Interaction of Insulin with other drugs

The action of insulin depends not only on the dose but also on everything a person takes in parallel. Some drugs enhance the lowering of glucose, others weaken it, and some conceal the early symptoms of hypoglycemia. Our editors systematized the most important groups of interactions described in the official prescribing information of insulin products and in clinical guidelines.

Three types of interactions with insulin

Unlike many tablet drugs, insulin hardly interacts with other medicines at the level of the hepatic cytochrome P450 enzyme system. It is broken down mainly by the liver and kidneys with the help of the insulin-degrading enzyme and other proteases. Therefore most interactions of insulin are pharmacodynamic — they concern the final effect on the glucose level.

Such interactions can be conditionally divided into three groups. The first is substances that themselves lower glucose or increase sensitivity to insulin, that is, increase the risk of hypoglycemia. The second is substances that raise glucose or cause insulin resistance and may require a review of therapy. The third is agents that change the perception of hypoglycemia symptoms.

The prescribing information of insulin products approved by the FDA and EMA contains a separate section on interactions, where precisely these groups are listed. A doctor takes them into account when prescribing new medicines and, if necessary, monitors glucose more often.

The pharmacokinetic interaction through the kidneys deserves separate mention: with a worsening of their function, in particular against the background of nephrotoxic drugs, insulin is eliminated more slowly and its action is prolonged.

What enhances the action of insulin

The most obvious group is other glucose-lowering agents. Sulfonylurea drugs and glinides stimulate the secretion of one’s own insulin, so in combination with insulin therapy the risk of hypoglycemia rises the most. Metformin, SGLT2 inhibitors, GLP-1 receptor agonists and pioglitazone rarely cause hypoglycemia on their own, but in combination with insulin may require a reduction of its dose.

The prescribing information of insulins also mentions ACE inhibitors, monoamine oxidase inhibitors, salicylates in high doses, fibrates, fluoxetine, pentoxifylline, sulfonamide antibiotics, disopyramide and propoxyphene as substances that can enhance the hypoglycemic effect. Certain fluoroquinolones are associated with glucose disturbances in both directions.

Pioglitazone in combination with insulin, according to the prescribing information, increases the risk of fluid retention and heart failure. This is an example of an interaction that concerns not only glucose.

The clinical significance of each interaction differs: some become noticeable only in certain patients. Therefore it is not a matter of banning combinations but of the need for monitoring when starting or changing the dose of another drug.

What weakens the action of insulin

The best-known “antagonists” of insulin are glucocorticoids. Prednisolone, dexamethasone and similar agents enhance glucose production by the liver and reduce tissue sensitivity to insulin. Against the background of a course of steroids, sugar often rises, especially in the second half of the day.

The same group includes thiazide diuretics, thyroid hormones, sympathomimetics (for example, salbutamol, adrenaline), growth hormone, danazol, estrogens and progestogens, including in oral contraceptives, some atypical antipsychotics (olanzapine, clozapine), HIV protease inhibitors, niacin in high doses and isoniazid.

An important nuance: withdrawal of such a drug can be more dangerous than its prescription. If the insulin dose was raised for the duration of a course of corticosteroids, after they are stopped the need drops sharply, and the old dose can cause hypoglycemia.

Anabolic steroids are described in the prescribing information as substances that can enhance the hypoglycemic effect, whereas growth hormone, on the contrary, reduces sensitivity to insulin. Such opposite directions make combining insulin with hormonal drugs outside medical supervision especially unpredictable.

Masking of hypoglycemia and alcohol

Non-selective and, to a lesser extent, selective beta-adrenergic blockers suppress the reaction to adrenaline that provides the early signals of hypoglycemia: palpitations and trembling. Sweating is usually preserved, however. In addition, beta-blockers can slow glucose recovery after an episode. Clonidine, guanethidine and reserpine are also mentioned in the prescribing information as agents that can mask symptoms.

Alcohol is a separate and very important interaction. It suppresses gluconeogenesis in the liver, so with depleted glycogen stores (after training, on a diet, at night) the glucose level falls and the liver cannot compensate for it. At the same time intoxication masks neuroglycopenic symptoms, and those around perceive them as ordinary intoxication.

• Hypoglycemia after alcohol can be delayed and develop many hours later, in particular in the morning.
• Glucagon is less effective when the glycogen stores in the liver are depleted.
• The combination of alcohol, an evening workout and insulin is a classic scenario of severe nighttime hypoglycemia.

For patients with diabetes the guidelines advise not to consume alcohol on an empty stomach, to monitor glucose before bed and to warn those close to them about the risks.

The sports context and supplements

Physical exercise itself behaves like a “drug” that enhances the action of insulin: muscle contraction increases glucose uptake independently of insulin, and sensitivity to the hormone remains elevated for hours after a workout. The consensus on physical exercise in type 1 diabetes (Riddell et al., 2017) describes in detail how patients adjust therapy and nutrition around workouts.

As for dietary supplements, there are few reliable data on clinically significant interactions with insulin. Some herbal agents, such as berberine or cinnamon, have been studied for their effect on glucose; theoretically they can enhance the action of glucose-lowering therapy, so patients should inform their doctor of their use. Stimulants, in particular high doses of caffeine and synephrine, can change the perception of symptoms.

In non-medical use of insulin in bodybuilding, the risk of interactions rises manyfold: combination with growth hormone, anabolic steroids, thyroid hormones, diuretics and strict diets creates an unpredictable picture in which the glucose level can either crash or get out of control. Such combinations are potentially fatal.

A practical rule for patients: before starting any new drug or supplement, inform your doctor or pharmacist that you are receiving insulin, and in the first days monitor the glucose level more often.

Editorial conclusions

The interactions of insulin are predominantly pharmacodynamic: other drugs enhance or weaken its effect on glucose or mask the symptoms of hypoglycemia. The most important groups are other glucose-lowering agents, glucocorticoids, beta-blockers and alcohol.

Dangerous are not only the start but also the withdrawal of a concomitant drug, when the need for insulin changes sharply. Physical exercise also acts as a powerful modulator.

The safe tactic is simple: a complete list of drugs and supplements for the doctor, intensified glucose monitoring when therapy changes, and refusal of any use of insulin outside a medical prescription.

We also recommend reading our materials on the signs of insulin overdose, on the effect of insulin on the liver and kidneys and on tests during its medical use.

References

1. U.S. Food and Drug Administration. Humulin R (insulin human injection): prescribing information. Section: Drug interactions.
2. European Medicines Agency. Lantus (insulin glargine): summary of product characteristics. Section 4.5: Interaction with other medicinal products.
3. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384–1395.
4. Riddell MC, Gallen IW, Smart CE, et al. Exercise management in type 1 diabetes: a consensus statement. Lancet Diabetes Endocrinol. 2017;5(5):377–390.
5. Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev. 1998;19(5):608–624.
6. Holt RIG, Sönksen PH. Growth hormone, IGF-I and insulin and their abuse in sport. Br J Pharmacol. 2008;154(3):542–556.
7. Preston CL, ed. Stockley's Drug Interactions. London: Pharmaceutical Press; актуальне видання.