Eye-opening research on 5 commonly prescribed medications

Naveed Saleh, MD, MS | May 27, 2021

As a good physician, you want to know everything about the drugs that you prescribe. With more than 20,000 prescription drug products approved for marketing by the FDA, acquiring a full knowledge of every drug isn’t realistic.

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Closeup shot of prescription being handed to customer

Medical research shows that some commonly prescribed drugs may have more indications than originally thought.

Moreover, considering that 24% of patients have taken three or more drugs during the past month, and 12.8% of patients have five or more drugs, patients are likely to be taking certain drugs with effects that even the most knowledgeable physician may not fully understand.

The following are recent eye-opening studies concerning five commonly prescribed drugs.

Metformin

On the surface, it may seem strange that the antidiabetic mainstay metformin could protect against emphysema. But according to the results of a study published in the American Journal of Respiratory and Critical Care Medicine, this may be the case.

In mouse models, researchers found that metformin protected against pulmonary inflammation, airspace enlargement, and small-airway remodeling induced by cigarette smoke exposure. The AMPK signaling pathway was likely mediating the protective effects of the drug. In humans, the researchers found that participants taking metformin exhibited slower progression of emphysema.

“Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, emphysema, and systemic pathologies,” wrote the authors. “Metformin is beneficial against aging-related diseases, and we hypothesized that it may ameliorate CS-induced pathologies of emphysematous COPD.”

They concluded: “Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.”

ACE inhibitors vs ARBs

When angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are both indicated, there is typically a debate over which drug to choose. Both drugs inhibit the renin-angiotensin-aldosterone system and are used to treat hypertension, heart failure, coronary artery disease with left ventricular dysfunction, and chronic renal failure. 

Based on results from early studies, researchers suggested that ACE inhibitors were more effective than ARBs at lowering the incidence of myocardial infarction, cardiovascular death, and all-cause mortality in patients with hypertension, diabetes, and increased cardiovascular risk. ACE inhibitors were also considered to be more effective for lowering all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF).

According to the Cleveland Clinic, “This presumed superiority of ACE inhibitors over ARBs was thought to be a result of a greater vasodilatory effect caused by inhibiting the degradation of bradykinin and leading to increased levels of nitric oxide and vasoactive prostaglandins. Another proposed explanation was that because ARBs block angiotensin II AT1 receptors but not AT2 receptors, the increased stimulation of markedly upregulated AT2 receptors in atheromatous plaques in response to elevated serum levels of angiotensin II was deleterious.”

In light of this information, ACE inhibitors have been selected as first-line therapy. For those who cannot tolerate ACE inhibitors, ARBs are used.

Such calculus is flawed, however, according to the experts. The results of early clinical trials that indicated the outperformance by ACE inhibitors could have suffered from a “generational gap in the trials,” according to the Cleveland Clinic, thus invalidating the improved efficacy of ACE inhibitors over ARBs.

One advantage of ARBs vs ACE inhibitors, however, is that ARBs tend to cause fewer adverse effects, and are thus better tolerated. When compared with the general population, serious adverse effects induced by ACE inhibitors include a higher risk of angioedema in Black individuals and a higher risk of cough in Chinese Americans.

In one recent clinical trial, researchers found that the use of ACE inhibitors in patients with hypertension was associated with decreased respiratory function as measured by lung-function tests. These adverse effects were observed in neither the experimental group receiving ARBs nor the control group. 

The authors concluded: “ARBs are not associated with any harmful effects on respiratory functions in hypertensive patients, unlike ACE [inhibitors]. As such, they could represent a first-choice treatment for hypertensive patients who are at high risk [for] the respiratory adverse effects.”

Amlodipine

Calcium-channel blockers (CCBs) are commonly prescribed to treat hypertension, arrhythmias, and coronary artery disease. What’s good for the heart, however, may also be good for the bones, according to emerging research. 

In a study published in European Cellular Materials involving mouse models, researchers found that CCBs enhanced fracture healing by triggering bone formation, callus remodeling, and osteoclast activity.

“At 2 and 5 weeks, histomorphometric analysis revealed a significantly larger amount of bone tissue within the callus of amlodipine low-dose- and high-dose-treated animals when compared to controls,” the authors wrote. “This was associated with a smaller amount of cartilaginous and fibrous tissue, indicating an acceleration of fracture healing.”

They added: “Biomechanics showed a slightly, but not significantly, higher bending stiffness in amlodipine low-dose- and high-dose-treated animals. Western blot analysis revealed a significantly increased expression of bone morphogenetic protein (BMP)-2 and vascular endothelial growth factor (VEGF). Moreover, the analysis showed a five-fold higher expression of osteoprotegerin (OPG) and a 10-fold elevated expression of the receptor activator of NF-κB ligand (RANKL), indicating an increased bone turnover.”

Gabapentin

Formal FDA-approved indications for this drug include postherpetic neuralgia in adults, adjunctive therapy in partial-onset seizures, and epilepsy. It also boasts a host of off-label uses, including for some psychiatric conditions.

In a population-based study published in Psychiatric Services, researchers mined the National Ambulatory Care Medical Survey to find out more about “gabapentin” visits. 

They found that between 2011 and 2016, 2.8% of psychiatric visits involved the prescription of gabapentin; less than 1% of the prescriptions were related to its aforementioned indications. 

The breakdown of off-label users included 5.3% with a depressive disorder, 3.5% with an anxiety disorder, and 1.8% with bipolar disorder. Gabapentin was most frequently combined with antidepressants (24.3%), opioids (22.9%), and benzodiazepines (17.3%). 

“In this nationally representative sample, <1% of outpatient gabapentin use was for approved indications,” the authors concluded. “High concomitant use of CNS-D [CNS depressant] drugs and off-label gabapentin for psychiatric diagnoses underlines the need for improved communication about safety.”

Gabapentin’s adverse effects include dizziness, double/blurred vision, anxiety, and more. In addition, gabapentinoids are also commonly misused.

Statins

Countless people who were infected with COVID-19 also took statins. But what is the impact of statins on those with COVID-19?

In a prospective study published in Arteriosclerosis, Thrombosis, and Vascular Biology, Korean researchers assessed the correlation between statin use and COVID-19 death. The researchers demonstrated that there was a significant decrease in death linked to statin use after controlling for age, sex, and comorbidities. 

But why?

“This protective effect was supported by the potential inhibitory effect in the context of the SARS-CoV-2 main protease—a key coronavirus enzyme,” according to the authors.

Despite the protective effects exhibited by statins in the context of COVID-19 in the current study, controversy consumes the co-prescription of statins and antivirals.

“The concern is that the use of statins in patients with COVID-19 may be further reduced due to possible drug interaction with antiviral/antibacterial agents and lower cholesterol levels in the acute stress condition,” the authors wrote. “However, our findings suggested that statins need not be discontinued during the COVID-19 treatment.”

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