Cardiovascular disease is the leading cause of death in people with diabetes, so the question of whether insulin helps or harms the heart is of great practical importance. Large randomised trials have given it a fairly clear answer for medical use, but at the same time have shown where the real risks lie. The editors analysed what is known about the interaction of insulin with the cardiovascular system.
Insulin itself: heart neutral?
For decades, it has been hypothesized that high levels of insulin in the blood (hyperinsulinemia) itself contribute to atherosclerosis. It was fueled by observational studies in which people with higher fasting insulin were more likely to have heart events. However, in such studies, hyperinsulinemia was a marker of insulin resistance, obesity, and metabolic syndrome, and it is difficult to separate the effect of the hormone from the effect of the condition.
The answer to the question about the safety of exogenous insulin was given by randomised studies. In the ORIGIN study (Gerstein et al., 2012), more than 12,000 people with prediabetes or early type 2 diabetes and high cardiovascular risk received basal insulin glargine or standard therapy. After a median follow-up of more than six years, the incidence of cardiovascular events did not differ between groups.
The DEVOTE study (Marso et al., 2017) compared two basal insulins — degludec and glargine — in more than 7,000 high-risk type 2 diabetes patients. The incidence of major cardiovascular events was similar, but there were fewer severe hypoglycaemias with degludec. Interestingly, in the study itself, severe hypoglycaemia was associated with a higher risk of death.
Therefore, according to available data, correctly prescribed insulin in people with diabetes is cardiovascular neutral: it does not increase or decrease the risk of heart attacks and strokes by itself. The main risks for the heart are not related to the hormone as such, but to hypoglycaemia and accompanying changes.
| Research | Who participated | What was compared | The main conclusion about the heart |
|---|---|---|---|
| ORIGIN (2012) | Dysglycaemia/early T2DM, high risk | Glargine vs standard therapy | Neutral effect on cardiovascular events |
| DEVOTE (2017) | T2DM, high risk | Degludec vs glargine | Similar events, less severe hypoglycaemia on degludec |
| ACCORD (2008) | T2DM, high risk | Intensive vs standard control | Higher mortality in the intensive group |
| ADVANCE (2010 analysis) | T2DM | Consequences of severe hypoglycaemia | Severe hypoglycaemia is associated with vascular events and death |
Hypoglycaemia as cardiac stress
During hypoglycaemia, the body activates a counterregulatory response, and adrenaline plays a key role in it. Its release increases the heart rate and contractility of the myocardium, increases the heart's need for oxygen, and narrows some of the vessels. For a healthy heart, this is mostly a load; for a heart with atherosclerosis of the coronary arteries — a potential trigger of ischaemia.
Hypoglycaemia and adrenaline also reduce the level of potassium in the blood and prolong the QT interval on the electrocardiogram — the period of ventricular repolarization. Prolonged QT creates conditions for dangerous ventricular arrhythmias. A review by Frier, Schernthaner, and Heller (2011) summarized these mechanisms and the association of hypoglycaemia with sudden cardiac death.
In addition, hypoglycaemia activates platelets, increases the level of pro-inflammatory markers and coagulation factors. These changes may contribute to thrombosis in people with coronary artery stenoses. Nocturnal episodes are especially dangerous: bradycardia can change to tachycardia during sleep, and the person does not experience symptoms.
Studies with continuous glucose monitoring and ECG in people with diabetes have reported more frequent arrhythmias during hypoglycemic episodes, especially at night. Although causality with specific deaths is difficult to establish, the physiological mechanism is well established.
Lessons from ACCORD and ADVANCE: When Control Becomes Too Much
The ACCORD trial tested whether very intensive glucose control (target HbA1c below 6%) would reduce cardiovascular risk in people with type 2 diabetes. The intensive care unit was stopped early due to higher overall mortality. Severe hypoglycaemia occurred many times more often in this group, although the researchers could not directly explain all the excess mortality with them.
Analysis of the ADVANCE study (Zoungas et al., 2010) showed that severe hypoglycaemia was associated with a significantly higher risk of major vascular events and death in subsequent years. The authors noted that hypoglycaemia can be both a cause and a marker of the patient's general vulnerability.
The practical consequence of these studies was the individualization of treatment goals. Current ADA guidelines recommend less stringent targets for people with significant cardiovascular disease, the elderly, and those with frequent hypoglycaemia or impaired recognition.
The choice of drugs has also changed: for patients with type 2 diabetes and established cardiovascular diseases, GLP-1 agonists and SGLT2 inhibitors with proven cardio- and nephroprotective effects are now considered as a priority, and insulin is used when they are insufficient.
Potassium, fluid and weight
Insulin moves potassium into cells, and high doses or intravenous administration may cause hypokalemia. Low potassium increases myocardial excitability and the risk of arrhythmias, especially in combination with prolonged QT, cardiac drugs (eg, digoxin), or diuretics.
Insulin also promotes sodium and water retention by the kidneys. This is usually manifested by mild swelling at the beginning of therapy, but in people with heart failure it can worsen the course of the disease. The combination of insulin with pioglitazone is known to increase the risk of fluid retention and requires caution.
- Potassium monitoring — during intensive or intravenous insulin therapy.
- Edema and weight control — in patients with heart failure.
- Revision of glucose targets—in people with coronary heart disease and frequent hypoglycaemia.
- ECG evaluation — in the presence of arrhythmias or taking drugs that prolong QT.
Weight gain on insulin therapy indirectly affects the heart via blood pressure, lipids, and myocardial load. Therefore, in obese people, doctors try to minimize insulin doses, combining it with drugs that promote weight loss.
Risks outside medicine
All the described mechanisms become much more dangerous when insulin is used without medical indications - for example, in bodybuilding. A person without diabetes has a normal self-secretion, so any additional dose directly increases the risk of hypoglycaemia with all its cardiac consequences. Severe hypoglycaemia in such a situation can cause arrhythmia, coma, and death.
The situation is complicated by the combination with other substances. Anabolic steroids lower "good" cholesterol, increase blood pressure and can cause myocardial hypertrophy; stimulants and fat burners add stress to the heart rate. Dhar et al.'s (2005) review of the cardiovascular toxicity of doping substances emphasizes that such combinations pose a cumulative and unpredictable risk.
Physical activity also enhances the action of insulin, because working muscles absorb glucose independently of it. Intense training against the background of exogenous insulin is a scenario in which glucose can drop rapidly, and the heart at this moment is already working with an increased load.
Finally, there is no ECG monitoring, no potassium monitoring, and no experienced staff outside of medicine. What in the hospital is a manageable risk, in the gym or at home turns into a situation where help may not be in time.
Editorial conclusions
Large randomised studies ORIGIN and DEVOTE showed that medically prescribed insulin is cardiovascular neutral: it does not increase the risk of heart attacks and strokes by itself.
The main threat to the heart is hypoglycaemia: it causes adrenaline stress, reduces potassium, prolongs QT and promotes thrombosis. ACCORD and ADVANCE data have forced medicine to abandon excessively aggressive glucose control in vulnerable patients.
Outside of a medical context, especially when combined with steroids and intense exercise, the cardiac risks of insulin increase dramatically and can be fatal.
We also recommend our materials "Side Effects of Insulin", "Contraindications to Insulin" and "Why Insulin is Used in Sports: Expectations and Reality".
List of used literature
- ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319â328.
- Marso SP, McGuire DK, Zinman B, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377(8):723â732.
- Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545â2559.
- Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363(15):1410â1418.
- Frier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular risks. Diabetes Care. 2011;34 Suppl 2:S132âS137.
- Dhar R, Stout CW, Link MS, et al. Cardiovascular toxicities of performance-enhancing substances in sports. Mayo Clin Proc. 2005;80(10):1307â1315.
- American Diabetes Association Professional Practice Committee. Standards of Care in Diabetesâ2024. Diabetes Care. 2024;47(Suppl 1).
