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Homoeopathic potencies within versus beyond Avogadro limit: Efficacy on glycaemic control among pre-diabetic adults — A comparative, randomised, exploratory study
*Corresponding author: Dr. Avidipta Hazra, Department of Organon of Medicine, Metropolitan Homoeopathic Medical College and Hospital, Kolkata, West Bengal, India. dr.avidiptahazra@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Hazra A, Das D, Ghosh R, Ghosh C, Sarkar T. Homoeopathic potencies within versus beyond Avogadro limit: Efficacy on glycaemic control among pre-diabetic adults — A comparative, randomised, exploratory study. J Integr Stand Homoeopath. doi: 10.25259/JISH_121_2025
Abstract
Objectives:
Pre-diabetes (PD) is a global health concern, with up to 50% of cases progressing to type-II diabetes mellitus within 5 years if untreated, leading to complications such as kidney failure, blindness, neuropathy and foot issues.
Material and Methods:
An exploratory, randomised, comparative study was conducted over 6 months at the outpatient department of Metropolitan Homoeopathic Medical College and Hospital, Kolkata. Pre-diabetic adults with glycated haemoglobin (HbA1c) between 5.7% and 6.4%, impaired fasting glucose (IFG) between 100 and 125 mg/dL, and/or impaired oral glucose tolerance (IGT) between 140 and 199 mg/dL were randomised to receive individualised homoeopathic medicines (IHMs) within Avogadro Limit or potencies within 12CH/24X (IHMs-WA, n = 35), otherwise beyond Avogadro limit or beyond 12CH/24X (IHMs-BA, n = 35) for 3 months. The primary outcome was HbA1c, with IFG and IGT as secondary outcomes, measured at baseline and after 3 months.
Results:
Of 154 screened participants, 70 were included in the intention-to-treat analysis. After 3 months, intergroup differences were not statistically significant in HbA1c (p = 0.37), IFG (F1,68 = 1.8, p = 0.18), IGT (F1,68 = 0.56, p = 0.456) and intra-group differences were shown notable significance in both groups in HbA1c (IHMs-WA: p < 0.01; IHMs-BA: p < 0.001), IFG (IHMs-WA: p < 0.05; IHMs-BA: p < 0.001) and IGT (IHMs-WA: p < 0.01; IHMsBA: p < 0.001). After 3 months, a lower progression rate from PD to diabetes in IHMs-BA group (8.6%, 11.4% in IHMs-WA), and higher rate of conversion to non-diabetic status in IHMs-BA (43.0%, 31.4% in IHMs-WA) were observed with inter-group non-statistical significance differences (p < 0.05). No adverse events were reported.
Conclusion:
This exploratory, randomised, comparative trial demonstrated no statistically significant inter-group differences; while demonstrating significant intra-group improvements, and higher percentage of participants progressing to non-diabetic status in both groups. This may suggest that IHMs administered beyond the Avogadro limit (comparative higher dilution) are equivalent to those the within limit (comparative lower dilution), in their efficacy on glycaemic control. Although, observed slightly more promising trend in magnitude of improvement on IHMs-BA, require validation through further robust, long-term, multi-centric, blinded superiority trials with larger sample sizes.
Keywords
Avogadro limit
Homoeopathy
Individualised homoeopathic medicine
Pre-diabetes
Randomised trial
INTRODUCTION
Pre-diabetes (PD) is a metabolic disorder and an ever-increasing global health concern. It is an intermediate state of hyperglycaemia characterised by elevated blood glucose concentrations, such as impaired fasting glucose (IFG), impaired glucose tolerance and elevated glycated haemoglobin (HbA1c). According to the American Diabetes Association, pre-diabetic conditions can be detected by impaired oral glucose tolerance (IGT), ranging between 140 and 199 mg/dL, and/or IFG ranging between 100 and 125 mg/dL, and/or HbA1c percentages of 5.7– 6.4%.[1,2] Pre-diabetic adults (20–79 years of age) are at high risk for developing type 2 diabetes mellitus (T2DM);[3] if left untreated, up to 50% progress to T2DM within 5 years with severe complications of kidney failure, heart disease, blindness, neuropathy and foot complications.[4] The International Classification of Diseases (ICD)-11 code for PD diagnosis is 5A40, although this code also includes IFG, IGT, as well as decreased HbA1C in the PD range. According to the World Health Organization, diabetes resulted in 1.6 million deaths, thus becoming the ninth leading cause of death globally.[5] The global prevalence of impaired glucose tolerance is estimated to be 7.5% (374 million) in 2019 and projected to reach 8.0% (454 million) by 2030 and 8.6% (548 million) by 2045.[6] While in India, this number is expected to rise over 135 million by 2025, as compared to 65.1 million in 2013, and ranks second after China in the global diabetes epidemic.[7] According to the National Family Health Survey-5, the prevalence of pre-diabetic adult males and females is, respectively, 15.6% and 13.5%.[8] A growing number of diabetic patients are turning to homoeopathic medicine every day.[9] A previous double-blind randomised placebo-controlled study was conducted amongst 60 patients, and the results showed significant improvement in reduction of glycaemic control after intervention of highly diluted individualised homoeopathic medicines (IHMs).[2] Another recently published study also demonstrated that the proportion of participants converted from PD to T2DM was significantly less with highly diluted IHMs.[10] One placebo-controlled, crossover trial was also conducted to explore the efficacy of Magnesium sulphate 30CH, which showed the efficacy of potentised IHMs on the reduction of HbA1c in 79 patients with T2DM.[11] However, the efficacy of highly diluted homoeopathic beyond Avogadro limit is still under doubt in the community. Avogadro limit is a materialistic concept of chemistry, which states that no molecule of original medicine remains left on potencies beyond 12CH in the centesimal scale or 24X in the decimal scale of serially diluted solution of homoeopathic medicines.[12,13] Homoeopathy employs potentisation through serial dilutions and succussions, with potencies theoretically devoid of original molecules, yet emerging evidence hints at retained bioactivity via nanoscale particles.[14] A research gap still exists regarding the efficacy of IHMs beyond Avogadro limit in comparison with those within the limit. This study aims to fill the existing research gap by comparing the efficacy of potencies of IHMs within and beyond Avogadro limit among pre-diabetic adults.
MATERIAL AND METHODS
Study design and setting
An exploratory, randomised (1:1 allocation), comparative clinical trial was conducted in the outpatient department (OPD no. 03, Room no. H/6) of the Metropolitan Homoeopathic Medical College and Hospital, Kolkata, West Bengal, India. Patients attending the OPD were screened and voluntarily enrolled in the study.
Participants
On preliminary screening, individuals with an Indian Diabetic Risk Score (IDRS) ≥60 were screened and further evaluated. A total of 70 diagnosed pre-diabetic adults with impaired glucose regulation (HbA1c percentages within 5.7– 6.4% and fasting plasma glucose concentration within 100– 125 mg/dL and/or 2 hours. post 75 g glucose load plasma glucose value within 140–199 mg/dL),[1,2] aged between 20 and 79 years, were taken part in this study. An informed consent form (available in three vernacular languages: Bengali, English, Hindi) was signed before participating in this study to confirm voluntary participation.
Inclusion criteria
1. Patient age within 20–79 years, both sexes
2. IDRS ≥60
3. Patient diagnosed on ICD-11 classification 5A40,[15] with impaired glucose regulation (HbA1c percentages within 5.7–6.4% and fasting plasma glucose concentration within 100–125 mg/dL and/or 2 hours post 75 g glucose load plasma glucose value within 140–199 mg/dL)
4. Literate patients with written consent to participate in this study.
Exclusion criteria
5. IDRS <60
6. Patients are already diagnosed with diabetes
7. Pregnant women/lactating mothers
8. Patient with self-reported immunocompromised states
9. Patient suffering from uncontrolled systemic illness, life-threatening infections or any vital organ failure/s
10. Patient without consent to take part and an illiterate patient
11. Patient has been undergoing homoeopathic treatment for any chronic disease for the last 6 months.
Intervention and duration
Group 1
According to the patient’s signs and symptoms, IHMs on potencies within Avogadro limit (IHMs-WA) were administered in centesimal scale (3CH, 6CH, 12CH) and/or in decimal scale (3X, 6X, 12X); one to seven doses, once or twice daily as required for 3 months. Each dose comprised six to eight globules (no. 20) of cane sugar or distilled water, medicated with the indicated medicine (preserved in 90% v/v ethanol), taken orally on a clean tongue; repetition of dosage was dependent upon the requirement of each case. After taking medicine, patients were advised not to eat, drink or brush their teeth for 30 min, and in cases of globules, they were advised to suck the globules instead of swallowing. Homoeopathic medicines used in this trial were procured from a good manufacturing practice (GMP)-certified company, Hahnemann Publishing Co. Private Ltd., Kolkata, West Bengal, India and dispensed from hospital dispensaries. Based on symptom totality, history and constitutional features for every occasion, a single medicine was prescribed. Repertorisation was performed using appropriate repertoires whenever required, and Materia Medica was consulted. Follow-up has been done after every 14 days, for a period of 3 months from the start of the intervention. Regarding advice on adherence, participants communicated frequently through telephonic communication. A register log-book was maintained for recording data of prescribed medicines, potencies, etc.
Group 2
According to the patient’s signs and symptoms, IHMs on potencies beyond Avogadro limit (IHMs-BA) were administered mainly in centesimal scale (30CH, 200CH, 1M and/or 10M); one to seven doses, once or twice daily as required for 3 months. Each dose also comprised six to eight globules (no. 20) of cane sugar or distilled water, medicated with the indicated medicine (preserved in 90% v/v ethanol), taken orally on a clean tongue; repetition of dosage was dependent on the requirement of each case. After taking medicine, patients were advised of the same information mentioned above. Homoeopathic medicines used in this trial were procured from a GMP-certified company, Hahnemann Publishing Co. Private Ltd., Kolkata, West Bengal, India, and dispensed from hospital dispensaries. Single medicine was prescribed based on symptom totality, history and constitutional features for every case. Materia Medica was consulted, and repertorisation was performed using appropriate repertoires whenever required. Follow-up has been done after every 14 days, also for up to 3 months from the start of the intervention. Regarding advice on adherence, participants communicated frequently through telephonic communication. A register log-book was maintained for recording data of prescribed medicines, potencies, etc.
Outcome measurement and data collection
Primary outcome: HbA1c% was measured as the primary outcome at baseline and after 3 months.
Secondary outcomes: Other glycaemic control like IFG, IGT were measured at baseline, after 45 days (1.5 months) and 90 days (3 months).
All the tests were done on the national accreditation board for testing and calibration laboratories-accredited, registered out-sourced laboratory.
Concomitant care
A low-calorie diet with high fiber, containing at least 30 min of regular physical exercise and avoidance of both physical and mental stress, was advised as lifestyle modifications to the participants of both groups, in the same way. Participants were reminded to follow the advice on every subsequent visit.
Randomisation
A permuted fixed block randomisation method was adopted using 7 permuted blocks, each of size 10, to reduce the predictability of group assignments and minimise imbalances in baseline characteristics. Random sequences were generated by StatTrek® independent third-party random number generator, which was not allowed to influence the trial at any time.
Blinding
No blinding/masking was incorporated in this study. All included participants and the investigator remained aware of interventions.
Sample size
Due to the lack of any previously published studies of this similar design till protocol framing, it was not possible to determine the formal effect size and calculate the sample size. Instead, considering the constraints of time limitations imposed as per the scheme guideline,[16] we have targeted a sample size of 70 (35 participants in each group) to maintain study feasibility and attainable goal for this exploratory trial.
Allocation concealment
The randomization list was securely stored in a password-protected file so that no one involved in the recruitment or enrolment process could access it before patient assignment. The allocation sequence was generated and maintained by a blind, independent third party on centralised computer software. A blind scholar (A.H.) was involved in screening, enrolment and entering patients’ identification data into a centralised computer software, and remained unaware of group allocation till the study end. The centralized computer software system assigned patients randomly into either group as per the randomization chart. After that, password-protected allocation data were only accessible by visiting homoeopathic physician (D.D.), who has a postdoctoral degree with at least 5 years of experience in clinical practice. Thereafter, screened patients were taken, examined and prescribed by a visiting homoeopathic physician (D.D.) by considering and viewing their allocated group. Outcome assessor (A.H.) was also blinded to the group allocations till the complete study ended. Computer-assigned random allocation concealment was used to minimise selection bias.
Statistical analysis
The intention-to-treat (ITT) method was adapted, i.e., each included patient was entered in the final analyses. Missing values were replaced by predicted values from a linear regression model. Histograms, Q-Q plots, Kolmogorov– Smirnov and Shapiro–Wilk tests were used to analyse the data distribution; no detectable deviation from normality was found. Inter-group differences were detected using Pearson’s Chi-squared statistics (Yates corrected) for the categorical data, whereas Two-Way Repeated Measures analysis of variance (ANOVA) models and Unpaired T-tests were used to address the between-group and time interactions, group differences at various time points, respectively. Effect sizes were expressed as partial eta-squared (η2; small effect, 0.01; medium effect, 0.06; large effect, 0.14) for ANOVA models, and Cohen’s d (small effect, 0.2; medium effect, 0.5; large effect, 0.8) for t-tests. Intra-group differences were detected using One-Way Repeated Measures ANOVA, means and confidence intervals (CIs) were reported for intra-group variations over time using Bonferroni-adjusted CIs and Paired T-test. p values were set at <0.05 two-tailed as statistically significant.
The Statistical Package for the Social Sciences for Windows (SPSS), version 23.0 was used for all statistical computations.[17]
Reporting of adverse events (AEs)
Participants were directed to report any harm, serious AEs, unintended effects or undue aggravations or worsening of symptoms through a call or by directly visiting the OPD.
Reporting guidelines
Study reporting adhered to the Consolidated Standards of Reporting Trials (CONSORT)[18] and Reporting Data on Homoeopathic Treatment (RedHot) guidelines.[19]
Completed CONSORT and RedHot checklists can be found in [Supplementary files].
RESULTS
Participant flow
A total of 154 patients were screened, 84 (illiterate: 04, due to above/below age: 08, denied consent: 06, beyond/below IFG, IGT, HbA1c% range: 51, already under homoeopathic treatment: 15) were excluded, and 70 were enrolled by fulfilling pre-specified eligibility criteria and subsequently randomised (1:1 allocation) and recruited. The total study was run from 29th February to 22nd July 2024. 02 (two lost to follow-up for some reason) dropped out of the Group 1 (IHMs-WA), and 01 (one lost to follow-up for some reason) from the Group 2 (IHMs-BA) [Figure 1].
- Consolidated standards of reporting trials flow diagram. IHMs: individualised homoeopathic medicines, ITT: Intention-to-treat.
Numbers analysed
In total, 33 out of 35 were completed in Group 1 (IHMs-WA) and 34 out of 35 completed the trial in Group 2 (IHMs-BA); the others dropped out in both groups. All 70 participants (IHMs-WA: 35; IHMs-BA: 35) entered into the final ITT analyses.
Baseline confounders
No significant difference in the distribution of the variables between the two groups could be identified. Continuous data were presented as mean ± standard deviation, unpaired t-tests were applied; categorical data were presented as absolute values (percentages), Chi-square test (Yate’s corrected) was applied; also showing no significant differences [Table 1].
| Characteristics | Group 1 (n=35) | Group 2 (n=35) | p-value |
|---|---|---|---|
| Age (years)a | 45.4±15.88 | 42.9±14.15 | 0.49 |
| Genderb | |||
| Male | 15 (42.9) | 08 (22.9) | 0.35 |
| Female | 20 (57.1) | 27 (74.3) | |
| Others | 00 (00.0) | 01 (02.8) | |
| Blood pressurea | |||
| Systolic (mm/Hg) | 117.37±11.34 | 115.72±12.03 | 0.84 |
| Diastolic (mm/Hg) | 76.54±4.73 | 78.32±5.45 | 0.72 |
| Residenceb | |||
| Rural | 06 (17.1) | 08 (22.9) | 0.26 |
| Semi-Urban | 21 (60.0) | 13 (37.1) | |
| Urban | 08 (22.9) | 14 (40.0) | |
| Marital statusb | |||
| Single | 08 (22.9) | 10 (28.6) | 0.78 |
| Married | 27 (77.1) | 25 (71.4) | |
| Education statusb | |||
| 8th standard or below | 04 (11.4) | 06 (17.1) | 0.14 |
| 9th-12th standard | 16 (45.7) | 07 (20.0) | |
| Higher than 12th standard | 15 (42.9) | 22 (62.0) | |
| Employment statusb | |||
| Business | 08 (22.9) | 10 (28.6) | 0.93 |
| Service | 04 (11.4) | 05 (14.3) | |
| Dependent or others | 23 (65.7) | 20 (57.1) | |
| Socio-economic statusb | |||
| Poor | 07 (20.0) | 04 (11.4) | 0.39 |
| Middle | 20 (57.1) | 27 (77.1) | |
| Affluent | 08 (22.9) | 04 (11.5) |
Group 1, group received potencies within Avogadro limit; Group 2, group received potencies beyond Avogadro limit; aContinuous data presented as mean±standard deviation and unpaired t-tests applied. bCategorical data presented as absolute values (percentages) and Pearson Chi-squared (Yate’s corrected) test applied; p<0.05 (two-tailed) considered as statistically significant
Comparison of progression and improvement status
HbA1c%
After 3 months, the percentage progression status from pre-diabetic to diabetic (04/35, 11.4%) was higher, and pre-diabetic to non-diabetic (11/35, 31.4%) was lower in Group 1 (IHMS-WA) as compared to pre-diabetic to diabetic (03/35, 08.6%) and pre-diabetic to non-diabetic (15/35, 43.0%) in Group 2 (IHMs-BA). However, there was no such statistical difference between the two groups (p = 0.81, Chi-squared test). The percentage improvement status was also comparatively higher (74.3%) in Group 2 (IHMs-BA) than in 68.6% of Group 1 (IHMs-WA) [Table 2].
| Outcomes | Time points | Interventions | Glycaemic status | Improvement status | pa | |||
|---|---|---|---|---|---|---|---|---|
| Non-diabetic | Pre-diabetic | Diabetic | Improved (%) | Not-improved (%) | ||||
| HbA1c% | Month 3 | Group 1 (n=35) | 11 (31.4) | 20 (57.1) | 04 (11.4) | 68.6 | 31.4 | 0.81 |
| Group 2 (n=35) | 15 (43.0) | 17 (48.6) | 03 (08.6) | 74.3 | 25.7 | |||
| IFG | Month 1.5 | Group 1 (n=35) | 12 (34.3) | 19 (54.2) | 04 (11.4) | 65.8 | 34.2 | 0.49 |
| Group 2 (n=35) | 07 (02.0) | 25 (71.4) | 03 (08.6) | 77.1 | 22.9 | |||
| Month 3 | Group 1 (n=35) | 09 (25.7) | 22 (62.8) | 04 (11.4) | 60.0 | 40.0 | 0.81 | |
| Group 2 (n=35) | 12 (34.3) | 18 (51.4) | 05 (14.3) | 74.3 | 25.7 | |||
| IGT | Month 1.5 | Group 1 (n=35) | 08 (22.8) | 22 (62.8) | 05 (14.3) | 65.7 | 34.3 | 0.97 |
| Group 2 (n=35) | 10 (28.6) | 21 (60.0) | 04 (11.4) | 74.2 | 25.8 | |||
| Month 3 | Group 1 (n=35) | 09 (25.7) | 22 (62.8) | 04 (11.4) | 71.4 | 28.6 | 0.98 | |
| Group 2 (n=35) | 10 (28.6) | 22 (62 8) | 03 (08 6) | 77 2 | 77 8 | |||
Group 1, group received potencies within Avogadro limit; Group 2, group received potencies beyond Avogadro limit; HbA1c: Glycated haemoglobin, IFG: Impaired fasting glucose, IGT: Impaired oral glucose tolerance, Categorical data presented as absolute values or percentage values; Month 1.5, after 45 days from starting of intervention; pa: Inter-group differences of diabetic status detected by Pearson Chi-squared tests (Yate’s corrected) or Fisher’s exact test
IFG
After 3 months, the percentage progression status from pre-diabetic to diabetic (04/35, 11.4%) was lower, and pre-diabetic to non-diabetic (09/35, 25.7%) was also lower in Group 1 (IHMS-WA) as compared to pre-diabetic to diabetic (05/35, 14.3%) and pre-diabetic to non-diabetic (12/35, 34.30%) of Group 2 (IHMs-BA). However, there was no such statistical difference between the two groups (p = 0.81, Chi-squared test). The percentage improvement status was also comparatively much higher (74.3%) in Group 2 (IHMs-BA) than 60.0% in Group 1 (IHMs-WA) [Table 2].
IGT
After 3 months, the percentage progression status from pre-diabetic to diabetic (04/35, 11.4%) was higher, and pre-diabetic to non-diabetic (9/35, 25.7%) was lower in Group 1 (IHMS-WA) as compared to pre-diabetic to diabetic (03/35, 08.6%) and pre-diabetic to non-diabetic (10/35, 28.6%) of Group 2 (IHMs-BA). However, there was no such statistical difference between the two groups (p = 0.98, Chi-squared test). The percentage improvement status was also comparatively higher (77.2%) in Group 2 (IHMs-BA) than 71.4% in Group 1 (IHMs-WA) [Table 2].
Outcomes and effect size
Glycated haemoglobin (HbA1c%)
After 3 months, the inter-group difference between the two groups was not statistically significant (mean difference = 0.07; 95% CI: −0.08 to 0.22, p = 0.37, unpaired t-test) with a small effect size (Cohen’s d = 0.23). Intra-group difference was statistically significant in both groups IHMs-WA group (mean difference = 0.11; 95% CI: 0.02–0.19, p < 0.01, paired t-test) and IHMs-BA group (mean difference: 0.20 with 95% CI: 0.10–0.30, p < 0.001, paired t-test) [Table 3].
| Outcomes | Baseline | After 3 months | Mean difference±SD (95% confidence interval) | t34 | pb |
|---|---|---|---|---|---|
| Glycated haemoglobin (HbA1C) % | |||||
| Mean±SD | 6.0±0.22 | 5.92±0.30 | 0.11±0.25 (0.02, 0.19) | 2.594 | 0.01** |
| Group 1 (n=35) | |||||
| Mean±SD | 6.1±0.20 | 5.85±0.32 | 0.20±0.29 (0.10, 0.30) | 4.051 | 0.001*** |
| Group 2 (n=35) | |||||
| Mean difference±SE | -0.02±0.05 | 0.07±0.08 | |||
| 95% CI | -0.12, 0.08 | -0.08, 0.22 | |||
| t68 | -0.41 | 0.91 | |||
| pa | 0.69 | 0.37 | |||
| Effect size (cohen’s d) | 0.23 |
Group 1, group received potencies within Avogadro limit; Group 2, group received potencies beyond Avogadro limit; CI, confidence interval, SD: Standard deviation, SE: Standard error; t34: t score at 34 degrees of freedom. t68: t score at 68 degrees of freedom. pa: Inter-group differences detected by Un-paired t-tests; pb: Intra-group differences detected by paired t-tests; **p<0.01, ***p<0.001
IFG
After 3 months, inter-group difference showed no statistical significance difference between both groups, unpaired t-test (mean difference: −10.01, 95% CI: −0.08–0.22, p = 0.11) and two-way repeated measures ANOVA (F1,68 = 1.801, p = 0.184) with small size effect (Cohen’s d = 0.39, partial eta-squared η2 = 0.026). Intra-group difference was statistically significant in both groups IHMs-WA group (F2,68 = 3.04, p < 0.05, partial eta-squared η2 = 0.08; one-way repeated measures ANOVA), and IHMs-BA (F2,68 = 10.65, p < 0.001, partial eta-squared η2 = 0.238, one-way repeated measures ANOVA) [Table 4].
| Outcomes | Baseline | After 1.5 months | After 3 months | Mean difference (95% confidence interval) | Wilks’ lambda | F2, 68 | pc | Partial eta squared | |
|---|---|---|---|---|---|---|---|---|---|
| After 1.5 months | After 3 months | ||||||||
| Impaired fasting glucose (IFG) | |||||||||
| Mean ± SD Group 1 (n = 35) |
113.4 ± 5.3 | 108.4 ± 9.8 | 109.8 ± 10.5 | 4.97 (0.86, 9.08) | 3.57 (-0.43, 7.57) | 0.830 | 3.04 | 0.05* | 0.082 |
| Mean ± SD Group 2 (n = 35) |
111.7 ± 6.9 | 107.5 ± 10.7 | 105.3 ± 12.5 | 4.23 (1.66, 6.79) | 6.40 (3.25, 9.54) | 0.640 | 10.65 | 0.001*** | 0.238 |
| Mean dif.±SE | -1.69 ± 1.48 | -0.94 ± 2.45 | -4.51 ± 2.76 | ||||||
| 95% CI | -4.63, 1.26 | -5.82, 3.94 | -10.0, 0.98 | ||||||
| t68 | -1.14 | -0.39 | -1.64 | ||||||
| Pa | 0.26 | 0.70 | 0.11 | ||||||
| Effect size (cohen’s d) | 0.09 | 0.39 | |||||||
| Two-way repeated measures ANOVA | |||||||||
| F1, 68 | 1.801 | ||||||||
| Pb | 0.184 | ||||||||
| Partial eta squared | 0.026 | ||||||||
| Impaired oral glucose tolerance (IGT) | |||||||||
| Mean ± SD Group 1 (n = 35) |
171.9 ± 14.6 | 161.5 ± 24.3 | 158.6 ± 26.3 | 10.37 (2.77,17.97) |
13.26 (3.49, 23.02) |
0.781 | 5.55 | 0.01** | 0.140 |
| Mean ± SD Group 2 (n = 35) |
170.3 ± 17.2 | 157.5 ± 22.7 | 154.8 ± 20.4 | 12.77 (6.29,19.25) |
15.54 (9.57, 21.52) |
0.549 | 17.41 | 0.001*** | 0.339 |
| Mean Dif.±SE | 1.57 ± 3.81 | 3.97 ± 5.62 | 3.86 ± 5.63 | ||||||
| 95% CI | -6.03, 9.18 | -7.24, 15.19 | -7.37, 15.09 | ||||||
| t68 | 0.41 | 0.71 | 0.68 | ||||||
| pa | 0.68 | 0.48 | 0.49 | ||||||
| Effect size (cohen’s d) | _ | 0.17 | 0.16 | ||||||
| Two-way repeated measures ANOVA | |||||||||
| F1,68 | 0.562 | ||||||||
| Pb | 0.456 | ||||||||
| Partial eta squared | 0.010 | ||||||||
Group 1, group received potencies within Avogadro limit; Group 2, group received potencies beyond Avogadro limit; ANOVA: Analysis of variance, CI: Confidence interval, SD: Standard deviation, SE: Standard error. t68: t score at 68 degrees of freedom. pa: Inter-group differences detected by unpaired t-tests. pb: Inter-group differences detected by two-way repeated measures ANOVA models. pc: Intra-group changes detected by one-way repeated measures ANOVA. *p < 0.05, **p < 0.01, ***p < 0.001
IGT
After 3 months, inter-group difference was shown no statistical significance difference between both groups, unpaired t-test (mean difference: 3.86, 95% CI: −7.37– 15.09, p = 0.49) and two-way repeated measures ANOVA (F1,68 = 0.562, p = 0.456) with very small size effect (Cohen’s d = 0.16, partial eta-squared η2 = 0.010). Intra-group difference was statistically very significant in both groups IHMs-WA group (F2,68 = 5.55, p < 0.01, partial eta-squared η2 = 0.14; one-way repeated measures ANOVA), and IHMs-BA group (F2,68 = 17.41, p < 0.001, partial eta-squared η2 = 0.339, oneway repeated measures ANOVA) [Table 4].
Medicines used
Overall, in this study, 22 different medicines were prescribed with different potencies. The most frequently prescribed medicines were Sulphur (n = 8, 11.4%), Lycopodium clavatum (n = 7, 10.0%) and Natrium muriaticum (n = 6, 8.6%) [Table 5].
| Name of the medicine | Total n (%) | Group 1 (n=35) n (%) | Group 2 (n=35) n (%) |
|---|---|---|---|
| 1. Arnica montana | 02 (2.9) | 00 (0.0) | 02 (5.7) |
| 2. Arsenicum album | 02 (2.9) | 01 (2.9) | 01 (2.9) |
| 3. Belladonna | 02 (2.9) | 01 (2.9) | 01 (2.9) |
| 4. Bryonia alba | 02 (2.9) | 01 (2.9) | 01 (2.9) |
| 5. Calcarea carbonica | 03 (4.3) | 01 (2.9) | 02 (5.7) |
| 6. Carbo vegetabilis | 04 (5.7) | 02 (5.7) | 02 (5.7) |
| 7. Chelidonium majus | 01 (1.4) | 01 (2.9) | 00 (0.0) |
| 8. China officinalis | 03 (4.3) | 01 (2.9) | 02 (5.7) |
| 9. Gelsemium sempervirens | 02 (2.9) | 01 (2.9) | 01 (2.9) |
| 10. Hepar sulphur | 02 (2.9) | 02 (5.7) | 00 (0.0) |
| 11. Insulinum | 01 (1.4) | 01 (2.90 | 00 (0.00 |
| 12. Lycopodium clavatum | 07 (10.0) | 03 (8.6) | 04 (11.4) |
| 13. Medorrhinum | 01 (1.4) | 01 (2.9) | 00 (0.0) |
| 14. Natrium muriaticum | 06 (8.6) | 04 (11.4) | 02 (5.7) |
| 15. Nitricum acidum | 02 (2.9) | 00 (0.0) | 02 (5.7) |
| 16. Nux vomica | 04 (5.7) | 02 (5.7) | 02 (5.7) |
| 17. Pulsatilla nigricans | 03 (4.3) | 02 (5.7) | 01 (2.9) |
| 18. Rhus toxicodendron | 02 (2.9) | 00 (0.0) | 02 (5.7) |
| 19. Ruta graveolens | 03 (4.3) | 01 (2.9) | 02 (5.7) |
| 20. Sepia officinalis | 02 (2.9) | 01 (2.9) | 01 (2.9) |
| 21. Sulphur | 08 (11.4) | 04 (11.4) | 04 (11.4) |
| 22. 'Thuja occidentalis | 01 (1.4) | 00 (0.0) | 01 (2.9) |
AEs
Participants were actively monitored for AEs throughout the study. Monitoring protocols included scheduled visits every 14 days and telephonic follow-ups, during which participants were queried about any new or worsening symptoms using a standardised AE reporting form designed for AYUSH interventions.[20] Each reported event was evaluated for onset, duration, severity and potential causality by the AYUSH Pharmacovigilance Committee, if required. No serious AEs were observed and reported from both groups during the study, and any minor AEs may have been self-limiting and unknowingly resolved without additional intervention.
Statement of ethics
Approval was obtained from the Institutional Ethics Committee (Ref. No. MHMCH/A-12/38; dated 22 January 2024), and this trial was prospectively registered in the Clinical Trials Registry—India (CTRI/2024/02/063065) before starting this trial, with a secondary identifier of U1111-1302-1628 (universal trial number); full data sheet of protocol is available on https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTAwMjMz&Enc=&userName=CTRI/2024/02/063065. The study protocol followed the latest revised Declaration of Helsinki on Human Experimentation.[21] Before enrolment, each participant was provided with an information sheet in the local language detailing the objectives, methods, risks and benefits of participating, and confidentiality issues. Written informed consent was obtained from all patients.
DISCUSSION
This exploratory, randomised, parallel-arm trial was designed to compare the efficacy of potencies of IHMs administered beyond the Avogadro limit with within limits, in managing glycaemic control original pre-diabetic adults. HbA1c percentage was considered the primary outcome, and measured at baseline and after 3 months of intervention. IFG and IGT values were considered as secondary outcomes; and measured at baseline and after intervals of 45 days and 90 days from intervention. After 3 months, no statistically significant inter-group differences were observed in HbA1c (p = 0.37), IFG (F1,68 = 1.8, p = 0.18) and IGT (F1,68 = 0.56, p = 0.456) with small effect sizes of 0.23, 0.39, and 0.46, respectively. The absence of statistically significant inter-group differences after 3 months suggested equivalence of IHMs-BA with IHMs-WA, and comparative efficacy of both homoeopathic treatment groups managing glycaemic control. Intra-group differences were shown to be of notable significance in both groups in HbA1c (IHMs-WA: p < 0.01; IHMs-BA: p < 0.001), IFG (IHMs-WA: p < 0.05; IHMs-BA: p < 0.001) and IGT (IHMs-WA: p < 0.01; IHMs-BA: p < 0.001) after 3 months of intervention. IHMs-BA group exhibited a lower progression rate from PD to diabetic (8.6% vs. 11.4% in the IHMs-WA group) and a higher rate of conversion to non-diabetic status (43.0% vs. 31.4% in the IHMs-WA group). Hence, slightly more notable statistical significance was observed in the magnitude of improvements on IHMs-BA group, which may be highlighting the impact of more dynamic effects of highly diluted homoeopathic medicines, despite the absence of detectable drug molecules as per theoretical expectations; this may be due to random variation, and needs to be further investigated. Although we observed a small effect size in HbA1c, IFG, IGT and moderate mean reduction in HbA1c (0.20% in IHMs-BA, 0.11% in IHMs-WA), while modest, it could be clinically significant since even small reductions in HbA1c are associated with a reduced risk of diabetes-related complications when applied to a larger population or over a long period. After a lack of similar comparative studies, this study’s findings align with a previous study,[2] which reported significant intra-group reductions in FBS but no significant inter-group differences in OGTT over 6 months with highly diluted IHMs. Similarly, another previous study demonstrated that highly diluted IHMs significantly reduced HbA1c and OGTT values compared to placebo, though FBS differences remained non-significant.[10] Differences in study duration (3 vs. 6 months) may explain the variance in findings, indicating that longer trials may be necessary to detect significant inter-group effects. This study has several strengths, including its randomization (to minimise selection bias), comparative design, rigorous ITT analysis, supplementary analysis and adherence to standardised diagnostic criteria (HbA1c, IFG, IGT). Principles of homoeopathy were adhered to throughout this trial; a single medicine was prescribed to treat a single case as per the totality of symptoms. 22 different homoeopathic medicines were used, Sulphur (11.4%), L. clavatum (10.0%), and N. muriaticum (8.6%) being the most common. However, limitations include a smaller sample size, short study duration, and an open-label design that may introduce expectation, performance and detection bias. Lack of placebo or standard-care control and the exploratory nature of the study necessitate cautious interpretation. In addition, we did not account for potential confounding effects of dietary advice, as adherence data were not systematically collected, which may have some probable influence on outcomes. Future research should focus on larger, blinded, multi-centric equivalent or superiority trials with extended follow-ups to confirm findings, explore the mechanisms of highly diluted homoeopathic medicines, and assess the potential role of potencies beyond Avogadro limit in glycaemic control. Future trials should include a placebo or standard-care control group to better isolate the specific effects of homoeopathic interventions. In addition, incorporating biomarkers such as insulin resistance (HOMA-IR) and objective measures such as quality of life (QoL) assessments will provide a more comprehensive evaluation of treatment efficacy.
CONCLUSION
This exploratory, randomised, parallel-arm comparative trial demonstrated no statistically significant inter-group differences, while significant intra-group improvements amongst HbA1c, IFG and IGT levels in both groups, with a higher percentage of participants progressing to non-diabetic status in both groups, which may suggest that despite theoretical differences regarding the presence of active molecules in high dilutions, IHMs administered beyond Avogadro limit are equivalent to within the limit in their efficacy for glycaemic control. Sulphur, L. clavatum, N. muriaticum were the most frequently prescribed medicines in the trial. Due to the exploratory nature of this study, over-generalisation of the interpretation of these findings should not be advised. Although promising trends were observed on IHMs-BA, they require validation through further robust, multi-centric and blinded superiority trials with larger sample sizes to confirm the potential superiority of IHMs-BA and to better delineate the comparative efficacy of homoeopathic medicines at different potency levels.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Highlights
Comparative efficacy of IHMs at potencies beyond Avogadro limit with those within it was evaluated in an open-label randomised trial of 3 months duration, on 70 pre-diabetic adults.
No statistically significant differences were observed between the two groups, although significant intra-group improvements and higher percentage of participants progressing to non-diabetic status were observed in both groups. IHMs potencies beyond the Avogadro limit shown slightly more pronounced effect on within-group findings, which may be due to random variation and should be further investigated.
Acknowledgment:
Regards to higher authorities of the institute for their continuous support, and to Prof Dr. Subhamoy Ghosh, Prof Dr. Subhasish Ganguly, and Prof Dr. Sangita Saha for guiding in framing the study protocol. Acknowledgement for the institutional ethics committee members, all the visiting physicians, professors, medical officers, other hospital staffs, patients, library staffs, all my friends and senior and junior fellows for their cooperation that provided an opportunity to complete the study. Acknowledgment to central council for research in homoeopathy (CCRH) for giving us an opportunity to conduct this study under short-term studentship in homoeopathy (STSH).
Ethical approval:
The research/study was approved by the Institutional Ethics Committee at Metropolitan Homoeopathic Medical College and Hospital, vide number MHMCH/A-12/38, dated 22nd January 2024 and this trial was prospectively registered in the Clinical Trials Registry—India (CTRI/2024/02/063065).
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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