If your doctor recommends a new drug to treat high blood pressure, diabetes, hypothyroidism or elevated LDL cholesterol, you should be informed about the most common or worrisome side effects. Actually, that should be true for just about any medicine you take. During the first few days or weeks you are likely to be vigilant for adverse drug reactions. If nothing bad happens, doctors and patients assume all is well. But sometimes delayed drug side effects don’t become apparent for months or even years.
Recognizing Delayed Drug Side Effects Can Be Challenging:
A surprising number of medications can work well for a long time without causing obvious problems. Then, seemingly out of the blue, a patient may develop unexpected complications. Many people don’t connect their new symptoms with a pill they have been taking safely for years.
Doctors may not be much better at detecting delayed drug side effects. That can make it difficult to diagnose the problem. What makes this so challenging is that there are no easy tests to predict who will and who won’t develop delayed drug side effects.
We have been monitoring this problem for decades. What follows is an abbreviated list of medications that can seem perfectly fine for months, years or even decades. Then, without warning, strange or serious symptoms start to show up. That’s why we always like to rule out adverse drug reactions first.
Metformin and Diarrhea – Delayed Drug Side Effects:
One medication that can trigger side effects after years of safe use is metformin. At last count, over 20 million people take this drug to help control the elevated blood sugar levels of type 2 diabetes. It is often an add-on with other diabetes medications such as Janumet (sitagliptin and metformin), Invokamet (canagliflozin and metformin) and Synjardy (empagliflozin and metformin).
Metformin has become popular off label–that is to say, for conditions other than diabetes. Some studies suggest it may be useful against certain cancers, and there are hints it might even reduce the risk of dementia. (Cancers, May 30, 2023; Journal of Clinical Medicine, Sept. 25, 2023; European Journal of Medical Research, Sept. 29, 2023; Journal of Gastrointestinal Cancer, Aug. 1, 2023)
Despite the good news about metformin, debilitating side effects may surface even after someone has taken the drug for years.
Here is one reader’s story:
“I took metformin safely for many years, but then started to experience episodes of diarrhea. I was having embarrassing accidents. It got so bad that I was afraid to leave the house.
“When I described my problems, my doctor suspected metformin. It took several weeks for the episodes of diarrhea to disappear, but the drug was clearly the problem. Please warn your readers that this diabetes drug can cause problems even after years of safe use.”
This reader is not alone. Another reader had a similar experience with delayed drug side effects:
“I took metformin for years, but then I started to have severe diarrhea. I did not know what was causing it, but I was having a lot of accidents, and I could not leave the house.
“A colonoscopy showed that all was fine, but I still had severe diarrhea. My doctor felt it was the metformin, so he prescribed a different drug for my diabetes. He told me it would take a while to get the metformin out of my system. If that was the culprit, then the diarrhea would eventually go away.
“He was absolutely correct. Now, after three months, I no longer am having an issue.”
Diarrhea is not the only problem that may appear after many years of taking metformin. Although scientists believe metformin can protect the kidneys from damage, some readers report that complication.
Here’s one example:
“I lost 40 pounds on metformin, maybe because it caused such severe diarrhea that I couldn’t leave the house.
“Ultimately, a substitute doctor saw my records and called to tell me to stop taking metformin immediately. Following his instructions, I saw a kidney specialist as soon as possible, but it was too late.
“My kidneys had already been damaged and I now have Stage 4 kidney disease. I wish that my primary care physician had caught this sooner.”
Metformin can cause a serious metabolic condition called lactic acidosis. It occurs when lactic acid builds up in the bloodstream. Symptoms include nausea, fatigue, muscle cramps, confusion and rapid breathing. It can lead to nasty kidney problems.
ACE Inhibitors and Angioedema – Potentially Deadly Delayed Drug Side Effects:
Looking beyond metformin, we find that certain blood pressure medications can surprise patients with serious adverse reactions after years of safe use. We are referring to ACE (angiotensin converting enzyme) inhibitors such as lisinopril, captopril, enalapril, quinapril and ramipril.
Sometimes people develop a serious, even life-threatening, reaction called angioedema. When lips and tongue swell suddenly, they can sometimes block the airway.
Angioedema definition:
Swelling of mucous membranes. Tissues affected can include the lips, mouth, tongue and/or throat. It can be hereditary or brought on by drugs.
Angioedema is one of the most dramatic delayed drug side effects we have encountered.
Here are some stories to demonstrate the severity of this reaction:
“I am a pharmacist and had taken lisinopril for over 12 years before I had an angioedema attack. About 8:00 PM I started having allergic symptoms and by 10:00 PM my face was swelling, and I was having trouble talking. I rushed to a hospital emergency room, fortunately only 2 miles away.
“I was immediately diagnosed with angioedema and admitted. Steroids started and about midnight I was well on the way to recovery. Spent the night in the ICU and was discharged about 11:00 the next morning.
“I am a pharmacist and had never thought that such a delayed (12 years) reaction could occur. IT SHOULD BE EMPHASIZED DURING PATIENT COUNSELING THAT SUCH A LIFE THREATENING DELAYED REACTION CAN OCCUR!”
Jenny describes her husband’s close call with delayed drug side effects:
“My husband was on lisinopril for about seven years when he had the reaction. In hindsight, we didn’t realize the signs leading up to his event. He was always coughing and blowing his nose. I found out later that he was vomiting daily, but he thought it was just from post-nasal drip from whatever allergy he thought he had.
“A few months before the big reaction, his upper lip swelled up, and he went to a walk-in clinic. He was given steroids. They prescribed an EpiPen in case it ever happened again. The doctor there had no idea what my husband had reacted to.
“Fast-forward a few months. One night I was in the living room watching television, and he came in holding his throat and handing me his EpiPen. His neck was huge, and he couldn’t talk. I used the EpiPen on him and called 911. By the time we got to the ER he was in full code. The ER surgeon finally got a trach tube in, thank goodness, but he was on a ventilator and sedated for a week.
“He couldn’t write or anything when he awoke. He acted compulsive for weeks, and to this day he’s just a little different than before the reaction. The docs said it was angioedema due to lisinopril. It was horrible. I’m so happy he’s alive.”
Abdominal Angioedema and ACE Inhibitors:
The biggest problem with delayed drug side effects is getting the correct diagnosis. The urgent care doctor was smart to send Jenny’s husband home with an EpiPen. It doubtless saved his life.
But the doctor should have recognized the swollen lip as an early warning sign of angioedema brought on by lisinopril. The lisinopril should have been discontinued and a different kind of blood pressure medicine substituted instead.
Emergency physicians have become quite good at recognizing angioedema of the face or throat brought on by ACE inhibitors. What is a lot harder to diagnose is something called abdominal angioedema. It is considered rare, but we are not so sure about that.
The Silo Challenge:
In the “old days” most people went to family physicians. These doctors were “generalists.” That is to say, they handled the vast majority of health problems a patient encountered over a lifetime. These family docs often prescribed every drug a patient took.
These days people often consult several different specialists. Someone who develops chest pain sees a cardiologist. Skin problems are sent to dermatologists. And a bad bellyache will be referred to a gastroenterologist. The various health care providers that we see do not always communicate well with one another.
Although each doctor may review the list of meds a patient is taking, connecting the dots to delayed drug side effects can often be time consuming and challenging. Such is the case with abdominal angioedema.
Just as ACE inhibitors like lisinopril can cause swelling of the lips, mouth, tongue or throat, so too such drugs can do much the same thing in the abdomen. But it can be hard to diagnose problems within the gastrointestinal tract. A bad bellyache could be triggered by gas, appendicitis or abdominal obstruction.
It could also be caused by a delayed reaction to lisinopril.
Alan shares his experience with abdominal angioedema:
“After taking lisinopril for several years, I developed bad stomach bloating. I was unable to eat large meals. I made a number of trips to my local clinic. The doctors assumed I had IBS [irritable bowel syndrome].
“I suffered with this condition for more than two years. It made me very anxious. I was constantly thinking about my stomach problems. I could no longer enjoy food the way I used to.
“I asked the doctor whether lisinopril could cause any of these symptoms, and he ruled that out.
“While I was on vacation this spring I had a really bad attack. It felt like my ribs were being crushed. I had pain in my back, a taste of metal in my mouth and pins and needles all over my body. I went to see the doctor and he blamed my symptoms on a panic attack.
“One other symptom developed since March. I had a burning sensation in my nose, lips and tongue. This was the final straw for me. I did an experiment where I just stopped taking the lisinopril. After three days I felt all the pains had gone except for the burning lips. I felt great but the only downside was that my blood pressure was creeping back up.
“I then took the lisinopril for one day, and the very next day I had all the pains back. I knew then that the lisinopril was the cause and was poisoning my body. I am now switching over to a beta blocker instead of an ace inhibitor. I am visiting a gastro doctor. Hopefully I haven’t had any lasting damage from this drug. Listen to your body!”
Jess developed abdominal angioedema very quickly:
Thank goodness I went to your website and read your article “Bad Bellyache Could Be Deadly Drug Reaction.”
“I was writhing in agony from lisinopril. My stomach felt like I had eaten a bag of glass. After hours of agony and consulting Dr. Google I knew what it was and went to the ER.
“None of the doctors had even heard of it before. I kept yelling to my husband, ‘Tell them about the intestinal angioedema!’ And all three doctors were flabbergasted that just one dose of lisinopril could do this to a person.
“I was in the hospital for four days. I looked about 6 months pregnant from the bloat and inflammation and am severely uncomfortable. I was told to expect to be miserable for another few days and to keep up with my pain meds and plethora of other medications they gave me to go home.
“Moral of the story – be your own advocate! If I had not read these stories and searched specifically for the term “intestinal angioedema” no one would have ever believed me.”
It appears that angioedema can occur after one dose or after 500 doses.
L. shared this story:
“When I went to the ER with a bad bellyache they told me it was gas. The third time it happened I passed out. The Ambulance had to take me to the hospital. That time the doctors ordered a CT Scan. You could see the swelling from the scan. At first, the gastroenterologist thought my problem was Crohn’s disease. The radiologist said to take me off lisinopril because it causes intestinal swelling.”
Some Delayed Drug Side Effects Could be Anticipated:
Statins and Cataracts:
Statins are among the most prescribed drugs in the world. The three most popular statins in the US are atorvastatin (Lipitor), rosuvastatin (Crestor) and simvastatin (Zocor). At last count, over 42 million Americans take one of those three drugs daily.
Cardiologists love the idea of lowering cholesterol. They seem to think that cholesterol was a colossal biological mistake. And yet cholesterol is essential for cellular functioning. It’s also necessary to make hormones like estrogen and testosterone. You need cholesterol to make vitamin D! It also plays an important role in the eye.
Lovastatin (Mevacor) was approved by the FDA in 1987. Even before the first statin hit the market, though, there was a signal that the drug could trigger cataract formation.
That’s because researchers reported (Pharmacotherapy, Nov-Dec, 1987):
“The most common adverse effects are gastrointestinal, while the most serious are elevated transaminase levels and the potential for lens opacities. Lovastatin is the first of a new class of lipid-lowering agents, and is effective when added to diet therapy or in combination with other drugs.”
“The detection of lens opacities in 13 of 100 subjects caused concern in the Lovastatin Study Group II study.”
“Adverse effects that should be monitored carefully include transaminase elevations, myositis, and creatinine phosphokinase elevation, and possible lens opacities.”
“Lens Opacities” is a technical way of saying cataracts. For reasons that mystify me, the statin-cataract connection seemingly disappeared for decades. So did the myositis issue raised with lovastatin in 1987. And yet both adverse reactions are extremely noteworthy as you will shortly discover.
A study in BMJ (May 20, 2010) involving more than 2 million patients in the UK detected
“…moderate or serious myopathy [muscle pain], and cataract.”
Researchers at the University of Waterloo in Ontario, Canada also reported cataracts associated with statin use (Optometry and Vision Science, Aug. 2012):
“The 50% probability of cataract in statin users occurred at age 51.7 and 54.9 years in patients with type 2 diabetes and without diabetes, respectively. In non-statin users, it was significantly later at age 55.1 and 57.3 years for patients with type 2 diabetes and without diabetes, respectively (p < 0.001).
“In this population, statin use was substantially higher in patients with type 2 diabetes and was associated with AR [age-related] cataracts.”
Since those early studies, many other researchers have also reported an association between statin use and cataracts. You can read about those reports at this link.
We find the link between early-onset cataracts (age 20-55) especially disconcerting (Regulatory Toxicology and Pharmacology, Aug. 2021). But we must be honest, the final word is not in on statins and cataracts. Some researchers believe there is no “cataractogenic effect” (Pharmaceuticals, May 7, 2023). So after 36 years we still do not have an official answer to the cataract question.
If someone develops cataracts after years on statins, no one thinks twice. Doctors will often chalk up cataracts to aging.
For example, Jim shared this story:
“I was taking simvastatin 20 mg for 3 years. In that time, I developed a cataract that went from non-existence to needing surgery in 9 months, high liver enzymes, memory loss and elevated blood sugar for which I now must take metformin. None of these side effects were listed.
“I have been off it for 6 months and my liver returned to normal and my memory has improved some.”
Cliff added this:
“Maybe fifteen years ago I briefly consulted a pair of ophthalmology researchers at a major medical school in Chicago. Upon learning I was taking a statin, they alerted me to a likely causal tie between such drugs and developing cataracts, except they used the words ‘will’ and ‘when’ rather than ‘may’ and ‘if’. At the time, at least one statin manufacturer was claiming in TV ads that their product prevented cataracts. I soon wound up switching to another class of medications, because the statin seemed to be really aggravating my essential tremor. I did indeed develop cataracts.”
Statins and Myositis:
The article we cited from Pharmacotherapy in 1987 warned about something called “myositis.” It is different from muscle pain and weakness.
Myositis means inflammation of the muscles. It can be extremely serious and includes polymyositis, dermatomyositis and necrotizing myositis. It is an autoimmune disorder that can lead to permanent disability and death.
There is no mention of myositis with simvastatin or rosuvastatin. Atorvastatin has one mention of myositis amidst dozens of other drug side effects listed under the category “Postmarketing Experience.” It’s in a place that is easily ignored by clinicians.
Readers report Delayed Drug Side Effects With Statins:
LDG shares this experience with statins:
“I had been taking statins for about 10 years. About a year ago, I began losing weight. Finally, my doctor found that my enzyme level was elevated. I was diagnosed with myositis from statins. I have been told that I will continue to deteriorate. There is no way to reverse this. I now use a walker/rollator and not any long distance.”
Allison’s sister developed polymyositis after taking atorvastatin:
“My sister is in a nursing home now because of polymyositis. She has had this disease for about 15 years. We believe it started with her taking atorvastatin. She used to be able to walk 2-3 miles per day. All of a sudden, she starting falling down, them falling down more and more. She went from being on a cane, to using a walker to a wheelchair.”
“She is now completely bed-ridden in a nursing home. Seeing my sister just cry and cry because she cannot do anything for herself is heartbreaking. She is only 66 and has been in a nursing home for 3 years.”
Jean blames atorvastatin for her myositis:
“I have necrotising myositis, diagnosed by a muscle biopsy, triggered by atorvastatin. After 15 months and the failure of treatment with corticosteroids and rituximab, I have started infusions of immunoglobulin and methotrexate taken in tablet form.
“I am now so weak I cannot get up from most ordinary chairs or use a normal toilet. I cannot walk far and can only get up my stairs very slowly and with great effort. I cannot lift anything above my shoulders or from below my hip level. I cannot go for a walk or do my own shopping, and I can hardly get into and out from the car. Life has been wrecked by this. I am 59, and until this happened enjoyed hill walking and keeping my half acre garden.”
We do suspect that myositis is a relatively rare drug side effect. And people who have experienced a heart attack or other cardiovascular problem can benefit from statins. No one should ever stop any medicine without discussing the benefits and risks with the prescriber!
Always Ask About Delayed Drug Side Effects:
Many other medications can cause delayed adverse drug reactions. When people take corticosteroids for years or decades, there is the risk of osteoporosis, diabetes, glaucoma and cataracts, to name just a few of the negative consequences of long-term use.
Proton pump inhibitors (PPIs) used long-term for heartburn can lead to a lot of mischief. For one thing, they can make it hard for the body to absorb essential nutrients such as calcium, iron and magnesium. Vitamin B12 can also be depleted. Consequences of long-term PPI use may include kidney stones and kidney damage, osteoporosis and bone fractures, cardiovascular complications and dementia. Here is a link to an article about worrisome PPI delayed drug side effects.
Final Words:
You may find it hard to believe but we have only scratched the surface when it comes to delayed drug side effects. Drugs for benign prostate enlargement may cause significant sexual side effects that persist after the drugs are discontinued. That also appears to be true of some antidepressant medications.
That’s why it makes sense to ask whether a drug you take regularly might cause trouble after a long time. We recently interviewed a fascinating gastroenterologist about a class of drugs called “biologics.” They are prescribed for inflammatory bowel disorders like ulcerative colitis. She discussed how immune modulating drugs like Enbrel, Remicade or Humira may actually trigger other autoimmune diseases such as psoriasis or rheumatoid arthritis. You can listen at this link.
One final issue that has worried us for decades. The ultimate delayed drug side effect is cancer. The FDA does not seem to know what to do about this. A surprising number of the drugs you see advertised on television mention things like thyroid cancer or lymphoma among other malignancies. It almost seems like an after thought. We ask the question: “Does Your Medicine Pose a Cancer Risk?” You can read about it at this link.
What should you do about delayed drug reactions? Always ask about them! Someone starting an ACE inhibitor should ask about angioedema. The prescriber should let you know about side effects that could take years to reveal themselves. That way you can monitor your body for any warning signs of trouble.
Please share your own experience with delayed drug side effects in the comment section below. If you think this article is worthy of sharing, please pass it on to friends or family members. Thank you for supporting our work.
