Type 2 diabetes mellitus (T2DM) is one of the important public health problems and accounts for 90-95% of all diabetes. ¹ T2DM is a long-lasting metabolic disease caused as a result of a combination of resistance to insulin action and an insufficient compensatory insulin secretory response. ^{2 , 3} Globally, the number of people having diabetes mellitus is rising. ^{4 , 5} In 2017, 6.28% of the world’s population had T2DM, which is equivalent to approximately 462 million individuals. Furthermore, these estimates are expected to rise to 7,079 individuals per 100,000 by the year 2030. ⁴ T2DM ranked seventh and ninth in the year 2017, among the leading causes of disability adjusted life years lost and deaths, respectively, as compared to the nineteenth and eighteenth position, respectively, in 1990. ⁴

Diabetes in general has a significant effect on individuals' functional capacities and quality of life (QoL). ⁴ Individuals with diabetes are vulnerable to many health-related complications such as cardiovascular diseases, kidney failure, delayed wound healing (leading to diabetic foot and ultimately to leg amputation if not treated), vision loss, nerve damage ^{2 , 6} and microvascular damage. ^{5 , 7} It is also known to reduce life expectancy. ² Diabetes and its complications bring about significant financial loss to individuals with diabetes and their families through direct medical cost and loss of work and wages, and in some cases catastrophic health spending. ² Increased duration of treatment, presence of complications, hospitalization, surgery and insulin therapy leads to increased expenditure ⁸ affecting the health system and national economy. ²

Alternative treatments with potential anti-hyperglycemic effects are commonly used for chronic diseases such as T2DM. “Complementary and Alternative Medicine” (CAM) is defined by the World Health Organization as “ broad set of health care practices that are not part of that country’s own tradition or conventional medicine and are not fully integrated into the dominant health-care system”. ⁹ CAM includes various types of therapies such as acupuncture, body work (e.g., massage), energy healing (e.g., reiki), herbal or traditional medicines (e.g., naturopathy, Ayurveda, Chinese medicine), mind body techniques (e.g., meditation, yoga), faith healing and music therapy. ^{10 , 11}

The global use of CAM varies between 9.8% and 76% of the population. ^{12 – 14} Every four out of five individuals living in developing countries still depend on CAMs for treatment of certain health conditions. ¹⁰ A recently published meta-analysis found a global prevalence of CAMs to be 51% (95% confidence interval 43, 59). Use of CAM as a complementary medicine in addition to conventional therapy was found to be 78%. However, as an alternative to conventional medicine was found to be 21%. ⁹ CAM has been used extensively also for other conditions, for instance, 40% cancer patients using CAM. ¹⁵ A review also found that about 67% of the people who use CAMs did not disclose its use to healthcare professionals. ⁹ Furthermore, individuals with diabetes are 1.6 times more likely to use CAMs than non-diabetics as reported in 2014. ¹⁰ Similarly, diabetes is one of the main diseases, for which patients consult Ayurvedic practitioners and consume Ayurvedic medications. ⁶ In the United States, around 2-3.6 million people depend on CAMs for the treatment of diabetes, whereas in Australia and the United Kingdom about 46% rely on it. India showed a very high use of CAMs among diabetics accounting for 67% in 2014. ¹⁰ Reasons for the high proportion of individuals with diabetes using CAMs are multi-faceted. These reasons could be higher cost, high level of medication adherence and fear of side-effects of modern allopathic medicines, dissatisfaction with healthcare providers, and easy availability of CAMs without doctor’s prescription. ¹⁰

Diabetes, a complex disease, caused due to pathophysiological changes that affects the whole-body glucose homoeostasis, is a typical example requiring an integrative medicine method for its holistic (complete) management. The pathophysiological web of diabetes along with obesity, inflammation and insulin resistance is a challenge for its management. The current diabetes treatment based on modern medicine focusses on reducing hyperglycemia through targeted molecular medications, which needs long-term use and adherence, along with a continuous increase in dose. ¹⁶ CAMs may act as complementary to modern medicines and help in contributing to a holistic approach. Table 1 provides the list of some of the CAMs and its possible effect in lowering blood glucose levels.

Reducing premature mortality from non-communicable diseases including T2DM by one-third, achieving universal health coverage and providing access to affordable essential medicines to all by 2030 are the targets set by member states as a part of the agenda for 2030 Sustainable Development. ² The emergence of T2DM into global epidemic and accessibility and availability issues of modern medicines to many individuals in low resource-settings have encouraged low-cost, easily available alternative therapies. Most of these alternative therapies claim to manage diabetes in no or minimal side-effects, due to which, most of the people using CAMs for T2DM use it along with conventional therapy. ²¹

Evidence on assessing the effectiveness or efficacy of CAM has increased in recent years. For instance, systematic reviews assessing the efficacy of CAMs on chronic kidney diseases. ^{33 , 34} CAMs are also being evaluated for blood pressure control, chronic pelvic pain and symptom management in palliative cancer care. ^{35 – 37} Furthermore, it is recommended by the American Diabetes Association position statement that a CAMs can be used based on evidence from research. ³⁸ To make the process of implementation of global partnership stronger, SDG 17 is persuading collection, monitoring and accountability of the data. ³⁹ Therefore, timely, good quality and reliable data on CAM therapies for T2DM will help subsequent governments and organizations to take effective steps. Good quality data are also essential in framing the clinical practice guidelines. To inform policymakers, CAMs and the outcomes measured among T2DM and its complications should be known for implementing findings for policy, program development and direct future research. A scoping review can contribute to prioritizing evidence needs as suggested by SDG goal number 17. Scoping reviews map and summarize the extent of literature available on a given topic and identify gaps, which are important for informing future research. ^{40 , 41} To the best of our knowledge, till date there is no scoping review in the area of CAMs and T2DM. Therefore, this scoping review intends to map the evidence on effectiveness of CAMs for T2DM and its associated complications. We will also identify research gaps in key outcomes and CAMs.

Evidence source: Publications that were eligible for inclusion were randomized controlled trials (RCTs) and quasi randomized controlled trials (QRT) (i.e., interventional studies having two groups assessed pre and post and might not have adhered to strict randomization procedures) published until March 2020. Single group pre-post studies, systematic reviews and observations studies were excluded.

Population: Adults (>/= 18 years of age) with a confirmed diagnosis of T2DM (based on appropriate standards such as American Diabetic Association), metabolic disorder or prediabetic condition (marked by elevated levels of blood glucose) were eligible for inclusion. Additionally, individuals experiencing complications, which are associated with DM were included. We excluded adults living with T2DM with multiple organ dysfunction and failure, and those with life support. Additionally, we excluded studies involving type-1 DM, gestational diabetes or diabetes insipidus. In case of mixed population, we coded information of individuals with population of this review interest, if information on the subgroup was provided. If information on the subgroup was not available or in the case of missing information, the study was excluded.

Concept or interventions: Considering the heterogeneity in types, and investigators’ limited resources and experience and knowledge related to other forms of CAM, this review restricted the inclusion of specific types of CAM therapies. The included CAM modalities were Ayurveda, herbal medications, homeopathy, yoga, Unani, Siddha, massage therapy and naturopathy involving multiple modalities. Although CAMs included a wide range of strategies, we did not include vitamin and mineral nutritional supplementations and other CAMs such as Chinese traditional medicines, qigong, tai-chi and reiki. Additionally, a combination of CAM or CAM administered along with conventional medications and lifestyle modifications were eligible. However, these interventions had been equally distributed in all the arms of clinical trials. For orally administered therapy, a drug could be mono- or combi-preparation of any dose, frequency or duration, but it should have been restricted to one type of therapy (e.g., Ayurveda). Similarly, for yoga and massage therapy there was no restriction on type, length per session, frequency and duration. Any mode of administration of these therapies were eligible to be included such as oral or topical application.

Comparison: No intervention, placebo or lower dose of the same intervention, comparison between different therapy and active medications of conventional medicines (e.g., oral hypoglycemic medications) were eligible for inclusion. In case of co-intervention, one arm should have received at least one CAM.

Outcome measures: We considered the following outcomes after reviewing the literature, after consulting the CAM practitioners (who are known to authors). a.

Clinical outcomes: ○

Glycemic control: glycosylated hemoglobin (HbA1c), blood sugar levels: fasting blood sugar levels (FBSL) and 2-hour post-prandial blood sugar levels (PPBSL)

Context: We did not impose any geographic or setting restriction. Studies could have been hospital or community-based.

A comprehensive search was conducted to locate relevant records in electronic bibliographic databases, using a comprehensive search strategy. The scoping review included published studies on CAMs. However, due to time and financial constraints we considered only English publications. Search was undertaken in the following list of databases from their inception till March, 2020. 1.

Electronic databases- Medline (PubMed- NCBI), Web of Science (Clarivate)), “Cochrane Central (Wiley)”, “Cumulative Index to Nursing and Allied Health Literature (EBSCO)”, “SCOPUS (Elsevier)”, and “ProQuest (Central)”.

Search terms such as “Alternative Medicine”, “Alternative Therapies”, “Complementary Medicine”, “Complementary Therapy”, “Ayurveda”, “Yoga”, “Homoeopathy”, “Massage therapy”, “Diabetes” etc. were used to identify relevant literature. A pre-set search strategy was formed by referring to previous studies and trial search carried out initially in PubMed, which was modified with incorporating more keywords and MESH terms. A search string that was resulted from the process was altered to fit the identifiers of each database separately. The PubMed search strategy as an example can be found in the Extended data - DOI: 10.6084/m9.figshare.19512349.v2. ⁴³

Search results of all databases and records identified from other sources were exported to EndNote X7 software and duplicates were removed. Screening, coding and presentation of data was undertaken in Microsoft Excel.

Screening was undertaken at three stages (title, abstract and full texts) by two review authors, independently. A thorough discussion was held between the review authors until consensus, in the case of any discrepancies on the exclusion of eligible records. We followed an extensive screening protocol. The review team did not have expertise in Naturopathy, Unani and Sowa-Rigpa therefore, once the screening was completed, a list of medicines was prepared to be confirmed by professionals working in the field (through our extensive contacts). Based on the experts' recommendations CAMs were categorized.

A pretested coding list was used that consisted of the following variables in details; citation details, study design, country, population (number, age, duration of diabetes, history of oral hypoglycemics and details on the complications), CAM therapies (type, dose, frequency, duration), comparator and outcomes. Data charting was done by six authors. As data charting was not done independently, each study extraction was cross-checked by the second author. Any discrepancy on charted data was resolved with discussion until consensus. We did not carry out critical appraisal of included studies.

The extracted information was mapped descriptively using tables. Frequencies of population, intervention, study details, and country have been reported.

Table 2A contains detailed characteristics of included studies and citations and is provided in the Extended data- DOI: 10.6084/m9.figshare.19512349.v2. ⁴³ In the below text, we have summarized the characteristics of included studies.

Study design: Majority of the studies were RCTs, however we also included quasi-randomized/non-randomized studies having an intervention and control group. Twenty-one studies were efficacy, feasibility or pilot interventional studies.

Country: Studies were carried out in various parts of the world. The geographical distribution of the studies is depicted in Figure 3. As seen in the figure, most of the studies were conducted in India and Iran; both contributing to three-fourths of the identified studies. About four-fifth studies were conducted in Asia compared to other continents.

Population details: Population comprised of prediabetes/metabolic syndrome (n = 28 studies), T2DM not on any hypoglycemic drugs (n = 46), T2DM with hypoglycemic drugs (n = 116) and T2DM with comorbidity (n = 59). Most commonly studied comorbidity was diabetic foot ulcer (n = 27 studies), followed by peripheral neuropathy (n = 11) and other conditions (n = 21). Fifteen studies included newly diagnosed T2DM population (within one year of diagnosis) and remaining others (n = 113) included chronically diagnosed T2DM, however, ninety-three studies did not report the duration of T2DM diagnosis. Majority of the studies (n = 167) included populations with mean ages ranging between 45 to 60 years, however, some studies included older adults or mean ages > 60 years (n = 37) and mean ages younger than 45 years (n = 16), while remaining others (n = 29) included adult population with varying ages. The sample size employed by the studies ranged between 10 and 375. We categorized the studies into sample size of 20 or less (n = 15), 21-50 (n = 84), 51-100 (n = 104), 101-200 (n = 31), and greater than 200 (n = 15).

Intervention details: Herbal or Ayurveda products were assessed by majority of the studies (n = 146), followed by yoga therapies (n = 52), other CAM including massage and topical applications of herbal products (n = 52), Unani medicines (n = 2), Sowa-Rigpa (n = 1) and Homeopathy (n = 1). Within these broad categories various unique complementary therapies were identified and are listed using botanical or trade names in the Extended data – DOI: 10.6084/m9.figshare.19512349.v2. ⁴³

With the help of tables, we have mapped the studies that measured the effectiveness of various CAMs on outcomes among individuals known to have prediabetes or metabolic syndrome, T2DM without any comorbidities and T2DM with comorbidities.

Our extensive scoping review provided the groundwork for a systematic review in coming times to investigate the effect of CAMs on important health outcomes. Our intent was to map the evidence by following JBI methods ^{40 , 41} hence, we did not critically appraise the included studies. We also did not group the multiple publications arising from the same studies. However, future researchers intending to do systematic reviews could overcome these shortcomings. Although we carried out extensive exercise of identifying the literature, databases such as EMBASE and other important subject specific databases were not freely accessible, and had language barriers. Additionally, while searching we did not use unique names (or botanical names) of the individual drugs. Due to the aforementioned reasons, we do not refute the possibility of missing important publications.

Changes from protocol: We changed the title and throughout the manuscript terminology of ‘AYUSH system’, which has restricted usage in India to ‘Complementary and alternative system’ of medicine so as to focus globally. At the protocol stage, we had an intent of mapping systematic reviews, however, due to large volumes of studies we excluded at a full text screening stage.

Figshare. Complementary and alternative system of medicine for type 2 diabetes mellitus and its complications: A scoping review. DOI: https://doi.org/10.6084/m9.figshare.19512349.v2. ⁴³

This project contains the following underlying data: •

This review aims to map the evidence on the effectiveness of Complementary and Alternative Medicine (CAM) for Type 2 Diabetes Mellitus (T2DM) and its associated complications and identify research gaps in key outcomes and CAMs. The protocol was registered with Open Science Forum with DOI: 10.17605/OSF.IO/6CNH7.

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Figshare. PRISMA-ScR checklist. DOI: https://doi.org/10.6084/m9.figshare.19512349.v2. ⁴³

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).