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Continuous Glucose Monitoring as a Pharmacodynamic Bioassay for Identifying Suspected Counterfeit GLP-1 Receptor Agonists

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dr Leonard Andreas Wiyadharma, BMedSci

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Introduction

Glucagon‑like peptide‑1 receptor agonists (GLP‑1 RAs) have become central to the management of type 2 diabetes mellitus (T2DM) and, increasingly, obesity, because they improve glycemic control, promote weight loss, and reduce cardiovascular risk. [1–3] Large randomized trials and network meta‑analyses consistently show HbA1c reductions in the order of 1.0–2.0 percentage points and meaningful body‑weight reductions with once‑weekly agents such as semaglutide and dulaglutide, and dual incretin agonists such as tirzepatide. [3, 4] These therapeutic advances, combined with aggressive direct‑to‑consumer marketing and off‑label uptake for weight loss, have driven global demand to unprecedented levels.

High demand and supply constraints have, however, created fertile conditions for the entry of counterfeit, substandard and falsified GLP‑1 products into both informal and regulated supply chains. [5–7] In parallel, continuous glucose monitoring (CGM) has matured from a specialist tool into a widely available modality for real‑time glycemic assessment, with international consensus standards for data interpretation and strong evidence that CGM‑derived metrics such as time in range (TIR) predict microvascular and macrovascular outcomes. [8–10]

CGM can serve as a practical, patient‑level pharmacodynamic bioassay for GLP‑1 RA authenticity. While CGM cannot identify chemical composition, it can demonstrate whether the expected biological effects of an active GLP‑1 RA are present.

The Emerging Counterfeit GLP‑1 RA Crisis

Global Alerts on Falsified Semaglutide

In June 2024, the World Health Organization (WHO) issued Medical Product Alert N°2/2024 regarding three falsified batches of Ozempic (semaglutide) detected in Brazil, the United Kingdom and the United States. [6] These products had entered the regulated supply chain and were identified when the genuine manufacturer, Novo Nordisk, confirmed that the batch and serial numbers did not match authentic manufacturing records. WHO emphasized that the falsified products misrepresented their identity and source and warned that their use could lead to ineffective treatment, unpredictable adverse effects, or life‑threatening complications due to contamination or substituted ingredients. [6]

The alert noted that reports of falsified semaglutide products had been received from all WHO regions since 2022, in parallel with rapid growth in global demand for semaglutide for diabetes and obesity. [11] WHO explicitly advised healthcare professionals to report suspected lack of effectiveness or unexpected adverse reactions as potential signals of falsification. [6]

National Regulators and Specific Counterfeit Patterns

Several national regulators have provided detailed descriptions of counterfeit GLP‑1‑like products. The Health Products Regulatory Authority (HPRA) in Ireland reported, in October 2025, the detention of a small consignment of counterfeit tirzepatide pens which laboratory tests confirmed contained insulin instead of tirzepatide. [12] These pens, sourced online from outside Europe and labelled to resemble Mounjaro, posed a “serious risk of severe hypoglycemia” in unsuspecting users. [13] The HPRA highlighted that the counterfeit pens were visually similar to authorized products and urged the public to obtain prescription medicines only from registered pharmacies. [12, 13]

Similar cases have been documented for semaglutide. Manufacturer testing and pharmacovigilance reports in Europe and the United States describe fake Ozempic pens that were, in fact, insulin devices, associated with hospitalizations for seizures and profound hypoglycemia. [14, 15] These incidents illustrate a second pattern of falsification: substitution of an incorrect but pharmacologically active ingredient.

A third pattern involves products that contain a GLP‑1‑like peptide at incorrect strength or purity. A 2024 analysis in JAMA Network Open examined semaglutide products purchased online without a prescription and found major quality concerns: variable active ingredient content, mislabeling, and incomplete documentation, raising substantial safety risks. [16] Earlier laboratory work on non‑prescription semaglutide obtained from illegal online pharmacies likewise demonstrated wide variability in peptide purity and detectable endotoxin contamination, with some products containing only a fraction of the labelled semaglutide content. Pharmacovigilance analyses of the FDA Adverse Event Reporting System (FAERS) have identified signals for semaglutide related to “drug misuse” and “prescription without prescription,” consistent with circulation of unregulated products via online channels. [17]

Although specific prevalence estimates are limited, the pattern across WHO alerts and national warnings is clear: a non‑trivial proportion of “semaglutide” and “tirzepatide” products in circulation are counterfeit or substandard, including products that appear to be legitimate pens and vials.

Pharmacological Basis: How Authentic GLP‑1 RAs Affect Glucose

Incretin Physiology and GLP‑1 RA Mechanisms

GLP‑1 is an incretin hormone secreted by intestinal L‑cells in response to nutrient ingestion. It enhances glucose‑dependent insulin secretion, suppresses glucagon during hyperglycemia, delays gastric emptying, and acts centrally to reduce appetite and food intake. [18–22] Pharmacological GLP‑1 RAs (e.g. liraglutide, semaglutide, dulaglutide) are modified peptides that activate the GLP‑1 receptor with prolonged half‑lives, enabling once‑daily or once‑weekly dosing. [21, 23, 24]

Figure 1. Systemic effects of GLP-1 on metabolism, appetite, and cardiovascular–renal function across multiple organs. [25]

At the β‑cell level, GLP‑1 receptor activation increases intracellular cyclic AMP, closing ATP‑sensitive potassium channels and enhancing glucose‑stimulated insulin exocytosis; importantly, this effect diminishes as glucose approaches normal levels, preserving counterregulatory responses and limiting hypoglycemia risk. [22, 26] GLP‑1 also suppresses inappropriately elevated glucagon secretion from α‑cells in hyperglycemia, reducing hepatic glucose output and improving fasting and overnight glycaemia. [21, 22, 27] Short‑acting GLP‑1 RAs exert a particularly pronounced effect on gastric emptying and postprandial glucose excursions, whereas longer‑acting agents have stronger effects on fasting and overall glucose but retain some gastric emptying effect. [23, 27–29]

Expected Glycemic Effects in Trials and Practice

Systematic reviews and meta‑analyses show that GLP‑1 RAs lower HbA1c over 6–12 months, with semaglutide and higher‑dose dulaglutide at the upper end of this range. [30–32] Network meta‑analyses suggest that semaglutide and tirzepatide are among the most potent agents for both glycemic control and weight loss. [21, 31–33] Observational cohorts focusing on once‑weekly GLP‑1 RAs report sustained HbA1c reductions of around 1% and weight loss of 2–5 kg at 6–12 months, including in patients switched from another GLP‑1 RA. [34–36]

These changes are complemented by characteristic effects on CGM metrics, particularly in studies that systematically collect CGM data before and after GLP‑1 RA initiation or intensification. [35, 37, 38]

CGM Metrics and the GLP‑1 RA “Signature”

Core CGM Metrics and Targets

CGM provides near‑continuous interstitial glucose measurements and enables the calculation of metrics that better capture glycemic patterns than isolated finger‑stick readings or HbA1c alone. [9, 39, 40] The 2019 international consensus on CGM recommends focusing on TIR (70–180 mg/dL), time above range (TAR) and time below range (TBR), along with mean glucose, glucose management indicator (GMI) and glycemic variability (standard deviation and coefficient of variation) [8, 40]. For most non‑pregnant adults with T2DM, the consensus target is TIR ≥70% with TBR <4% (<70 mg/dL) and <1% (<54 mg/dL). [8, 41]

A subsequent methodological analysis showed that 14 days of CGM data with ≥70% sensor wear provides sufficiently stable estimates of TIR for clinical decision‑making, while 28–29 days further reduce estimation error and bring 90% of patients within a 5% mean absolute error margin for TIR versus 3‑month average. [42, 43]

Evidence for GLP‑1 RA‑Related CGM Changes

A multicentre retrospective CGM study in China evaluated 202 adults with T2DM using CGM who initiated GLP‑1RA‑based therapy (liraglutide, semaglutide, dulaglutide or PEG‑loxenatide) and matched them 1:1 to patients treated with oral antidiabetic drugs alone. [35] After 3–6 months, the GLP‑1RA group achieved a mean TIR of 76.0%, compared with 65.7% in the oral therapy group (p < 0.001). The GLP‑1RA group also had significantly lower TAR, lower mean glucose and lower standard deviation, indicating improvements in both overall control and glycemic variability. These findings align closely with CGM outcomes from trials of long‑acting GLP‑1 RAs and dual agonists in both T2DM and, to a lesser extent, type 1 diabetes. [44–46]

Case series and expert opinion pieces further illustrate these patterns at an individual level. Ehrhardt et al. described insulin‑treated adults with T2DM who, after initiation or intensification of GLP‑1 RA therapy combined with CGM, demonstrated marked increases in TIR and reductions in mean glucose and coefficient of variation, allowing de‑intensification of prandial insulin in some cases. [37] Time in range improvements after several months of GLP‑1 RA therapy are typical in such reports. [47, 48]

These data justify the concept of a “GLP‑1 RA CGM signature” characterized by: [8, 9, 35, 37, 49]

  • Increased TIR (often by 10–30 % points relative to baseline).
  • Reduced TAR, especially time >250 mg/dL.
  • Lower mean glucose and GMI.
  • Reduced glycemic variability, reflected in lower standard deviation and coefficient of variation.
  • Flattened and shortened postprandial excursions on the AGP.
  • Minimal increase in TBR in patients not treated with insulin or sulfonylureas.

CGM as a Pharmacodynamic Bioassay for Authenticity

Conceptual Rationale

From a pharmacological perspective, an authentic GLP‑1 RA administered in adequate doses to a person with residual β‑cell function should produce at least some of the CGM changes described above within a few weeks. [32, 34, 50] The magnitude may vary with disease duration, concomitant therapy and baseline control, but a complete absence of effect is rare. [50]

Conversely, counterfeit products that contain no active GLP‑1 analogue are expected to produce no specific glycemic effect beyond background variability. [6, 51] Products containing insulin or other hypoglycemic agents may produce a different CGM pattern, dominated by insulin‑type hypoglycemia rather than GLP‑1‑typical flattening of postprandial peaks. [13, 14] Substandard products with incorrect doses or degraded peptide may produce partial or erratic effects. [16, 17]

CGM thus offers a form of in vivo pharmacodynamic “reality check”: it answers the clinical question, “is this pen behaving like a GLP‑1 RA in this patient?” when the chemical composition of the product is unknown.

Three CGM “Red Flag” Scenarios

Based on the above, three CGM patterns warrant heightened suspicion for counterfeit or substandard GLP‑1 RA products.

Red flag 1: No Discernible Glycemic Effect

A first red flag is the absence of any clinically meaningful change in CGM metrics or AGP morphology over 8–12 weeks of therapy, despite documented adherence and standard dose titration. Specifically: [23, 32, 50, 51]

  • TIR remains essentially unchanged compared with baseline and does not drift upward.
  • Mean glucose and GMI show no downward trend.
  • TAR, including time >250 mg/dL, does not decrease.
  • Glycemic variability metrics (standard deviation, coefficient of variation, MAGE if available) are unchanged.
  • Postprandial peaks on AGP retain similar height and width.

Simultaneously, the patient reports no change in appetite, weight, or gastrointestinal symptoms, and laboratory HbA1c remains static at 3–6 months. This pattern is inconsistent with the body of evidence on GLP‑1 RA efficacy in T2DM. It is, however, entirely compatible with injections of an inert solution, as documented in cases where regulators have found that imported “semaglutide” products contained no GLP‑1 analogue.

While non‑response due to severe β‑cell failure is possible, studies of β‑cell function markers indicate that even patients with advanced disease often exhibit partial improvement in glycaemia with GLP‑1 RAs rather than none at all. [23, 24] A genuinely flat CGM profile therefore warrants close scrutiny of product authenticity after addressing adherence and technical factors.

Red flag 2: Insulin‑type Hypoglycemia After Injections

A second, more urgent red flag is recurrent hypoglycemia in a patient not using insulin or sulfonylureas, with temporal clustering after supposed GLP‑1 RA injections. On CGM, this appears as: [52–55]

  • Abrupt drops in glucose into the hypoglycemic range (<70 mg/dL, often <54 mg/dL) within 1–4 hours of injection.
  • Increased TBR, sometimes exceeding the 4% threshold, without a clear explanation in terms of missed meals or increased activity.
  • A pattern that resembles unplanned rapid‑acting insulin exposure more than GLP‑1‑mediated, glucose‑dependent insulin secretion.

In monotherapy or in combination with metformin, GLP‑1 RAs rarely cause significant hypoglycemia because insulinotropic effects abate as glucose normalizes. Meta‑analyses and safety reviews consistently show that most GLP‑1 RA‑associated hypoglycemia occurs when combined with insulin or sulfonylureas. [56] In this context, a new pattern of unexplained hypoglycemia linked to injections strongly suggests that the administered product contains insulin or another potent hypoglycemic drug.

This scenario maps directly onto the HPRA report of counterfeit tirzepatide pens containing insulin, and to manufacturer reports of insulin‑containing counterfeit Ozempic pens associated with severe hypoglycemia in Europe and the United States. [12–15]

Red flag 3: Erratic or Pharmacologically Implausible Patterns

A third scenario involves erratic CGM patterns that do not align with known GLP‑1 RA pharmacokinetics or the patient’s clinical context. Examples include: [23, 24]

  • Large, unpredictable glucose swings unrelated to meals or activity.
  • Very early or very delayed effects after injections that do not match the time–action profile of weekly GLP‑1 RAs.
  • Alternating episodes suggestive of overdosing and underdosing, despite stable self‑reported injection practices.
  • New systemic symptoms that do not fit the typical GLP‑1 RA adverse‑effect profile, such as atypical neurological or cardiovascular events.

Such patterns are plausible if the product contains an unstable mixture of degraded peptide, incorrect doses, contaminants, or multiple active ingredients. Pharmacovigilance analyses of FAERS data for semaglutide and other GLP‑1 RAs highlight safety signals involving off‑label use, device misuse, and adverse effects in the context of unregulated procurement. [17] Laboratory studies of online semaglutide products confirm that active content can deviate markedly from label claims and that endotoxin contamination is not uncommon. [16]

In these situations, CGM does not point to a single alternative active ingredient (as in the insulin case) but signals that the pharmacodynamic behaviour of the injected product is incoherent with GLP‑1 biology.

A CGM‑Based Clinical Protocol

Phase 1: Baseline Characterization

Before initiating GLP‑1 RA therapy, clinicians should aim to collect at least 14 days of CGM data on the patient’s existing regimen, with ≥70% sensor wear, in line with consensus recommendations. Baseline metrics should include: [8, 9, 21, 40, 57]

  • TIR (70–180 mg/dL), TAR (>180 mg/dL, >250 mg/dL) and TBR (<70 mg/dL, <54 mg/dL).
  • Mean glucose and GMI.
  • Standard deviation and coefficient of variation.
  • AGP curves, with attention to the timing and height of postprandial excursions and overnight control.
  • Weight, appetite (e.g. via a simple 0–10 scale) and gastrointestinal symptoms should also be recorded, as they provide additional markers of GLP‑1 RA effect.

Where feasible, an extended baseline of 28–30 days can improve the precision of TIR estimates and better capture day‑to‑day variability. [42, 43]

Phase 2: Early Response Assessment

After GLP‑1 RA initiation at the starting dose, clinicians should review CGM data over the subsequent 2–4 weeks. Early pharmacodynamic signals typically include modest reductions in postprandial peak height, a small decrease in mean glucose, and early weight and appetite changes. Even in this early window, the emergence of insulin‑type hypoglycemia or complete absence of any change may raise suspicion and justify closer scrutiny. [37, 47, 58, 59]

Phase 3: Titration Monitoring

During dose escalation (e.g. semaglutide 0.25→0.5→1.0 mg weekly), each 4–8‑week interval should be accompanied by CGM review over at least 14 days. Clinicians should look for a dose‑response relationship in TIR and AGP flattening, adjusting for dietary and lifestyle modifications. The absence of any trend over multiple titration steps, once adherence and technique are confirmed, is a strong signal for non‑effect and should prompt systematic evaluation, including product inspection and consideration of laboratory testing. [9, 35, 58, 59]

Phase 4: Steady‑state verification

At maintenance dose (typically after 12–16 weeks), GLP‑1 RA steady‑state levels and full clinical effect are expected. At this stage, a repeat CGM assessment over 14–28 days allows definitive evaluation. Authentic, effective therapy should be associated with: [8, 34, 35, 59, 60]

  • A meaningful increase in TIR (ideally approaching or exceeding 70%).
  • Substantial reduction in TAR.
  • Lower mean glucose and GMI compared with baseline.
  • Reduced variability and a narrower AGP band.

If these targets are not approached despite good adherence, minimal confounding changes in therapy or diet, and preserved β‑cell function, product authenticity should be questioned. In parallel, clinicians should assess for adverse patterns (e.g. new hypoglycemia) suggesting wrong active ingredient. [12, 16, 17, 32, 50]

Limitations and Caveats

CGM‑based assessment of GLP‑1 RA authenticity has important limitations. First, it is a pharmacodynamic response test, not a chemical assay; a lack of response may also arise from poor adherence, incorrect injection technique, improper storage, severe β‑cell failure, or major lifestyle changes. [50, 61–63] These factors must be systematically excluded before attributing non‑response to counterfeit product.

Second, some counterfeit or substandard products may contain partial or variable amounts of active GLP‑1 analogue and thus generate partial, inconsistent responses that are difficult to distinguish from genuine but suboptimal response. [16, 17, 64] Pharmacogenetic heterogeneity, including GLP‑1 receptor polymorphisms, may also modulate response magnitude. Third, CGM access remains uneven globally, particularly in low‑resource settings where counterfeit medicines are more prevalent. [5, 7, 65, 66]

Fourth, CGM interpretation requires training, and over‑reliance on a single metric such as TIR without considering clinical context may be misleading. [5, 7–9, 60] For example, TIR may improve modestly even with fake products if concurrent lifestyle changes occur, whilst hypoglycemia due to other causes could be misattributed to counterfeit GLP‑1 RA.

Despite these caveats, CGM remains one of the few tools that can provide objective, patient‑specific evidence of pharmacodynamic effect in real time, and therefore has a role as an adjunct to supply‑chain controls and laboratory testing.

Clinical and Public Health Implications

At the individual level, a CGM‑based framework offers clinicians a way to move beyond subjective impressions of “this drug is not working” to a more structured assessment grounded in quantitative metrics and mechanistic reasoning. It can guide decisions about whether to persist with titration, switch to another agent, or investigate the authenticity of the product being used. [9, 60]

At the health‑system level, widespread use of CGM in populations receiving GLP‑1 RAs could generate early warning signals when clusters of patients fail to respond as expected, potentially indicating counterfeit penetration into specific geographic or distribution networks. Aggregated, anonymized CGM data linked to prescribing records might be leveraged for pharmacovigilance to complement regulatory surveillance systems. [5, 7, 41, 67]

From a broader counterfeit‑medicine perspective, WHO and other bodies have emphasized the need for multiple layers of defense, from secure manufacturing and distribution to end‑user awareness and reporting. CGM‑based pharmacodynamic monitoring does not replace these measures but adds a patient‑level layer: it allows clinicians to detect a missing or aberrant drug effect even when packaging and labelling appear convincing. [5, 7]

Conclusions

The rise of GLP‑1 RAs and the parallel emergence of counterfeit semaglutide and tirzepatide products create a new type of clinical problem: how to verify, at the bedside, that an injectable pen contains what its label claims. Continuous glucose monitoring cannot provide chemical identification, but what it can provide is a high‑resolution map of how the patient’s glucose responds to each injection and dose escalation.

Authentic GLP‑1 RAs, in patients with residual β‑cell function, reliably produce a recognizable CGM signature: improved TIR, lower mean glucose, reduced variability, and flattened postprandial excursions, with minimal intrinsic hypoglycemia when used without insulin or sulfonylureas. A CGM profile that fails to change at all, that shows insulin‑type hypoglycemia in a non‑insulin‑treated patient, or that behaves in ways that are pharmacologically implausible for GLP‑1 biology should immediately prompt careful evaluation of adherence, technique, and product authenticity, especially when the drug has been obtained from unregulated sources or in the context of known falsified batches.

In this sense, CGM functions as a practical pharmacodynamic bioassay available to any clinician with access to a sensor. It cannot, and should not, replace secure supply chains or laboratory confirmation, but it can help clinicians and patients recognize when a GLP‑1 RA is not doing what decades of clinical pharmacology say it should. In an era of expanding GLP‑1 use and growing counterfeit risk, integrating CGM‑based response assessment into routine care may become an important component of safe and effective incretin‑based therapy.

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