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.

Table 1. Incidence of Hypoglycaemia

Table 2. Gastrointestinal Adverse Effects

Table 3. Risk Factors for Adverse Events

The present prospective observational study provides valuable real-world evidence on the safety and adverse clinical outcomes associated with concurrent use of herbal medicines and metformin in patients with type 2 diabetes mellitus (T2DM). While metformin is widely regarded as a safe and effective first-line antidiabetic agent, the increasing and often unregulated use of herbal products raises important concerns regarding potential herb–drug interactions and patient safety. The findings of this study highlight that herb–metformin co-administration is associated with a significantly higher incidence of hypoglycaemia and gastrointestinal adverse effects, underscoring the clinical relevance of pharmacodynamic interactions in routine diabetes care.

A key observation in this study was the significantly higher occurrence of hypoglycaemic episodes among patients using herbal medicines in conjunction with metformin compared to non-users. Metformin alone is associated with a low risk of hypoglycaemia due to its insulin-independent mechanism of action. However, many commonly consumed antidiabetic herbs possess intrinsic hypoglycaemic properties, including stimulation of insulin secretion, enhancement of insulin sensitivity, and inhibition of intestinal glucose absorption. When such herbs are combined with metformin, additive or synergistic glucose-lowering effects may occur, predisposing susceptible individuals to hypoglycaemia.

This finding is clinically important, as hypoglycaemia is associated with significant morbidity, impaired quality of life, and increased cardiovascular risk, particularly in elderly patients. The present study demonstrated that older age and longer duration of diabetes were significant risk factors for adverse events, suggesting that physiological vulnerability and reduced counter-regulatory responses may amplify the impact of herb–metformin interactions in these populations. These observations emphasize the need for careful risk stratification and individualized patient counseling when herbal medicines are used alongside metformin.

In addition to hypoglycaemia, gastrointestinal adverse effects were significantly more common among herbal users. Gastrointestinal intolerance is a well-recognized adverse effect of metformin therapy, typically manifesting as diarrhea, nausea, abdominal discomfort, and bloating. Several antidiabetic herbs, including fenugreek and aloe vera, are also known to affect gastrointestinal motility and intestinal absorption. The concurrent use of these agents may potentiate gastrointestinal symptoms through overlapping mechanisms, including delayed gastric emptying, increased intestinal fermentation, and modulation of gut microbiota.

The higher prevalence of gastrointestinal adverse effects observed in this study has important implications for medication adherence. Gastrointestinal intolerance is a leading cause of metformin discontinuation or dose reduction. When compounded by herbal use, these effects may further compromise adherence and undermine long-term glycaemic control. Clinicians should therefore consider herbal use as a potential contributing factor when evaluating gastrointestinal complaints in patients receiving metformin.

Another important finding of this study is the strong association between non-disclosure of herbal medicine use and increased adverse event risk. A substantial proportion of patients did not disclose herbal consumption to their healthcare providers, consistent with previous studies reporting poor communication regarding complementary medicine use. Non-disclosure may delay recognition of herb–drug interactions and lead to inappropriate intensification of pharmacotherapy or misattribution of adverse effects. This highlights the critical role of effective patient–provider communication in ensuring medication safety.

The findings of this study align with existing literature suggesting that herb–drug interactions are frequently underrecognized in clinical practice. Most available data on herb–metformin interactions originate from experimental studies, small clinical trials, or case reports. While such studies provide mechanistic insights, they may not accurately reflect real-world patient behavior, including non-standardized dosing, polyherbal use, and variable adherence. The prospective observational design of the present study offers a more realistic assessment of safety outcomes under routine clinical conditions.

From a pharmacological perspective, the observed adverse outcomes are likely driven predominantly by pharmacodynamic rather than pharmacokinetic interactions. Metformin is not metabolized by hepatic enzymes and is eliminated unchanged via renal transporters. Although certain herbs may theoretically influence transporter activity, the increased incidence of hypoglycaemia and gastrointestinal adverse effects observed in this study is more consistent with additive glucose-lowering and gastrointestinal effects rather than altered drug clearance. Nonetheless, the possibility of transporter-mediated interactions cannot be excluded and warrants further investigation.

The strengths of this study include its prospective design, relatively large sample size, and systematic documentation of adverse events and herbal use patterns. By focusing on clinically meaningful safety outcomes, this study provides practical insights for clinicians managing patients with T2DM in settings where herbal medicine use is prevalent.

However, certain limitations should be acknowledged. The observational nature of the study precludes causal inference, and residual confounding may exist. Herbal products were not standardized, and detailed information regarding dosage and bioactive constituents was limited. Additionally, biochemical confirmation of hypoglycaemia was not available for all reported episodes. Despite these limitations, the findings remain highly relevant to real-world practice.

In conclusion, this study demonstrates that concurrent use of herbal medicines and metformin is associated with an increased risk of hypoglycaemia and gastrointestinal adverse effects in patients with T2DM. These findings highlight the importance of routine inquiry about herbal medicine use, patient education regarding potential risks, and vigilant monitoring of safety outcomes. Integrating awareness of herb–drug interactions into diabetes management is essential to optimize patient safety and therapeutic outcomes in an era of increasing integrative medicine use.

The increased risk of hypoglycaemia observed among herbal users highlights the clinical relevance of pharmacodynamic interactions, particularly in patients using herbs with intrinsic glucose-lowering properties. This risk was further accentuated in vulnerable subgroups, including elderly patients and those with longer duration of diabetes, emphasizing the need for individualized risk assessment. Additionally, the higher frequency of gastrointestinal intolerance among herbal users may negatively impact treatment adherence and long-term glycaemic control.

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