Drugs that Cause Diabetic Ketoacidosis - An Overview

Introduction

Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes. The body begins to break down fats instead of sugars for energy in this condition. Sodium-glucose cotransporter-2 (SGLT2) inhibitors in treating type 2 diabetes generally cause DKA. Some of the adverse effects of SGLT2 inhibitors must be informed before patients take these as a treatment.

What Is Diabetic Ketoacidosis (DKA)?

Insulin is key for glucose uptake by cells and is used as fuel among normal people without diabetes, but enough insulin is not produced among those with diabetes. Hence their bodies cannot use sugar as energy. In such conditions, the liver turns fat into acids called ketones. These ketones get into the blood, resulting in acidic blood, causing the DKA condition.

Generally, DKA is common among type 1 diabetes, but anyone with type 1 or type 2 diabetes may get DKA. Especially people taking insulin are more prone to DKA as they have severe diabetes.

Among people with type 2 diabetes following are more prone to DKA:

• Older people.

• Overweight people

• Nonwhite ethnic groups.

What Are The Causes of DKA?

Certain infections or illnesses cause to produce high levels of hormones leading to DKA.

Causes of DKA include the following:

• High blood sugar levels and low insulin.

• Illness or any problem with insulin therapy.

• Missing an insulin shot.

• Clogged insulin pump.

• Not using the correct insulin dosage.

• Alteration of hormones (cortisol and epinephrine) due to infection or illness.

• Heart attack.

• Stroke.

• Physical trauma.

• Emotional stress.

• Drug or alcohol misuse.

• Certain medications.

Type 1 diabetes and people who miss insulin frequently have a high risk of developing DKA. Some medications may increase the risk of DKA, even when blood sugar is not high.

What Are the Symptoms of DKA?

Symptoms of DKA may appear quickly. It may occur within 24 hours.

Symptoms of DKA include

• Nausea.

• Increased thirst.

• Frequent urination.

• Pain in the abdomen.

• Vomiting.

• Fast Breathing.

• Weakness.

• Confusion.

• Flushed face.

• Fruity-smelling breath.

• Confusion.

• Dry mouth and skin.

The absence of treatment for DKA may lead to coma and death. Acute cerebral edema occurs among one percent, especially in children, as a complication of DKA.

A recent study has shown that along with insulin deficiency, the production of increased hormones like catecholamines, cortisol, glucagon, and growth hormone is responsible for DKA.

These hormone levels increase in conditions like infection, myocardial infarction, trauma, pheochromocytoma, Cushing's disease, acromegaly, glucagonoma, and anaphylaxis. A sympathomimetic agent like Terbutaline Sulfate is responsible for DKA in diabetes. Cocaine increases catecholamines by stimulating the adrenal medulla to release epinephrine and norepinephrine, increasing corticotropin and cortisol levels.

What Is the Pathophysiology of DKA?

Triglycerides and amino acids are metabolized in the body in conditions of low insulin and increased production of hormones like cortisol, glucagon, and catecholamines. Serum levels of glycerol and free fatty acids increase because of lipolysis. Insulin stops ketone formation generally. In the absence or when sufficient insulin is not there, ketone formation occurs. Due to insulin deficiency, water, and electrolytes will be lost through urine. One of the complications, like hypokalemia, may develop during insulin therapy.

What Are the Drugs Involved in Precipitating DKA?

Drugs that are involved in DKA are:

Corticosteroids: Treatment with corticosteroids may cause hyperglycemia and lead to type 2 diabetes.

Thiazide Diuretics: These drugs impair glucose metabolism and cause DKA.

Sympathomimetics: These drugs tend to cause increased blood glucose levels.

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors: These drugs tend to precipitate DKA.

When diabetes treatment is done with SGLT2 inhibitors, they should see for signs and symptoms of DKA. These include:

• Canagliflozin.

• Dapagliflozin.

• Empagliflozin.

Some of the combination drugs causing DKA are:

• Canagliflozin plus metformin

• Dapagliflozin plus metformin extended-release

• Empagliflozin plus linagliptin

Studies showed diabetic people taking SGLT2 inhibitors for two weeks may be reported with DKA. DKA may also be caused due to an illness, decreased food intake, or reduced insulin dose.

Some of the other reasons include:

• Dehydration.

• Infection.

• Eating very less.

• A diet with high fat and protein.

• Taking less insulin dose.

SGLT2 inhibitors effectively treat diabetes without increasing weight and not causing hypoglycemia (low blood sugar levels). These patients must have more water and take low carbohydrate diets.

SGLT2 act in the kidney to block glucose from getting absorbed into the blood, thereby sugar in the urine. They also act as diuretics- allowing more water and glucose into the urine. People taking SGLT2 inhibitors have three times more severe complications of getting DKA when compared to people using other drugs.

According to a study, it was found that Dapagliflozin (Farxiga) was linked to having an 86 percent increase in DKA, but people using Empagliflozin had 2.5 times the risk of DKA. Canagliflozin was 3.6 times higher odds of getting DKA.

Other medications involved in getting DKA are high-dose Thiazide diuretics, second-generation antipsychotic agents, and sympathomimetic agents like Dobutamine and Terbutaline. One of the studies showed that steroids can precipitate DKA.

How To Diagnose DKA?

When a patient is suspected of having DKA, the following tests are done:

• Serum electrolytes.

• Blood urea nitrogen (BUN) and creatinine.

• Glucose.

• Ketones.

• Osmolarity.

• Urine for ketones.

• Arterial blood gas measurement.

When arterial pH is less than 7.30 with an anion gap greater than 12 and serum ketones, the glucose levels specificity varies. Blood glucose greater than 200 (11.1 mmol/L or millimoles per liter) or greater than 13.8 mmol/L is often specified. If triggering illness is present, cultures and imaging studies should be conducted. ECG (electrocardiogram) will be done to screen acute myocardial infarction and know the serum potassium abnormalities.

Other laboratory tests are done to know:

Hyponatremia.

Elevated serum creatinine.

Elevated plasma osmolality.

What Is the Prognosis of DKA?

The mortality rate for DKA is less than one percent. Mortality is higher in older people with DKA and other serious illnesses. The worst prognosis can be observed in shock or coma.

The reasons for death are

• Circulatory collapse.

• Hypokalemia.

• Infection.

Some studies showed that one-quarter of patients died due to cerebral edema, and 15 to 35 percent survived with neurological sequelae.

How to Treat DKA?

Treatment options for DKA are

• Correcting hypokalemia.

• IV (intravenous) insulin.

• Rarely IV sodium bicarbonate (if pH is less than seven after 1 hour of treatment).

Patients must be first given priority for:

• Rapid intravascular volume repletion.

• Hyperglycemia and acidosis correction.

• Prevention of hypokalemia (lower levels of potassium).

As hourly-based lab assessments are initially needed, treatment should be given in intensive care settings.

Conclusion

Diabetic ketoacidosis is a severe complication of diabetes. Many drugs given as treatments are responsible for causing this serious condition. It is challenging to treat as various factors and risks are involved with this condition. Hence knowing in detail about the condition helps one to identify the signs and symptoms and help in seeking a doctor’s help at the earliest. Early diagnosis always helps get effective treatment to resolve serious conditions.