Systematic Review of effects of Shodhana & Shmana Chikitsa in Ayurveda in the Management of Diabetes Mellitus Type-II (Prameha)

Introduction: Diabetes mellitus is a complex metabolic clinical condition. It induces some irreversible pathological changes in the body, which rise to multiple complications. Moreover, the side effects of the established anti-hyperglycemic agents in contemporary science on their long-term use make it more worst. Considering the higher incidence rate of Diabetes mellitus due to faulty lifestyle, it is essential to think over various safe but effective measures in alternative science. i.e., Ayurveda. In Ayurveda, diabetes mellitus can be correlated with Prameha or Madhumeha due to similarity in signs & clinical features. 
Aim & Objective: The prime aim of this study is to study the efficacy and safety of different Shodhana & Shamana Chikitsa in Ayurveda for glucose control & improvement in clinical features during the management of Diabetes Mellitus Type II(Prameha W.S.R). 
Materials & Methods: This is a meta-analysis of Ayurvedic interventions in Shodhana, or Shamana Chikitsa used to manage Prameha (Diabetes mellitus type II). On extensive Review of the literature, 42 clinical studies (R.C.T. & N.R.C.T.) fulfilling inclusion criteria & conducted with 1743 participants at different places were critically analyzed. Adequate details of the individual studies were tabulated and discussed. 
Observations & Results: It is reflected that the combinations of both these interventions are more effective than only Shaman Chikitsa in the management of Diabetes mellitus. 
Conclusion: All of these interventions in Ayurveda reviewed through this study are appeared to be generally safe and effective, having a prime or adjuvant role. However, Ayurvedic physicians should prescribe them based on their clinical judgment, patient’s references, type of pathology, chronicity of the disease & strength of the patient.


INTRODUCTION
Diabetes mellitus Type II is a metabolic disorder that causes high glucose levels in the blood. In non-insulin-dependent conditions characterized by peripheral insulin resistance at the cellular level. Diabetes Mellitus currently affects more than 62 million Indians, which is more than 7.2% of the adult population [1]. The average age on onset is 42.5 years in India [2]. The prevalence of Diabetes has been rising more rapidly in low and middle-income countries than in high-income countries [1][2][3][4]. It is the leading cause of 2.6% of global blindness & kidney failure [4]. Many textual references & clinical shreds of evidence show more chances of recurrent complications due to uncontrolled sugar. Adults with Diabetes have a two-to three-fold increased risk of heart attacks and strokes.
Its current management includes dietary restrictions, physical activity, oral antidiabetic agents, and insulin regimen, but it offers no permanent relief. Most hypoglycemic agents have adverse effects like Gastrointestinal upset, dizziness, etc. Lactic acidosis induced by them becomes life-threatening multiple times [5]. Considering the above need-based scenario, it becomes imperative to search or review safe & effective interventions for the management of Prameha in alternative science, i.e., Ayurveda.
In Ayurveda, Madhumeha (type of Prameha) can be correlated with Diabetes II. It is a urinary disorder with an increased frequency of turbid urination.
It is Bahudoshavasthajanya, Avaranajanya, or Tridoshaja Vyadhi, which is primarily hereditary or caused due to insalubrious activities [6]. In Ayurveda, Panchakarma is the essence of Ayurveda, and it includes five procedures viz. Vaman, Virechan, Basti, Nasya & Raktamokshana have immense potential to treat lifestyle disorders like diabetes mellitus because these procedures help remove toxins from the body at the cellular level. Therefore, it has become effective in curing many metabolic diseases. Previous clinical studies conducted with various Shodhana procedures or palliative treatments in the form of different herbal or herbo-mineral drugs with lifestyle regulations over diabetic patients showed encouraging results.

Aim and Objectives
Considering the above scenario, this systemic review study is planned to review various research articles based on the management of Prameha with various drugs(herbal or herbomineral) or Shodhana Karma (Vaman, Virechan, Basti, Nasya. etc.) & to make specific treatment protocol for it. The prime objective of this study is to assess the efficacy and safety of Shodhana & Shamana Chikitsa or their combinations for glucose control in patients with Prameha.

Study Selection
Data regarding all previous Ayurvedic clinical studies conducted in patients with Prameha is collected from NCBI from 2004 to 2019. References of key articles in only the English language were hand searched. Review studies, Case studies, Animal studies, or Clinical studies in Ayurveda on Diabetic complications were excluded from this study.

OBSERVATIONS AND RESULTS
Details of the trials included in the study were discussed descriptively as follows: 3.1 Neethu. K. J, et al. [7] In this study, ten diabetic patients underwent Virechana with Trivrut Lehya, preceded by Udwartarna with Triphala+Kolakulathadi Choorna, followed by Takra Dhara with Musta, Amlaki, Asnadi, and Takra for 14 days, followed by Shodhana Snehapana with Moorchita Til Taila and Sarvanga Abyanga with Moorchita Taila. After Sansarjana Karma, the patient was assessed for clinical features of Prameha, which showed significant results, which concluded that Rookshana Poorvaka Virechana Karma is highly beneficial in the management of Sthula Madhumeha [7].

Manjunath Akki et al. [8]
In this study, the study population(n=30) was equally divided into two groups, in which group A

Anchal Lalhal et al. [9]
In this study, the study population(n=20 patients) was equally divided into two. Among them, a group I underwent for Virechana was preceded by Shodhana Snehapana with Triphala Ghrita and followed by Tryushnadi Gutika 1 gm T.D.S. with lukewarm water for 45 days. Group II was prescribed only for Shaman Yoga, i.e., Tryushnadi Gutika (Chikitsa.).The clinical features Prabhuta Mutrata, Pipasaadhikya, Kshudhaadhikye, Shaithilya, Karapada Suptata, Pindiko Udveshtana, Mukha Shosha were statistically significantly reduced (p<0.05). Moreover, reduction in fasting blood sugar was significantly reduced by 29.88%.In objective parameters, a 29.88% reduction in fasting blood sugar was observed in group-I. In contrast, in patients of group II, a 1.88% reduction was observed, but the intergroup difference was insignificant statistically (p>0.05); Group I was found more effective than Group I [9].

Karda Rinku et al. [10]
In this study, the Group A (n= 30

Vardhan Vishnu et al. 2018
In the present clinical study, 27

Varsha Khot et al. [15]
Forty patients were divided equally into two groups and advised to undergo, i.e., Group. A with Shirodhara with Tila Taila daily once at 8 am and Group B with oral administration of Jatamansi Churna 1 gm with Koshna Jala for consecutive 21 days. Group B was found more effective than group A especially to reduce F.B.S. & P.P.B.S. by 91.06% and 75.78%, respectively [15].

Vikas Nariyal et al. [16]
A total of 30 diabetic patients were equally divided into three groups in this clinical study. Group A, group B, and Group C have prescribed Harishankar Ras (125 mg twice a day with lukewarm water), Khadir-Kramuk Kwath (40 ml B.I.D. in empty stomach), and a combination of both medicines, respectively. Group C was found significantly more effective in reducing the severity of clinical features, e.g., than group A & B Prabhutamutrata (71.42%), Pipasadhikya

Tank B. et al. [18]
The Clinical trial was carried out with ten patients in each three groups, i.e., Group A with Darvyadi Kwath (50ml twice a day with empty stomach), Group. B with Madhumehari Churna (5gm twice a day before half-hour for a meal with lukewarm water) & Group. C with both drugs for 30 days. Though all three groups are found effective in reducing blood glucose levels, Grp. C is comparatively more effective in reducing FBS, PPBS & HbA1c by 21.71%,25% & 5.49%, respectively [18].

Hakkandil Suresh et al. [19]
Thirty patients were equally divided into three groups. Group C was found more effective than the rest of the two groups to reduce F.B.S., F.U.S., P.P.U.S. & HbA1C by 25%, 73%, 83% & 5%, respectively, while Group B was more effective than group A & C to decrease P.P.B.S. by 23 [19].

Gupta V. et al. [20]
In this study, 90 recruited patients were randomly divided into two groups and Group A with cap. Shilajit (500 mg twice daily) and Group B with Asanadi Ghana Vati (2 Vati twice daily) were studied for three months. Ten patients were dropped from the study.

Jena Sonalika et al. [23]
This clinical study was carried out with 50 patients equally divided into three groups with different interventions for one month, i.e., Group I with Phalatrikadi Kwatha 50ml+ 1gm of Haridra Churna+ 10 ml honey twice daily before a meal (Trial Drug), Group II with Metformin 500mg1 tab O.D. (control drug) and Group III with placebo 50ml +1gm of Haridra Churna + 10 ml of Honey twice daily before a meal. Though all three groups effectively correct signs and symptoms of diabetes mellitus, a group I was found more effective to reduce Daurbalya, Pipasadhikya, Pindikaveshtam, P.P.B.S. by 74.58%, 94.34%,84.78% &16.66%, respectively. Group II was more effective than the rest of the two groups to decrease F.B.S. by 20.36% & group III significantly reduced Prabhutamutrata by 54.48% for p-value 0.001 [23].

Agarwal Prateek et al. [24]
Among 46 patients recruited in this study are equally divided into two groups with different interventions for one & a half months, i.e., Grp

Kumar S. et al. [25]
Total 84 Patients were randomly divided into three groups, i.e., Group-A (n=33) was treated with the trial Drug, i.e., Mamajjaka (500mg twice a day), Group B (n=23) was subjected to Shilajatu (500mg twice a day) and Group C (n=28) with the modern antidiabetic Drug. After assessment for three months, it was observed that the trial treatment could produce a statistically significant favorable shift in grade scores (p<0.01) in most of the symptoms (polyuria, polyphagia, polydipsia, weight loss, weakness, loss of libido, joint). The Mamajjaka treated patients have shown a better percentage of fall in F.B.S. (19.47%), in comparison to Shilajatu treated patients (8.93%), while in the case of P.P.B.S., the percentage of reduction was almost equal in both the groups, that is, 24.03% [25].

Kolhe N. S et al. [26]
Total 30 patients completed the study in which those were randomly and equally divided into three groups, i.e., Grp.1 with Katak Khadiradi Kashyayam (20 ml twice daily before meal), Grp.2 with Niruryadi Gulika (500 mg 2 tablets with lukewarm water twice daily before meal) & Grp.3 with combinations of both drugs.
After the interventions for 30 days, it was observed that Group 1 was found comparatively more effective to reduce HbA1C by 3.27% than the other two groups, while Group 2 was significantly effective in decrease the severity of clinical symptoms, e.g., Prabhutamutrata, Kshudhadhikya

Jindal N. et al. [27]
In this study, 20 diabetic patients were randomly but equally subdivided into two groups, i.e., group A with Vamana using Ikshwaku Beeja Choorna mixed with Honey in a dose of 4-8 gm as per the requirement of the patient) and group B with Virechana using Snuhibhavita Katuki in a dose of 6-10 g as per the Kostha).Deepana Pachana preceded both these interventions with Trikatu Churna(3-6 g/day in two divided doses for 3-5 days), which was followed by Aabhyantara Snehapana with Triphaladi Ghrita in increasing dose as per the Koshtha and Agni of the subject for 3-7 days, Sarvanga Abhyanga with Tila Taila  The researchers concluded that emesis therapy has a better role in the prevention of NIDDM in pre-diabetic subjects and also capable of maintaining long-lasting glycemic control in NIDDM subjects [28].

Karhade Mukund [29]
A total of 30 patients were subdivided into two groups with two distinct interventions, i.e.,

Pandey RK et al. [32]
This clinical study is conducted over 38 Sthula Pramehi patients in which they were divided into two groups, viz.

Thirunavukkarasu M S et al. [34]
It is a single group study of over 20

Parmar Darshan et al. [35]
Total 92 diabetic patients were studied within two groups with intervention with mineral compound orally that is prepared with two distinct methods, i.e.,

Khedekar S et al. [36]
In this clinical study, a total of 126 patients were treated with Makaradhwaja prepared from three different types of Swarna with Sahapana, i.e.,

Tate P. [38]
Total 56 patients equally divided into two groups, i.e., Group A with Naga Bhasma orally(60 mg B.D.) & Group B with Naga Bhasma with placebo capsules(1 cap.). After 28 days, significant relief in all signs and symptoms were observed, along with a significant decrease in blood glucose level (fasting and 2 hr) was found in both Drug treated groups. & Naga Bhasma prepared by both methods is equally effective [38].

Aithal P et al. [43]
In this clinical trial, a total of 24

Pakanikar Satish et al. [44]
In this clinical study, 26 patients were subjected to Group I (n=09) with kernel powder of the Kuberaksha seeds in the capsule form & Group II (n=17) with Kuberaksha Ghanavati of the kernel with Lukewarm water each for six weeks. Both Kuberaksha Ghanavati and the kernel powder of the seed had induced a reduction in blood sugar at a low dose. Still, in the Ghanavati group, the blood sugar level was increased but statistically significantly decreased in the kernel powder of the seed at a high dose [44].

Anand M. et al. [47]
Twenty-nine patients were divided into three groups, i.e., Group-I with Pramehaghna Ghana Vati orally (2 gm a day thrice with lukewarm water for 1 ½ month), Group-II with Pramehghna Basti for 16 days including Niruha and Anuvasana, and Group-III with Placebo capsule -500mg thrice a day. The study duration was two months. Strict diet control and exercise were advised to all groups. The researchers concluded that both Basti and Pramehaghna Ghana Vati offered more encouraging results. Still, percentage relief was more in Basti group than rest of two groups & Basti can prove better treatment modality for Avaranjanya Madhumeha because the drugs used in it acts against the Kapha, Meda, and Kleda and Sneha helpful to normalize Vata [47].

Jani Jalpa et al. [48]
The clinical study was done over a total of 50 patients between two groups, i.e., Group A(n=25) with Vastraputi Vanga Bhasma and Group B (n=22) 22 with Vanga Bhasma prepared by Jarana and Marana. A highly Significant result was observed in symptoms like Prabhutmutrata, Aavilmutrata, Kshudhadhikya, Trishadhikya, and Pindikoudvesthana groups. However, the interventions were not significant & effective in reducing blood glucose levels [48].

METHODS
The core observations of all these studies are summated as follows:

Type of Randomization and Methodology
The number of included trials with different methodology is mentioned in Table 1 . Among the total of 42 clinical trials enrolled, 01 trial study was multi-centric, and the rest all were single centric trial studies. Among them, 03 R.C.T.with single-blind while 01 R.C.T. has study design having a double-blind controlled study. The rest of the 38 were simple random studies. The sample size of the studies was found to vary; the minimum sample size was 05 & maximum 126. There are total R.

Inclusion-Exclusion Criteria
Confirmed cases of Diabetes Mellitus type II with either sex diagnosed based on clinical features & laboratory investigations were included in maximum clinical trials. All these patients recruited in the studies were from 30 and 65 years, irrespective of gender. Patients with ages between 30-60 years were primarily preferred in these trials. Both obese & non-obese patients of Diabetes mellitus are included. Further details are narrated in Table 2.
Patients having pre-diabetes, Type I DM [IDDM], Diabetes insipidus, Drug-induced, Uncontrolled, or Diabetes Mellitus with complications were excluded from this study. Diabetic patients on Insulin therapy were also not recruited in this study.

Assessment Parameters
All these studies were critically analyzed based on the type of Subjective or objective criteria used, type of intervention subjected & their therapeutic outcomes reported. Assessment in meta-analysis will be done by  The status of Oja & Agni was also taken into consideration. These details are given in Table 2.

Type of Intervention
Recruited trials are classified based on the type of treatment modalities or intervention (Shodhana Chikitsa, Shamana Chikitsa, or their combination) used to manage Prameha. The number of studies with these different interventions is tabulated in Table 3. Among Shodhana, these trials are again sub-classified under heads of Only single therapy of Panchkarma, i.e., Only Vamana, Virechana, Vasti, or comparison/combinations of any two or three that is depicted in Table 4. Among the use of Shamana Chikitsa, these trials are again subclassified under heads as Only herbal drugs, mineral drugs, or combination, i.e., herbo-mineral drugs or Lifestyle modifications with details of the dosages and duration of treatment that are provided in Table 5. Open study 02 4 Single-blind Studies 01 5 Double-blind Studies 01 6 Single-center study 41 7 Multi-center study 01 Studies conducted with only objective criteria 04 3 Studies with combinations of both 37

RESULTS AND DISCUSSION
Diabetes mellitus is a clinical condition that is strongly characterized by elevated blood sugar levels due to primary or secondary deficiency of insulin. Acharya Sushruta has classified the Prameha as Asantarpanoth & Santhoparsthanoth Prameha based on its pathology & he also narrated their specific management according to Hetu [49]. Therefore, the selection of any regime, procedure, or Drug for the management of Prameha should be meticulously after assessing this cause. Increased demand for Ayurvedic medicines or interventions due to the high cost and innumerable side effects of allopathic medications is vital.

Role of Shodhana Chikitsa
Panchakarma plays a vital role in preventing & manage Diabetes mellitus successfully as all recommended procedures detoxify the body by eliminating the stagnated, vitiated Doshas out of the body in a smooth manner. Shodhana therapy is the first line of treatment for the diabetic patient who is obese or overweight, according to various texts. The role of Panchakarma for the management of Prameha can be discussed one by one as follows:   Anti-oxidant & immunomodulatory improve metabolism, anti-inflammatory properties of such drugs (due to its Rasayana Guna), which may stimulate the Beta cells in the pancreas, which secretes the hormone insulin insufficient amount or may increases secretion of endogenous insulin by regeneration or revitalization of the residual beta cells or may check over the destruction of βcell or their necrosis. Improvement in better sensitivity of pancreatic β-cells with the prompt secretion of a large quantity of insulin in response to hyperglycemia due to their pancreatotrophic action can be explained.  Lekhana Dravyas are useful in Sthula Pramehi, which are also helpful skin lesions induced in Prameha due to its Rakthaprasadana, Kushtahara, and Vranaropana properties.

Role of Shamana Chikitsa
In a nutshell, as Shodhana Chiktsa destroys the root of disease, it is easily possible to check over the pathogenesis of Prameha to avoid the recurrence of diseases & to avoid the sideeffects of oral allopathic hypoglycemic agents with the help of above various Ayurvedic measures. These drugs may also become helpful to minimize doses of contemporary OHA or even to stop their use in a person with good control by using them in the early stage of the disease [50][51][52][53][54][55][56].

CONCLUSION
After critical analysis of all studies, it is found that Ayurvedic interventions, i.e., Shodhana Or Shamana Chikitsa, can successfully manage this condition and significant improvement in clinical features of D.M.This study proves that rational use of Ayurvedic interventions can successfully manage D.M. in primary stage or newly diagnosed cases. Moreover, these interventions also proved their supportive or adjuvant role with the contemporary treatment protocol. All reported interventions are pharmacological or nonpharmacological in approach. They have assessed their effectiveness in both prevention & management of the disease to avoid progression of disease& further complications of D.M. Other multi-centric trials with a large sample size are expected in the future to generate more substantial clinical evidence regarding the above interventions.