Can Immunotherapies Really Cause Diabetes? Understanding a Rare but Important Side Effect
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Immunotherapies, particularly immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4), are powerful treatments that extend survival in many cancers. Rarely, however, they can activate the immune system so strongly that it attacks pancreatic beta cells, causing sudden-onset diabetes. This guide explores, step by step, how often immunotherapy-related diabetes occurs, which type of diabetes it resembles, its risk factors, and practical management points for patients and healthcare professionals.
Cancer treatment is no longer limited to chemotherapy and radiotherapy: newer drugs such as targeted therapies and immune checkpoint inhibitors can achieve long-term disease control and even complete responses in many patients. However, by ‘releasing’ the immune system, these powerful treatments can occasionally cause autoimmune side effects that attack the body’s own tissues.
One such side effect is immunotherapy-induced diabetes. Most patients ask: ‘Can these drugs really cause diabetes, and if so, is it permanent?’ First, it is important to know that immunotherapy-induced diabetes is a very rare side effect; when it occurs, however, it generally resembles type 1 diabetes and requires insulin . Treatment should be individualized according to cancer type, the immunotherapy agent used, preexisting diabetes, and the patient’s overall condition.
1. Scientific Basis: The Connection Between Immunotherapy and Diabetes
Immune checkpoint inhibitors (ICIs) block ‘braking’ mechanisms on T cells, such as PD-1, PD-L1 and CTLA-4 , allowing the immune system to attack tumors more strongly. This can produce deep, long-lasting responses that chemotherapy cannot achieve in some patients.
However, the same mechanism may cause some people’s immune systems to perceive pancreatic beta cells as foreign and attack them. As a result:
- Insulin-producing beta cells are rapidly damaged,
- Blood glucose rises very quickly,
- The condition often resembles sudden-onset type 1 diabetes clinically.
Immunotherapy-induced diabetes therefore differs from conventional temporary steroid-induced blood glucose elevations: it involves insulin deficiency due to beta-cell loss that is often permanent in nature.
‘The Drug or the Immune System?’
Diabetes is actually caused not by the drug itselfbut by the immune response it activates. The immune checkpoint inhibitor releases T-cell brakes; in susceptible individuals, these cells may attack pancreatic islets as well as the tumor. The condition is therefore called ‘immune-related diabetes’ .
- An autoimmune mechanism resembling type 1 diabetes is thought to be involved.
- Most patients need insulin permanently.
- It differs from conventional ‘steroid diabetes,’ which resolves after steroids are stopped.
2. Which Immunotherapy Drugs Are Associated with Diabetes, and What Type Occurs?
Immune Checkpoint Inhibitor (ICI)-Associated Diabetes
Reported cases in the literature are most often associated with PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, etc.) and CTLA-4 inhibitors (ipilimumab, etc.). This condition is also called ‘ICI-induced type 1 diabetes’ and clinically closely resembles conventional type 1 diabetes:
Typical features:
- Typical diabetes type: Autoimmune type 1-like, insulinopenic disease (low C-peptide levels).
- Onset: Sudden; marked hyperglycemia, frequent urination, and weight loss develop over a few days to weeks.
- Presentation: A substantial proportion of patients present to emergency care with diabetic ketoacidosis (DKA) .
- Permanence: Once beta-cell damage develops, most patients’ insulin requirement persists over the long term .
- Preexisting type 2 diabetes: Glycemic control may deteriorate substantially in patients with preexisting type 2 diabetes; insulin may sometimes become necessary.
3. How Often Does It Occur? Is the Risk High?
Although sometimes exaggerated in media coverage, large series show immunotherapy-induced diabetes to be a very rare side effect. Across different phase III studies and cohort analyses:
- With anti-PD-1 / PD-L1 monotherapy, 0.2%–1.0% is the range.
- With anti-CTLA-4 alone, much lower (around 0.1% or less).
- With combination regimens (e.g., nivolumab + ipilimumab), rates around 1% may be reached.
- In a large cohort of more than 14 thousand patients, ICI-associated diabetes was reported in only approximately 0.45% of patients.
- Among patients receiving immunotherapy, only a few out of every 1000 patients develop serious diabetes.
- By contrast, the survival benefit immunotherapy provides in many cancers is much greater.
- Thus, the benefit–risk balance still clearly favors immunotherapy for most patients.
- Nevertheless, because this rare side effect can be severe, early diagnosis and monitoring are very important.
4. When Does It Occur, and How Does It Begin?
Patients often ask, ‘Does diabetes happen immediately, or does it appear months later?’ Studies show:
- Most cases develop within the first 3–6 months after immunotherapy begins.
- However, late-onset cases developing after one year have also been reported.
- Onset is usually sudden; HbA1c may remain relatively low because hyperglycemia has developed rapidly.
- A substantial proportion of patients are diagnosed after presenting to the emergency department with DKA .
Clinical Tip: If a patient receiving immunotherapy has recently increased thirst, frequent urination, sudden weight loss, unexplained weakness, nausea, or an ‘acetone odor’ on the breath, blood glucose and ketone levels should be checked without delay.
5. Who Is at Higher Risk? When Is Extra Caution Needed?
Although data remain limited, certain characteristics are associated with higher risk of immunotherapy-induced diabetes:
- Preexisting type 2 diabetes or prediabetes being present.
- A family history of type 1 diabetes or other autoimmune disease.
- Certain type 1 diabetes-associated HLA types and high polygenic risk scores (in studies with genetic analyses).
- Anti-PD-1 and anti-CTLA-4 used together in combination immunotherapy regimens.
Important Note: Some patients who develop immunotherapy-induced diabetes have no prior history of diabetes or autoimmune disease. An absence of risk factors therefore does not mean this side effect can never occur; consequently, regular glucose monitoring in all patients is recommended.
6. Frequently Asked Questions
Question 1: ‘I am receiving immunotherapy. How likely am I to develop diabetes?’
Answer: The overall risk is below 1%. Only a small number among the many patients receiving immunotherapy experience this side effect. By contrast, the survival extension and disease control rates provided by immunotherapy are much higher in many cancers.
Question 2: ‘If I develop diabetes, will I have to stop immunotherapy?’
Answer: During the acute phase (particularly with DKA), most centers temporarily withhold immunotherapy. Once glucose is controlled and insulin treatment is established, some patients may, under supervision, restart immunotherapyafter assessment of tumor response, other side effects, and overall condition. The decision must be made jointly by the medical oncology and endocrinology teams.
Question 3: ‘Will taking cortisone (steroids) make my diabetes worse?’
Answer: Steroids can raise blood glucose and worsen control in people with preexisting diabetes. However, the underlying problem in immunotherapy-induced type 1-like diabetes is beta-cell loss; this condition generally requires permanent insulin despite steroids. Steroids may therefore trigger diabetes, but usually cannot reverse the underlying immune mechanism.
Question 4: ‘Should fasting blood glucose and HbA1c be checked before immunotherapy?’
Answer: Yes. Most guidelines and expert opinions recommend checking fasting glucose and preferably HbA1c at least once before immunotherapy. During treatment, a simple glucose check before each cycle is also a practical, effective way to detect sudden hyperglycemia early.
7. Practical Advice for Patients
A few simple, effective steps to manage diabetes-related risks during immunotherapy:
- Recognize the main symptoms: Increased thirst, frequent urination, unexplained weight loss, blurred vision, and severe weakness may indicate high blood glucose.
- Do not miss routine laboratory tests: The blood tests requested before each cycle matter not only for kidney and liver function but also for blood glucose.
- If you are particularly at risk: If you already have diabetes or a family history of type 1 diabetes, occasional glucose monitoring at home may be valuable.
- Pay attention to food and fluid intake: A balanced diet, adequate hydration, and avoiding rapidly absorbed, highly sugary foods help prevent excessive glucose fluctuations.
- Do not stop medication on your own: If you notice a suspicious symptom, contact your team immediately rather than stopping immunotherapy.
When Should You Report Symptoms Immediately?
If you have a fever of 38°C or higher, persistent nausea–vomiting, severe weakness, breathlessness, abdominal pain, acetone-smelling breath, confusion, or a marked reduction in urine output , contact your treatment center without delay. These may signal diabetic ketoacidosis or another serious side effect.
DROZDOGAN Academy Note: ‘Managing Diabetes Well Can Preserve the Benefits of Immunotherapy’
Immunotherapy-induced diabetes has become a rare but important issue in clinical practice. Our experience shows that, with timely diagnosis and good management, patients can adapt to insulin treatment and, in many cases, continue benefiting from immunotherapy’s anticancer effects. The aim is therefore not to frame the decision as ‘either immunotherapy or diabetes’ but to adopt a patient-centered approach addressing both. In brief, the decision should be made not only for the tumor but ‘for you’ as a whole.
- Ruiz-Esteves KN, et al. Immune checkpoint inhibitor–induced diabetes mellitus: epidemiology and management. JAMA Oncol.
- Zhou L, et al. Immune checkpoint inhibitor–induced type 1 diabetes: mechanisms and clinical features. Front Immunol.
- Liu W, et al. Clinical characteristics of immune checkpoint inhibitor–induced autoimmune diabetes. Sci Rep.
- Wu L, et al. Risk factors for checkpoint inhibitor–induced autoimmune diabetes. Diabetes Care.
- Akturk HK, et al. Immune checkpoint inhibitor–induced type 1 diabetes: a systematic review. Diabet Med.
- Martins F, et al. Adverse effects of immune-checkpoint inhibitors: endocrine complications. Nat Rev Clin Oncol.
- Current ESMO / ASCO guidelines for managing immune-related adverse events (irAEs).
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