As I began my pharmacy career in 1980, I quickly realized that memorizing hundreds of medications would be a daunting task. I needed some reference textbooks that I could access in a timely manner. One of these references was the Physician’s Desk Reference (PDR). This textbook weighed about 10 pounds. I would research the indications of medications and their mechanism of action. What was particularly enlightening was observing that many of the medications’ indications listed in the PDR were not the same indication a medication was prescribed in clinical practice. This prescribing practice of a medication for a disease state or syndrome other than the original FDA indication studied is known as an “off-label use.”
“Off-label” use means the medication is being used for a condition not explicitly approved by regulatory bodies like the FDA. While some off-label uses are supported by clinical evidence and are widely accepted in medical practice, others are still being investigated and require more conclusive research.
For example, amiodarone is an antiarrhythmic medication that is prescribed in clinical practice for ventricular tachycardia and atrial fibrillation. It is the safest of all antiarrhythmic medications and is most commonly used to prevent atrial fibrillation. Amiodarone may cause ventricular tachycardia, pulmonary fibrosis, hypo/hyperthyroidism, opacities in the eye, and blue/gray skin discoloration. There are a few randomized controlled trials that included a small number of patients and five meta-analyses that studied the use of amiodarone in atrial fibrillation patients. Even with very few trials showing efficacy, amiodarone became the mainstay antiarrhythmic agent prescribed for atrial fibrillation patients (Am J Cardiol. 1995;75(10):693-697).
Amiodarone was originally developed in the 1960s as an antianginal (chest pain without having a heart attack) agent. It was widely prescribed in Europe for angina, but by accident, it was found to suppress arrhythmias. Argentinian physicians began using amiodarone to treat arrhythmias in the 1970s. US physicians initially obtained amiodarone from Canada and Europe. Under the threat of no shipment from Europe, the US Food and Drug Administration approved amiodarone in 1985 for use in life-threatening ventricular tachyarrhythmias (very fast heart rhythms) when other drugs are ineffective or poorly tolerated (Pacing Clin Electrophysiol. 1998;21(7):1457-14699670191).
My two oldies but goodies medications are metformin and spironolactone. Metformin (Glucophage) is a medication for type 2 diabetes (DMII) that lowers blood glucose (blood sugars) in patients who produce low amounts of insulin or poor-quality insulin. Poor-quality insulin is a term I use to explain to DMII patients why their own insulin is not lowering their blood glucose levels. As a review, insulin is produced in the pancreas. After eating, blood glucose levels go up, and the pancreas releases insulin. The insulin is the key to opening the door of cells which helps glucose to enter the cell and be used for cellular energy. Metformin’s mechanism of action is unique, and is very complex, so I will utilize the “keep it simple, stupid” (KISS) principle. Metformin inhibits glucose production in the liver and decreases glucose absorption in the gut. One of the few cons of metformin is that it smells like rotten fish when a tablet is taken out of the pill vial. Because of the complexity of metformin’s action, the disease state indications have increased.
Before metformin was marketed in the US, the medications that were primarily prescribed for DMII were a category of medications called sulfonylureas. Glipizide was commonly prescribed for patients. Sulfonylureas “squeeze” insulin from the pancreas. The side effects of these medications are weight gain and hypoglycemia (low blood sugar). Insulin, whether endogenous or manufactured, causes weight gain. The molecule lac-phe, discovered by Stanford Medicine researchers in 2022 and which is produced in the body by vigorous exercise, was also found in patients prescribed metformin. Lac-phe produced by vigorous exercise leads to weight loss. I saw patients lose two to three percent of their body weight due to metformin. I recommended metformin to all obese diabetic patients due to this phenomenon. A 10-year study was recently completed showing a decreased risk of dementia in obese diabetic patients who were prescribed metformin. The study was published online on August 6, 2025, in Diabetes, Obesity and Metabolism.
Polycystic ovary syndrome (PCOS) is a common hormonal disorder in women of reproductive age. It’s characterized by hormonal imbalances, particularly elevated levels of androgens (male hormones), which can lead to irregular periods, ovulation problems, and the development of ovarian cysts. Metformin can improve insulin sensitivity and reduce insulin resistance, which are key features of PCOS. By addressing these factors, metformin can help regulate menstrual cycles, improve ovulation, and potentially support fertility. Metformin may also help manage some of the hormonal imbalances associated with PCOS, like elevated androgen levels, which can lead to symptoms like hirsutism (excess hair growth).
Colorectal cancer (CRC) is also one of the most common cancers in the world, with an increasing incidence in low- and middle-income countries. Recently, numerous studies, including fundamental research, clinical trials, and epidemiological studies, showed that metformin might be a chemoprevention drug utilized to decrease the risk of CRC development. In 2004, a report demonstrated the relationship between metformin and CRC, and in the following years, the beneficial effects of metformin on the regulation of CRC development were reported in several studies (Diabetes Care, (2011) 34:2323–8).
Since 2002, my passion has been to ensure heart failure patients are on the guideline-directed medical therapy (GDMT). GDMT is a fancy way of saying ensuring each patient is being prescribed medications for the best outcomes. My favorite medication for heart failure, where the heart function is poor, is spironolactone (Aldactone). Spironolactone is categorized as a potassium-sparing diuretic. This means that spironolactone will help eliminate sodium and water, while holding onto potassium. Another mechanism of spironolactone is blocking aldosterone. Aldosterone is produced in the adrenal gland and causes sodium and water retention, fibrosis in the heart, and increases the release of epinephrine (adrenaline). The RALES trial in 1999 showed that administering spironolactone, in addition to other heart failure medications, decreased mortality and hospitalizations (N Engl J Med 1999;341:709-717).
Spironolactone is widely used to treat acne in women, particularly hormonal acne that flares around menstrual cycles or in those with conditions like polycystic ovary syndrome (PCOS). PCOS often involves elevated androgen levels, and spironolactone can be used to manage symptoms like hirsutism (hair growth) and irregular periods associated with this condition. Guidelines from the American Academy of Dermatology recommend it as a treatment option for certain females with acne. It works by blocking androgens (male hormones) in the skin, which can reduce oil production and improve acne.
Spironolactone can be prescribed off-label for female pattern hair loss (FPHL), where hair thinning occurs on the scalp, particularly at the crown. It can reduce testosterone production, which may help stimulate hair growth.
As the research grows for these two older medications, I see a path for new indications, better outcomes, and affordability. Patients who are prescribed metformin and spironolactone will not have to remortgage the house or take out a loan to pay for a medication. I see patients every day who have to choose between paying thousands of dollars a year for their meds or paying for food. You know what happens in the majority of these patients. Be well and fly safe.
