Decrease in HbA1c following administration of erythropoietin (EPO) or erythropoiesis-stimulating agents (ESAs) is a recognised clinical phenomenon that can mislead diabetes management if not properly understood. ESAs — prescribed for anaemia in chronic kidney disease, cancer, and other conditions — accelerate red blood cell production, flooding the circulation with younger erythrocytes that carry less glycated haemoglobin. The result is a measurable fall in HbA1c that reflects altered red cell turnover rather than genuine improvement in blood glucose control. This article explains the mechanism, clinical implications, relevant UK guidance, and the alternative monitoring strategies available when HbA1c becomes unreliable.

How Erythropoietin Administration Can Affect HbA1c Readings

ESA administration accelerates red blood cell production, increasing the proportion of younger erythrocytes that carry less glycated haemoglobin, thereby lowering HbA1c independently of actual blood glucose levels.

Erythropoietin (EPO) is an endogenous hormone produced primarily by the kidneys that stimulates the bone marrow to produce red blood cells. Erythropoiesis-stimulating agents (ESAs) are a class of medicines that mimic this action and are prescribed for anaemia associated with chronic kidney disease (CKD), cancer-related anaemia, and certain other conditions. ESAs licensed by the Medicines and Healthcare products Regulatory Agency (MHRA) for use in the UK include epoetin alfa (Eprex; biosimilars include Retacrit and Binocrit), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp), and methoxy polyethylene glycol-epoetin beta (Mircera). Product-specific information is available via the MHRA and the electronic Medicines Compendium (emc).

Haemoglobin A1c (HbA1c) is a widely used marker of long-term glycaemic control, reflecting average blood glucose levels over approximately two to three months. It is formed when glucose binds irreversibly to haemoglobin within red blood cells — a process known as glycation. Because HbA1c is measured as a proportion of total haemoglobin, any factor that alters red blood cell turnover or lifespan can directly influence the HbA1c result, independent of actual blood glucose levels.

When ESAs are administered, they accelerate red blood cell production, increasing the proportion of younger erythrocytes in circulation. These newer red blood cells have had less time to accumulate glycated haemoglobin, which can lead to a measurable reduction in HbA1c values. This effect is not a reflection of improved glycaemic control but rather a biological confounding of HbA1c due to altered red cell turnover. Clinicians and patients alike must be aware of this phenomenon to avoid misinterpreting HbA1c results during ESA therapy.

The NHS provides patient-facing information on the HbA1c test, including factors that can make results unreliable, and NICE guidelines NG17 (type 1 diabetes in adults) and NG28 (type 2 diabetes in adults) both acknowledge that HbA1c may be unreliable in conditions associated with altered red cell states.

Why HbA1c May Appear Lower in Patients Receiving ESAs

ESAs shift the red cell age distribution towards younger cells with shorter glucose exposure, causing HbA1c to fall even when glycaemia is unchanged or worsening; concurrent iron repletion can amplify this effect.

The primary reason HbA1c appears lower during ESA administration relates to red blood cell lifespan and turnover. Under normal physiological conditions, red blood cells survive for approximately 90 to 120 days. HbA1c accumulates progressively throughout this lifespan, so the measured value reflects a weighted average of glycaemia over that period. When ESAs stimulate accelerated erythropoiesis, the circulating pool of red blood cells becomes enriched with younger cells that have been exposed to glucose for a shorter duration.

This shift in red cell age distribution means that, even if blood glucose levels remain unchanged or worsen, the HbA1c value may fall. Published data in CKD populations suggest reductions in HbA1c following ESA initiation, though the magnitude varies depending on CKD stage, the degree of erythropoietic stimulation, iron status, and the assay method used; clinicians should interpret any quoted range with caution and in the context of individual patient factors. The UK Kidney Association (UKKA) and the Joint British Diabetes Societies (JBDS) both highlight this limitation in their guidance on glycaemic management in advanced CKD and dialysis.

Additional factors common in patients receiving ESAs — particularly those with CKD — can compound this effect:

• Correction of iron deficiency: Iron deficiency can prolong red cell lifespan and paradoxically raise HbA1c; when iron is repleted alongside ESA therapy, the resulting increase in red cell turnover may further lower HbA1c independently of glycaemia.

• Uraemia and assay interference: In some older assay methods, carbamylation of haemoglobin in uraemia could interfere with HbA1c measurement; modern high-performance liquid chromatography (HPLC) and immunoassay methods largely mitigate this, but the dominant confounding effect in ESA-treated patients remains altered red cell age distribution rather than direct assay interference.

Understanding these interacting variables is essential for clinicians interpreting HbA1c in patients with CKD-related anaemia who are receiving ESAs, as the result may not accurately represent the patient's true glycaemic burden.

Clinical Implications for Diabetes Monitoring on ESA Therapy

A confounded HbA1c during ESA therapy risks premature reduction of glucose-lowering treatment; clinicians should cross-check with SMBG or CGM data and not adjust therapy based on HbA1c alone.

For patients with both diabetes and conditions requiring ESA therapy — most commonly CKD — the unreliability of HbA1c poses a significant clinical challenge. If a clinician interprets a falling HbA1c as evidence of improved glycaemic control, they may inadvertently reduce antidiabetic medications, potentially leading to undetected hyperglycaemia and its associated complications, including progression of diabetic nephropathy, retinopathy, and cardiovascular disease.

Conversely, if the confounded HbA1c is not recognised, treatment targets may appear to be met when they are not, creating a false sense of reassurance for both the patient and the clinical team. This is particularly concerning given that patients with CKD and diabetes already carry a substantially elevated risk of adverse outcomes.

NICE NG17 and NG28 both note that HbA1c may be unreliable in conditions associated with altered red cell states, and the UKKA and JBDS advise that HbA1c should be interpreted with caution — or supplemented with alternative monitoring — in patients with advanced CKD or those receiving ESAs. Key clinical considerations include:

• Timing of HbA1c measurement: Initiating or significantly changing ESA dose can affect HbA1c for several weeks to months; ESA use should be documented on laboratory request forms.

• Cross-checking with glucose data: HbA1c results should be corroborated with self-monitored blood glucose (SMBG) or continuous glucose monitoring (CGM) trends and clinical symptoms, particularly when ESA dosing is started or changed.

• Correlation with symptoms: Symptoms of hyperglycaemia (polyuria, polydipsia, fatigue, blurred vision) should not be dismissed even when HbA1c appears satisfactory.

• Avoiding premature de-escalation: Glucose-lowering therapy should not be reduced solely on the basis of a falling HbA1c in ESA-treated patients; confirmation with glucose data is essential.

• Multidisciplinary awareness: Diabetologists, nephrologists, and GPs should communicate clearly about ESA use when reviewing glycaemic targets.

NICE and UK Specialist Guidance on HbA1c Interpretation in Renal Anaemia

NICE NG17, NG28, and NG8, alongside UKKA and JBDS-IP guidance, advise that HbA1c should be interpreted with caution in ESA-treated patients and supplemented with alternative markers where unreliable.

NICE guidance on the management of type 1 and type 2 diabetes (NG17 and NG28) recommends HbA1c as the primary tool for assessing long-term glycaemic control, but both guidelines explicitly acknowledge that HbA1c can be unreliable in conditions associated with altered red cell turnover — a category that encompasses patients receiving ESA therapy.

NICE NG8 (Chronic kidney disease: managing anaemia) addresses the use of ESAs in CKD in detail. Whilst it does not set specific HbA1c interpretation thresholds for this population, it supports individualised monitoring and recognises that standard biochemical markers may behave differently in patients with complex comorbidities.

The UK Kidney Association (UKKA; formerly the Renal Association) and the Joint British Diabetes Societies (JBDS-IP) provide the most directly relevant UK specialist guidance. Their recommendations for glycaemic monitoring in advanced CKD and dialysis advise clinicians to:

• Document ESA use when requesting or reviewing HbA1c results, so that laboratory and clinical teams can contextualise findings.

• Consider the degree of anaemia correction and reticulocyte response when interpreting HbA1c values.

• Use alternative glycaemic markers (discussed in the following section) where HbA1c is deemed unreliable.

Patients and healthcare professionals should be aware that laboratory reports do not always flag ESA use as a confounding variable, making clinical context and clear communication between care teams essential for safe and accurate diabetes management. Clinicians should consult the most current versions of UKKA and JBDS-IP guidance directly, as recommendations are updated periodically.

Alternative Glycaemic Monitoring Methods When HbA1c Is Unreliable

Fructosamine, glycated albumin, CGM, and SMBG are the principal alternatives; CGM and isCGM are unaffected by red cell biology and are available on NHS prescription for eligible patients under NICE criteria.

When HbA1c is considered unreliable due to ESA therapy or other haematological factors, several alternative methods can provide a more accurate picture of glycaemic control.

Fructosamine measures the total amount of glycated serum proteins, predominantly albumin, reflecting glycaemia over approximately two to three weeks. It is available through many NHS laboratories and is particularly useful when short-term glycaemic trends need to be assessed. However, its interpretation can be affected by conditions that alter albumin levels, such as nephrotic syndrome or malnutrition — both of which may be present in patients with advanced CKD. Glycated albumin is a more specific measure and may offer advantages in this population, though its availability in routine NHS practice is limited; use should be guided by local laboratory provision. The UKKA and JBDS-IP acknowledge these alternative markers in their guidance on glycaemic monitoring in advanced CKD, recommending their consideration where HbA1c is unreliable and local availability permits.

Continuous glucose monitoring (CGM) and self-monitored blood glucose (SMBG) provide real-time data and are unaffected by haematological variables. CGM devices — including intermittently scanned CGM (isCGM) such as the FreeStyle Libre — are available on NHS prescription for eligible patients in accordance with NICE NG17 and NG28 criteria. These devices offer detailed glycaemic profiles including time-in-range, which is increasingly recognised as a clinically meaningful endpoint alongside HbA1c. Key advantages include:

• No dependence on red cell biology

• Detection of hypoglycaemia and hyperglycaemia patterns

• Support for patient self-management

The choice of monitoring method should be individualised, taking into account the patient's clinical condition, renal function, access to technology, local laboratory availability, and the preferences of the multidisciplinary team. Clinicians should refer to current NICE NG17 and NG28 guidance for CGM and isCGM eligibility criteria.

Discussing ESA Therapy and Diabetes Management With Your Care Team

Patients on ESAs should inform all members of their care team so that HbA1c results are contextualised correctly and diabetes medications are not adjusted based on a potentially misleading result.

If you have diabetes and have been prescribed an ESA, it is important to inform all members of your healthcare team — including your GP, diabetologist, and renal specialist — so that your glycaemic monitoring can be appropriately adjusted. Open communication between specialties is essential, as HbA1c results reviewed in isolation, without knowledge of ESA use, may lead to incorrect clinical decisions.

Patients should feel empowered to ask their care team the following questions:

• 'Is my HbA1c result still reliable now that I am on an ESA?'

• 'Should I be using an alternative monitoring method?'

• 'Do my diabetes medication doses need reviewing in light of my anaemia treatment?'

It is equally important not to make any changes to diabetes medications — including insulin doses or oral glucose-lowering agents — based solely on a falling HbA1c without first discussing this with a clinician. An apparently improved HbA1c during ESA therapy may not reflect genuine glycaemic improvement, and reducing treatment prematurely could result in uncontrolled blood glucose.

If you experience symptoms suggestive of hyperglycaemia — such as increased thirst, frequent urination, unexplained fatigue, or blurred vision — contact your GP or diabetes nurse promptly, even if your most recent HbA1c appeared satisfactory. If you develop more severe symptoms such as vomiting, abdominal pain, drowsiness, or very high capillary glucose readings (particularly with ketones present), seek urgent medical attention, as these may indicate a serious condition such as diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS). Similarly, episodes of low blood sugar (hypoglycaemia) should be reported and investigated in the context of your full medication regimen.

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If you or a healthcare professional suspects that an ESA or any other medicine has caused an unwanted side effect, this can be reported to the MHRA via the Yellow Card scheme (available at yellowcard.mhra.gov.uk). Regular, coordinated review by a multidisciplinary team remains the cornerstone of safe diabetes management in patients receiving ESA therapy.

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