clinical site on the previous day evening and were provided with a standard dinner. It was ensured that the time of food administration was kept nearly the same for all the participants (window period ± 1 hour). Participants were to consume their meal at the latest by 10 pm and were required to stay overnight on-site to maintain fasting for nearly 10 hours. On visit days 1, 15, 29, and 43, FBG was obtained by withdrawing fingertip capillary blood through finger prick method and using validated Hemocue 201+. The FBG sample was collected prior to product administration [15 mins (±2 mins)]. Pre-weighed 60 g DSNS in 250 ml of double toned milk was provided to the test group (n = 100). Isocaloric snack of 56 g of cornflakes in 250 ml of double toned milk was provided to the control group (n = 99). The participants were instructed to consume the same within 15-minutes. Participants did not consume anything for the next 180 min (till the last 180 min. blood sample was drawn). After administration of test product/isocaloric snack, estimation of Postprandial Glucose (PPG) was performed at 30, 60, 90, 120, 150 and 180 min (±2 minutes) and it was recorded. The details of the test (DSNS) and control (isocaloric snack) products are presented in Table 1.

Table 1. Nutrient composition of DSNS and isocaloric snack.

Note: ^aAssessed on days 1, 15, 29 and 43. *In 250 mL double toned milk. **In 200 ml warm water. DSNS is a micronutrient fortified supplement rich in vitamins and minerals.

Initially, for the ABGR phase, the DSNS (60 g) was administered in water and isocaloric snack of 28 g of cornflakes in 200 ml of toned milk. During the first day (visit 2) for the first set of participants (n = 57; not included in the analysis for ABGR phase), the study team received feedback that participants felt hungry even after consuming the test and control products, likely due to the overnight fast. Also, the participants could not consume anything for the next 180 mins post the product administration. Hence, to support study compliance, smooth ethical conduct, and to improve the wholesomeness of both test and control snacks, the DSNS (60 g) was agreed to be reconstituted in 250 ml double toned milk. To match the energy delivery in control group, 56 g of cornflakes were administered in 250 ml double toned milk. This was well accepted by the following study participants.

2.4. Intervention Phase

2.4.1. DSNS + LC versus LC Alone

This phase was conducted to assess the impact of the DSNS along with lifestyle counselling (DSNS + LC) versus lifestyle counselling alone (LC alone) in prediabetic adults (Figure 2) post 4 weeks of intervention. At the baseline, data on FBG, Hb1Ac, body weight, height, BMI, body composition, blood pressure, along with demography, medical history, 24 hours dietary recall and physical activity questionnaire were collected. The actual intervention phase for DSNS + LC versus LC alone was for 4 weeks (28 days) from day 15 to day 42 with three visits in between visit 3 (day 15), visit 4 (day 29) and visit 5 (day 43, endline). The test group participants received DSNS + LC while the control group received LC alone during the intervention phase. All subjects were reassessed on the above parameters on visits days which coincided with their ABGR assessments visits.

The participants in DSNS + LC group were provided with a 14 day supply of DSNS sachets and counselled on method of reconstitution for consumption at home (Table 1) on day 15 and reconfirmed on Day 29. The participants were instructed to consume the DSNS twice a day (30 g each time with 200 ml warm water)—before breakfast and during early evening (between lunch and dinner). Shakers were provided to participants to ensure accurate dilution and compliance with consumption. The compliance was ensured by regular telephonic follow-ups and collecting empty sachets by the study staff before the next batch of sachets was handed over to the participants on day 28 (visit 4). The second batch of empty sachets was collected on day 42 (visit 5). The LC sessions were conducted twice (on days 15 and 29), for all participants during the intervention phase. The product compliance was 100% among study completers. The LC sessions focused on the importance of having a balanced diet, carbohydrate sources, reducing simple sugars and fats, increasing protein and fiber intake along with increasing intakes of fruits and vegetables. The sessions also emphasized daily walk at least for 30 minutes.

Body weight was measured to the nearest 0.1 kg using digital weighing scale (BodySCAN™ HBF 214 AP, Omron). Height was measured using a stadiometer (26SM, Biocon) to the nearest 0·1 cm. Body Mass Index (BMI) was calculated as

Figure 2. Intervention phase of the study.

weight (kg)/height (m²). Waist Circumference (WC) was measured midway between the iliac crest and the lowermost margin of the ribs, with the subject breathing normally using a non-stretchable tape. Body fat percentage (%) and skeletal mass (kg) were estimated using BodySCAN™ HBF-214 Body Composition Monitor (Omron). Systolic and diastolic blood pressure was measured using calibrated digital BP apparatus (BP 02XL, Dr. Morepen). Fasting blood glucose and HBA1c were assessed using venous blood samples on visit 1 and visit 5 (day 43). Twenty-four-hour dietary recalls were collected using a standard questionnaire. Information on physical activity was collected using modified Madras Diabetes Research Foundation physical activity questionnaire (MPAQ).

2.4.2. Continuous Glucose Monitoring (CGM)

Impact of DSNS on the ambulatory glucose profile was studied using a CGM device between two 14-day phases: CGM1 phase (baseline, days 1 - 14) and CGM2 phase (endline, days 28 - 42). The CGM system used was the Free Style Libre Pro (manufactured by Abbott Healthcare Pvt Ltd) and assessed the interstitial fluid glucose concentration. The CGM 1 phase was designed as the baseline for the 4-week intervention to elicit any differences in the CGM outcomes before and during/after the 4-week intervention (Figure 2). Randomized participants reported at the study site on day 0 and the CGM device was inserted in the back of the upper arm post dinner for all study participants. They were asked to continue wearing the device for the next 14 days. Participants in both the groups were instructed to continue with their habitual diet and routine physical activity for this CGM1 baseline. The CGM device was removed for all the study participants on Day 14 at bedtime (visit 3) providing a 14-day CGM1 phase data (baseline). All participants received lifestyle counselling on Day 15. In addition to LC, the test group was also provided the DSNS for daily consumption for the next 14 days. During this period, participants were not wearing any CGM device. All study participants reported back on day 29 (visit 4) for the CGM2 baseline.

On day 28, the participants reported back to the study site and a new CGM device was inserted post dinner (visit 4), for all participants. Again, the participants in both groups received lifestyle counselling and the test group was given the DSNS for daily consumption for the next 14 days. All the participants reported back on day 42 (visit 5) for the endline visit and CGM removal. CGM 1 phase (days 1 - 14) and CGM 2 phase (days 29 - 42) records were compared to assess the efficacy of intervention on mean blood glucose, estimated HbA1c, and Time in Range (TIR), among DSNS + LC as well as LC alone groups.

2.5. Data Analysis

The statistical analysis was done by using SAS^® statistical software (Version: 9.4 or higher; SAS Institute Inc., USA). Intention to treat analysis was conducted for 199 participants [test (n = 100) and control (n = 99)] who participated in this parallel phase study. During the study period, 35 participants in the test and 37 participants in the control group did not complete the study (reasons for dropout as listed in Figure 2). Consequently, a per protocol analysis was conducted, encompassing 65 participants in the test, and 63 in control group (Figure 1).

Continuous variables were summarized using tables of descriptive statistics: number of participants with recorded observations, mean, standard deviation, median, minimum, and maximum. Categorical variables were summarized using counts and percentages. Least square means with standard error were computed, wherever necessary. For continuous variables, the within-treatment analyses were conducted to compare baseline to post-intervention data using paired t-test. The data between the groups for various parameters was analyzed using an independent t-test. Mean glucose concentrations and TIR values during the CGM1 and 2 were obtained from the CGM device report. Using 54 - 140 mg/dl as normal range for CGM interstitial values, percent TIR was calculated. Estimated HbA1c% was calculated using mean glucose (mg/dl) values into a formula [eHbA1c = 3.38 + 0.023453 (mean glucose). The nutrient intake of foods was calculated using IFCT 2017 and food atlas (MDRF). The mean intakes and nutrient adequacy of major nutrients was compared with Recommended Dietary Allowances (RDAs) given by Indian Council of Medical Research (ICMR), RDA 2024. Percent energy contribution from macronutrients was also calculated. ANCOVA was used for assessing the differences between the two groups in various nutrient intakes and adequacies changes from baseline to endline. The physical activities are classified into sedentary, moderate, and vigorous categories in the MPAQ. We have used modified MAPQ, thus changes in physical activities under each category were calculated as mean duration (minutes) per day. Safety data was analyzed for the safety population defined as all enrolled participants who received at least one of the test products or isocaloric meals. Adverse Events were summarized with a number and the percentage. All statistical tests of hypothesis employed a level of significance of 0.05.

3. Results

All participants were between the age range of 30 - 63 years with a mean age of 44.2 (8.52) years and mean BMI of 25.9 (3.81) kg/m² in DSNS + LC and 25.9 (3.84) kg/m² in LC alone group. There were 124 males and 75 females in the study. All participants reported to have an HbA1c ≥ 5.7 - ≤ 6.4%. However, it was reported that 42% (n = 84) of prediabetic subjects had FBG between 100 - 125 mg/dl. Almost 28% (55) and 30% (61) participants had FBG < 100 mg/dl and >125 mg/dl respectively. There were no significant differences in anthropometric and body composition parameters between the two groups as shown in Table 2 at baseline.

3.1. Acute Blood Glucose Response Phase

3.1.1. Post-Prandial Blood Glucose (PPG)

DSNS group showed significantly lower PPG versus isocaloric snack on all visit days at 30 (p < 0.0001), 60 (p < 0.0001), 90 (p < 0.0001), 120 (p < 0.05) and 150 (p < 0.05) minutes. As per Intent to Treat (ITT) analysis, PPG response from

Table 2. Baseline characteristics of the participants.

Note: ^aData from visit 2. ^#Wilcoxan rank test of significance was used for comparing gender differences in the groups. All other parameters were compared using unpaired t-test, at p < 0.05 level of significance.

0 to 180 minutes after DSNS and isocaloric snack consumption by the participants in DSNS and control groups, respectively, on days 1, 15, 29, 43 is shown in Figure 3.

The maximum glucose peak was achieved at 60 minutes for both the groups on all the days. However, it was significantly lower in the DSNS group as compared to control group at all the days [day 1 (<0.0001), day 15 (<0.0001), day 29 (<0.0001) and day 43 (<0.0001)]. The differences in PPG levels reduced between DSNS and control group at 180 minutes for all the four days. The Per Protocol (PP) data showed similar results. Detailed data is given in Table S2.

3.1.2. Incremental Area under the Curve (iAUC)

The iAUC was significantly lower in DSNS group versus the control group at day 1 (<0.0001), day 15 (<0.0001), day 29 (<0.0001), and day 43 (<0.0001) as per ITT analysis (Figure 4). Similar results were obtained from PP data. Detailed data provided in Table S3.

3.2. Intervention Phase

3.2.1. Changes in Mean FBG, Anthropometric Markers, Body Composition, Blood Pressure and HbA1C

At baseline, no significant differences were observed in any of the parameters between the two groups as per ITT analysis. Post intervention, FBG, waist circumference, systolic and diastolic blood pressure reduced from baseline significantly

Figure 3. Post-prandial glucose levels at 0, 30, 60, 90, 120, 150 and 180 minutes on day 1, day 15, day 29 and day 43 in DSNS and control groups. Significant difference between the two groups was calculated using independent t-test at *p < 0.05 and **p < 0.0001.

Figure 4. Comparison of iAUC at days 1, 15, 29 and 43 between DSNS and control (isocaloric snack); values are least square of means with standard error bars. **Significant difference between the two groups using analysis of variance at p < 0.0001.

after 4 weeks of intervention for both the groups with the mean (SD) change being more pronounced in DSNS + LC group versus the LC alone group [FBG: DSNS + LC: −25.3 (26.51) mg/dl, p < 0.0001; LC alone: −24.4 (21.66) mg/dl, p < 0.0001; waist circumference: DSNS + LC: −1.13 (1.86) cm, p < 0.0001; LC alone: −0.88 (1.86) cm, p = 0.0004; Systolic BP: DSNS + LC: −3.3 (4.63) mm Hg, p < 0.0001; LC alone: −2.5 (4.51) mm Hg, p < 0.0001; Diastolic BP: DSNS + LC: −3.1 (3.63) mm Hg, p < 0.0001; LC alone: −2.6 (3.72) mm Hg, p < 0.0001]. A reduction in weight and percent body fat from baseline was reported by both the DSNS + LC and LC alone groups. While the change in weight was significant for DSNS + LC group [DSNS + LC: −0.4 (1.27) p = 0.0104, LC alone: −1.33 (6.27), kg/m², p > 0.05], the change in percent body fat was significant for LC alone group [DSNS + LC: −1.02 (4.34)%, p = 0.058; LC alone: −0.98 (3.5)%, p < 0.028]. Mean (SD) reductions in BMI were significant for both the groups [DSNS + LC: −0.29 (0.74) p = −0.0022, LC alone: −0.33 (0.74), kg/m², p = 0.0007]. Percent skeletal mass and Hb1AC did not show any significant changes after 4 weeks intervention in either of the groups. There were no significant differences observed between the test and control groups for any of the measures. The results were observed to be similar in PP analysis. Details are given in Table S4.

3.2.2. Changes in Dietary Intake and Physical Activity

The dietary intake of participants was assessed at baseline (day 1) and at the end of the study (day 43) using 24-hour recall method.

Macronutrients: Changes in percent energy contribution and nutrient adequacy

From the dietary data, average nutrient intake among the participants was computed. The percentage energy contribution from carbohydrate, protein and fat was similar between DSNS + LC and LC alone group at baseline. Post intervention, DSNS + LC group reported a significant reduction in the contribution of energy from carbohydrates, (DSNS + LC: −5.3 (9.22)%, LC alone: 1.6 (24.44)%, p = 0.0349), and a significant increase in protein energy percent (DSNS + LC: 1.5 (1.51)%, LC alone: 0.03 (1.37)%, p < 0.0001) compared to LC alone group, shown in Figure 5. There were no significant changes reported in fat energy percent.

Figure 5. Comparison between DSNS-LC and LC groups for intake of proportion of energy contribution from carbohydrates, protein and fat at baseline and endline. *Significant difference between the groups using independent t-test at p < 0.05. #Significant differences between baseline and endline within the group using paired t-test at p < 0.05.

Mean protein intake increased significantly (p < 0.05) in DSNS + LC group post intervention from baseline [50.4 (20.24) g] to endline [55.3 (15.96) g]; while there were no significant changes in the energy, protein, carbohydrate, and fat intakes in LC alone group as compared to baseline. Post intervention, percentage adequacy for protein intake increased in DSNS + LC group as compared to LC alone group (DSNS + LC: 10.3 (41.83)%, LC alone: −7.2 (31.64)%, p < 0.001). On adjusting the change from baseline, the percent adequacy for fibre intake also improved in DSNS + LC, compared to LC alone group (DSNS + LC:30.2 (13.10)%, LC alone: −7 (13.30)%, p = 0.0513).

Micronutrients: Changes in mean intake and percent adequacy

Micronutrient intake data was collected and analyzed for calcium, iron, vitamin B12 and chromium. Post intervention, the mean intakes of calcium, iron, vitamin B12, and chromium were significantly (p < 0.0001 for all) higher in DSNS + LC as compared to LC alone group (Table 3).

Percent adequacies of calcium, iron, vitamin B12, and chromium were found to be inadequate at baseline for both the groups. The percent adequacies for intakes of calcium, iron, vitamin B12, and chromium, not only increased substantially (p < 0.0001 for all) in DSNS + LC group post intervention as compared to baseline but were also significantly (p < 0.0001 for all) higher than LC alone group at endline (Table 3). The participants in the DSNS + LC group displayed significantly augmented nutrient intake at the endline compared to baseline levels. Similar results were obtained from per-protocol analysis.

Changes in physical activity

At baseline, majority of the participants were sedentary (DSNS + LC: 97%, LC alone: 97%) and engaged in light physical activities (DSNS + LC: 44%, LC alone: 47%). Only 13% of participants in DSNS + LC and 19% in LC alone groups were engaged in moderate activities. Following the lifestyle counseling sessions, a significant increase in the proportion of participants engaged in moderate activities was observed in both groups (DSNS + LC: 98%, p < 0.0001; LC alone: 100%, p < 0.0001). There was also a significant rise in the time (mean) spent on moderate activities, with participants in the DSNS + LC group increasing by 33.6 (15.47) minutes (p < 0.005) and those in the LC alone group increasing by 30 (18.71) minutes (p = 0.0007) as compared to their respective baseline. However, no significant differences in physical activity patterns were noted between the two groups. Data from ITT and PP analysis of physical activity pattern of prediabetic participants is shown in Table S5.

3.2.3. Changes in Continuous Glucose Monitoring (CGM) Indicators

The comparison between baseline and endline CGM data suggested that 4 weeks intervention (both DSNS + LC and LC alone) did not show any substantial changes in glycemic parameters in prediabetic individuals using a CGM device in prediabetics. Data not shown in the paper.

3.3. Safety

Safety data was analyzed for all participants who received either the DSNS or isocaloric snack. Only two minor adverse events (1%), one in DSNS + LC and one in LC alone group were reported. Both AEs were of mild intensity. Both subjects experienced discomfort and mild diarrhoea after consumption of test products. Their vital signs were within normal limits and both the participants

Table 3. Mean intakes and % mean adequacies of DSNS + LC and LC alone group at endline and baseline, as per ITT analysis.

Note: Values are Mean (SD) for baseline and endline. % nutrient adequacies were computed by comparing the nutrient intake values with RDA 2024 (ICMR), p-value for within group was calculated using paired t-test. Least square mean (SE) was used to compare the mean change from baseline between groups by ANCOVA, where p-value is significant at * < 0.05 and ** < 0.0001.

felt comfortable after taking a rest. No other participant reported any other adverse events either after consuming the DSNS or isocaloric snack.

4. Discussion

According to Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) nationwide survey report, overall weighted prevalence of prediabetes is 15.3% and diabetes 11.4%. The diabetic Indian population had an average glycated hemoglobin of 8.56%, FBG of 172 mg/dL, and PPG of 253 mg/dL. There is a substantial body of evidence reporting the positive role of DSNS in diabetic populations, specifically in reducing PPG levels, influencing glycemic variability, and lowering HbA1C. However, studies on efficacy of DSNSs on health status of prediabetic individuals are limited. To the best of our knowledge, ours is the first study investigating the efficacy of a DSNS on glycemic response in prediabetics in the Indian context. The strength of this study was its parallel phase study design including the acute blood glucose response of DSNS as well as the intervention phase including 4-weeks intervention and impact assessment of the DSNS on multiple parameters including anthropometry, body composition, nutrient intake, BP and CGM.

In the present study, ABGR for DSNS and isocaloric snack was measured with DSNS reporting significantly lower PPG versus isocaloric snack at 30 (p < 0.0001), 60 (p < 0.0001), 90 (p < 0.0001), 120 (p < 0.05) and 150 (p < 0.05) minutes on all visit days. iAUC for 0-180 minutes was significantly lower (p < 0.0001) for DSNS as compared to control for all visit days. The peak PPG at 60 minutes were significantly lower for DSNS than isocaloric snack on all the days, suggesting that elevation in blood sugar levels would be much lower after consuming DSNS (60 g with 250 mL double toned milk) as compared to standard breakfast (56 g cornflakes with 250 mL double toned milk) (Figure 3 and Figure 4). These findings corroborate with a recent study conducted in Japanese (n = 20, prediabetics) individuals. In this study, an energy dense, low carbohydrate, and high fibre Oral Nutritional Supplement (ONS) was given to participants on two separate days and it was observed that iAUC of blood glucose levels for 120 minutes was significantly lower after ONS ingestion (2207 ± 391 mg/dL.min) as compared to standard formula (3735 ± 391 mg/dL∙min, p < 0.001).

The DSNS used in the present study is a high fiber supplement containing 22% soluble fiber and with a high Monounsaturated Fatty Acids (MUFA) composition (70% of total fatty acids delivering ~18% of energy). Carbohydrates contribute 40%, protein 23%, and fat 25% of total energy. The high amounts of soluble fiber and MUFA may be contributing to better glycemic control.

PPG and FBG are main contributors to overall glycemic control among T2DM or prediabetic patients. Elevated PPG levels are risk factors for cardiovascular diseases and diabetic complications, especially in those with higher HbA1C %. Controlling PPG response in the overweight and obese population, who are also at risk for T2DM, is crucial for preventing the onset. Evidence indicates that DSNS controls elevation in PPG response and lowers iAUC levels among diabetic patients. A recent study on 66 prediabetic Indians aged 30-66 years observed reduction in post-prandial hyperglycemia and reversal to normoglycemia after consuming 30g almond premeal before breakfast for three months. Previous studies have consistently shown that lifestyle modifications, and certain pharmacological treatments, could effectively facilitate the reversal of prediabetes to normoglycemic levels, thereby preventing its progression to diabetes and improved outcome. A study by Amer et al. (2020) among Saudi prediabetic patients (n = 180), reported significant reversal to normal glucose levels with intensive lifestyle guidance, however the challenge was to sustain interest in adopting lifestyle changes for a longer duration of time. Therefore, compliance with nutrition counselling for a longer duration of time is imperative. The patients who had more nutrition counselling visits in a year had lower mean HbA1c levels as compared to patients with fewer visits per year. A recent study reported a 46% reduction in prevalence of prediabetes after 6 months of intervention, however, this decline was not maintained at 12-month follow-up. Another study on Swedish prediabetic individuals reported that cardiometabolic risk variables effects were controlled only as long as the lifestyle modifications were followed.

To maintain cardiometabolic health, it is important to reduce the glycemic and metabolic variabilities. Sustained hyperglycemia is a high-risk state for diabetes and cardiovascular diseases. Reversal to normoglycemia is associated with a significantly reduced risk of future diabetes. It is well established that HbA1C levels are the result of a combination of both FBG and PPG levels, therefore treatment may also influence FPG-PPG relationship. In the present study, lower spike in PPG levels after ingesting DSNS at all the four time points validated the use of DSNS as an alternative to isocaloric high carbohydrate, low fiber breakfast. The parallel intervention phase has shown that the participants who consumed DSNS for 28 days along with lifestyle counselling had significantly higher reductions in FBG, weight, BMI, waist circumference and systolic and diastolic blood pressure as compared to only lifestyle counselling group. While increase in moderate activities during the four-week intervention proved useful in both the groups, the reductions in weight, BMI, and waist circumference were more pronounced in the DSNS + LC group compared to the LC alone group.

The dietary intakes of various nutrients by the prediabetic participants were highly inadequate at baseline in both the groups. DSNS used in our study, is rich in protein, fiber, MUFA and micronutrients. The participants consuming DSNS had shown significant increase in percent nutrient adequacy versus RDA post intervention. The LC alone group did not report any improvements in intakes of protein, iron, calcium, vitamin B12, and chromium, despite lifestyle counselling focusing on importance of nutrient-rich and balanced diets.

The CGM did not show any changes in the glycemic outcomes in the present study. This could be attributed to the short duration of the study which was possibly not substantial enough to demonstrate significant changes in HbA1C, mean glucose levels and body composition after DSNS consumption in prediabetes. Studies in T2DM patients have demonstrated that mere use of intermittent CGM for 12 weeks had reduced HbA1C by 1% among poorly controlled individuals. Another study on prediabetic and diabetic patients showed positive changes in body composition and behavioral changes among participants regarding goal setting, increased exercise sessions and self-monitoring immediately and after 1 month, however, did not report any changes in HbA1C levels. Studies have demonstrated the use of CGM as behaviour modification tool for improving diet and exercise routine in T2DM patients. However, the data on use of CGM by prediabetes is still not defined. Future research is needed to evaluate the accuracy and efficacy of CGM among prediabetics.

In the present study, the DSNS was well tolerated and helped prediabetic individuals to meet nutrient requirements along with the improvement in fasting blood glucose levels and lowering the peak PPG levels after consumption.

5. Conclusion

The consumption of DSNS effectively controls postprandial glucose peaks and results in lower iAUC levels. Daily intake of DSNS, combined with lifestyle changes, is associated with significant reductions in body weight, BMI, and waist circumference. This study supports the use of DSNS as a snack for prediabetic or hyperglycemic individuals requiring nutritional support for improved glycemic control. However, long-term intervention studies could substantiate efficacy of DSNS on HbA1c and other metabolic outcomes in prediabetic individuals.

6. Salient Features of the Present Study

• The first study to investigate the efficacy of a DSNS on glycemic response in prediabetics in Indian context (to the best of our knowledge).
• DSNS showed significantly lower PPG and iAUC as compared to isocaloric snack at four different time points.
• Daily consumption of DSNS as snack along with life counselling showed significant changes in FBG, weight, BMI, waist circumference, and blood pressure from baseline in prediabetic participants.
• Low GI DSNS with a high fiber and MUFA helped prediabetic participants to improve the intake of protein, fibre, iron, calcium, vitamin B12, and chromium.

Acknowledgements

We acknowledge editorial and manuscript preparation support towards assembling tables and creating high-resolution images based on authors’ detailed directions, copyediting, fact-checking, bibliography management and referencing, provided by Dr. Shavika Gupta. We would like to place on record the support provided by Dr. R. Pirabhakaran and Dr. Minakshi Singh in providing the nutrient analytical report and CoA for the DSNS. We would like to acknowledge the contributions of Dr. Anjani Bartwal Luhana and Ms. Neha Srivastava in ensuring DSNS availability for the study. We acknowledge the support provided by Abbott, India for timely provision of the CGM device and training for its installation to the study site staff.

Authors’ Contributions

D.K., K.J.R., H.S.G., J.B. and M.P. were primarily involved in the conceptualization of the study; S.S. and P.J. were involved in the data collection and conduct of the study. K.J.R., H.S.G. and J.B. were involved in the quality checks and data verification. D.K., K.J.R., and H.S.G. were responsible for the scientific research. J.B. was involved in operational decision-making during the conduct of the study. J.G. was responsible for statistical analyses of results. D.K., K.J.R. and H.S.G. interpreted the study results and participated in data curation. D.K., K.J.R. and H.S.G. drafted and led the manuscript for its intellectual content, literature searches, interpretation of data, and graph generation. The final version of the manuscript was carefully reviewed and approved by all authors. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study protocol, all amendments, and the informed consent form were reviewed and approved by the Institutional Ethics Committee of OM Children Hospital (ECR/1168/Inst/GI/2018). The study was performed in accordance with the protocol, Good Clinical Practice (GCP) guidelines, local regulations governing clinical study conduct, and the ethical principles that have their origin in the Declaration of Helsinki. The study was registered with the Clinical Trials Registry India (CTRI/2023/02/049511).

Informed Consent Statement

The informed consent form was reviewed and approved by the Institutional Ethics Committee of Om Children Hospital (ECR/1168/Inst/GI/2018). All participants voluntarily gave written informed consent prior to enrollment.

Data Availability Statement

Ethical restrictions imposed by the IEC prevent public sharing of the data for this study. The data used in this publication is owned by HUL (Nutrition). Data access request will be evaluated by HUL (Nutrition) in consideration of IEC requirements. Interested researchers will need to sign a research collaboration agreement with HUL (Nutrition). Requests can be sent to D.K.

Funding

This research was funded by HUL, Nutrition R&D, India.

Supplementary

Table S1. Nutrient composition of Diabetic Specific Nutritional Supplement (DSNS).