Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disorder characterized by insulin resistance, relative insulin deficiency, and persistent hyperglycaemia. The global burden of T2DM has reached epidemic proportions, with a disproportionately high impact on low- and middle-income countries. India, in particular, faces a rapidly increasing prevalence of diabetes, driven by urbanization, lifestyle changes, genetic susceptibility, and aging populations. The long-term nature of diabetes necessitates sustained pharmacotherapy, often accompanied by lifestyle modification and continuous clinical monitoring.

 

Metformin remains the first-line pharmacological agent for the management of T2DM, as recommended by major international guidelines. Its widespread use is attributed to its proven efficacy, favorable cardiovascular profile, weight neutrality, low cost, and minimal risk of hypoglycaemia when used as monotherapy. Metformin exerts its antihyperglycaemic effect primarily by suppressing hepatic gluconeogenesis, improving peripheral insulin sensitivity, and reducing intestinal glucose absorption. Despite its overall safety, metformin therapy is not entirely free from adverse effects, with gastrointestinal intolerance being the most commonly reported complication.

 

In recent years, there has been a marked increase in the use of complementary and alternative medicine (CAM), particularly herbal products, among patients with chronic diseases such as diabetes. Herbal medicines form an integral component of traditional healthcare systems including Ayurveda, Unani, Siddha, and folk medicine, especially in India. Many patients perceive herbal remedies as “natural,” safer alternatives to conventional drugs, or as effective adjuncts capable of enhancing glycaemic control.

 

Several commonly used antidiabetic herbs—such as Momordica charantia (bitter gourd), Trigonella foenum-graecum (fenugreek), Gymnema sylvestre, cinnamon, aloe vera, and jamun—have demonstrated glucose-lowering properties in experimental and clinical studies. These herbs exert their effects through diverse mechanisms including enhanced insulin secretion, improved insulin sensitivity, delayed carbohydrate absorption, antioxidant activity, and modulation of inflammatory pathways. While these properties may offer potential therapeutic benefits, they also raise concerns regarding herb–drug interactions when used concomitantly with conventional antidiabetic agents.

 

Herb–drug interactions may be broadly classified into pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic interactions involve alterations in drug absorption, distribution, metabolism, or elimination, while pharmacodynamic interactions occur when herbs and drugs share similar or opposing mechanisms of action. Unlike many oral antidiabetic agents, metformin is not metabolized by hepatic cytochrome P450 enzymes; instead, it relies heavily on membrane transporters for absorption and renal elimination. Herbal constituents capable of modulating intestinal transporters or renal excretion pathways may therefore influence metformin exposure and safety.

 

Pharmacodynamic interactions are particularly relevant in the context of diabetes management. Many antidiabetic herbs possess intrinsic hypoglycaemic activity and may exert additive or synergistic glucose-lowering effects when combined with metformin. Although metformin alone rarely causes hypoglycaemia, its concomitant use with insulin-secretagogue or insulin-sensitizing herbs may increase the risk of excessive glucose lowering, particularly in vulnerable populations such as the elderly or patients with long-standing diabetes.

 

Another critical concern is the underrecognition of herb–drug interactions in routine clinical practice. Patients frequently do not disclose herbal medicine use to healthcare providers, often due to the belief that herbal products are inherently safe or due to fear of disapproval. Conversely, clinicians may fail to routinely inquire about CAM use. This communication gap increases the risk of unrecognized adverse events, inappropriate dose escalation of antidiabetic drugs, and delayed identification of interaction-related complications.

 

Despite growing awareness of herb–drug interactions, real-world clinical data on the safety consequences of herb–metformin co-administration remain limited. Most available evidence is derived from small randomized trials, experimental studies, or case reports, which may not reflect actual patient behavior or long-term outcomes. Prospective observational studies capturing naturalistic patterns of herbal use and associated adverse events are therefore essential to inform clinical practice.

 

The present study was designed to address this gap by systematically evaluating the safety profile and adverse clinical outcomes associated with concurrent use of herbal medicines and metformin in patients with T2DM. By focusing on hypoglycaemia, gastrointestinal intolerance, and other clinically relevant adverse events, this study aims to provide evidence-based insights into the real-world safety implications of herb–metformin interactions.

Study Design This study was designed as a prospective observational study aimed at evaluating the safety outcomes associated with concomitant use of herbal medicines and metformin in patients with type 2 diabetes mellitus. A prospective observational approach was selected to capture real-world treatment patterns and patient behavior without altering standard clinical management. Study Setting The study was conducted in the Departments of Medicine and Pharmacology of a tertiary care teaching hospital. Patients were recruited from both outpatient and inpatient services to ensure inclusion of individuals with varying disease durations and comorbidity profiles. Study Duration The total duration of the study was 18 months, comprising: • 3 months of patient recruitment and baseline assessment • 9 months of prospective follow-up • 3 months of data verification and validation • 3 months of statistical analysis and manuscript preparation Study Population Adult patients diagnosed with type 2 diabetes mellitus and receiving metformin-based therapy were screened for eligibility. Inclusion Criteria Patients meeting all of the following criteria were included: • Age between 30 and 70 years • Diagnosed cases of type 2 diabetes mellitus • Receiving metformin monotherapy or metformin-based combination therapy for at least six months • Willing to participate and provide written informed consent Exclusion Criteria Patients meeting any of the following criteria were excluded: • Type 1 diabetes mellitus or secondary diabetes • Insulin-only treatment regimens • Severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m²) • Severe hepatic dysfunction • Pregnant or lactating women • Patients unwilling or unable to provide informed consent Sample Size A total of 400 patients were enrolled in the study. This sample size was considered adequate to detect clinically meaningful differences in adverse event rates between herbal users and non-users, based on previously reported prevalence of herbal medicine use among patients with T2DM. Data Collection Data were collected using a pre-designed, structured case record form. The proforma was pilot-tested prior to implementation to ensure clarity and completeness. The following information was documented: Demographic and Clinical Data • Age and sex • Duration of diabetes mellitus • Body mass index (BMI) • Presence of comorbid conditions such as hypertension and dyslipidaemia Antidiabetic Therapy Details • Metformin dose and duration • Concomitant oral antidiabetic drugs, if any Herbal Medicine Use • Type of herbal product(s) used • Form of consumption (raw, powder, decoction, capsule, extract) • Duration and frequency of use • Source of herbal product • Disclosure of herbal use to healthcare provider Safety Outcome Measures The primary safety outcomes assessed were: Hypoglycaemia Hypoglycaemia was defined as the occurrence of symptoms consistent with low blood glucose, with or without documented plasma glucose levels <70 mg/dL. Episodes were classified as mild or moderate based on symptom severity and need for assistance. Gastrointestinal Adverse Effects Gastrointestinal adverse effects assessed included: • Diarrhea • Nausea • Abdominal bloating • Abdominal discomfort Other Adverse Events Any additional adverse events reported during follow-up were documented and evaluated. Adverse Drug Reaction Assessment All suspected adverse drug reactions were assessed using the WHO–UMC causality assessment scale. Severity was graded using standard clinical criteria. Appropriate medical management was provided when necessary. Laboratory Investigations Routine laboratory investigations, including fasting plasma glucose, post-prandial glucose, and HbA1c, were performed as part of standard clinical care and reviewed to contextualize adverse events. Statistical Analysis Data were entered into Microsoft Excel and analyzed using SPSS version 31. Continuous variables were expressed as mean ± standard deviation, and categorical variables as frequencies and percentages. Comparisons between herbal users and non-users were performed using the Student’s t-test for continuous variables and chi-square or Fisher’s exact test for categorical variables. A p-value <0.05 was considered statistically significant.