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Are Antidiabetic Drugs Safe in the Long Term?
Clinical and Research Perspectives from India
V. Mohan
Diabetes Specialities Centre and Madras Diabetes Research Foundation
This report shares the perspective of a physician who has been practicing in diabetes for more than forty years on the safety of various anti-diabetic drugs that have been used for several decades in millions of patients.

n India, it is generally believed that modern scientific medicines (or “allopathic medicines,” as scientific medicines are called in India) in general–and anti-diabetic drugs in particular–have a lot of side effects and hence should not be taken for long periods of time. I have never really understood how this false belief came about, but it’s quite deeply entrenched in our community. This probably stems from the fact that the ancient Indian systems of medicine such as Ayurveda and Siddha use plant based/herbal products which people perceive to be “safe.” On the other hand, many of these same people believe that modern scientific medicines are believed to be “chemicals” which can cause side effects, if taken for years. Few people realize that plants are also chemicals and that, conversely, many modern scientific medicines are derived from plant products.

Here are the major classes of antidiabetic drugs:

Metformin belongs to the Biguanide class of drugs. These compounds have been around for nearly sixty years. While some drugs in this class (e.g., phenformin) were later withdrawn due to side effects (predominantly lactic acidosis), metformin has stood the test of time and is one of the oldest and most prescribed antidiabetic drugs in the world today. It is also used as the first-line drug for the treatment of type 2 diabetes. Except for occasional gastrointestinal disturbances like abdominal bloating and diarrhea, metformin is a reasonably well tolerated drug. Through my work, I know of hundreds of thousands of people who have used metformin for several decades and are doing well. The popular belief that metformin can damage the kidney and other organs has no scientific basis; indeed, over the years, guidelines for the use of metformin have been further liberalized. Moreover, metformin is now known to have additional benefits like weight reduction, improvement in liver fat, and antiaging and even anticancer properties.

Metformin has recently been in the news because the US FDA has withdrawn certain metformin brands shown to contain the toxic compound N-nitrosodimethylamine (NDMA) as a contaminant, particularly extended-release varieties of metformin. However, only metformin made by certain companies were found to have this contaminant; the NDMA levels in most Indian brands were undetectable. It is also noteworthy that more than half of the metformin used in the US comes from India, and very few Indian companies have been involved with the FDA and this contamination issue. (We should also note that this is not a problem with the metformin molecule, but with its method of preparation – the molecule itself is safe.)

Sulfonylureas, like metformin, have been around for more than sixty years. Several generations of sulfonylureas have been developed: older ones such as acetohexamide, carbutamide, tolbutamide and chlorpropamide were later replaced, while glibenclamide is still in use. Glipizide, gliclazide and glimepiride came later: The latter two, referred to as “modern sulfonylureas,” are extremely popular. Hypoglycemia and weight gain are the main side effects of sulfonylureas but both are much less pronounced with the modern sulfonylureas. Many of my own patients have used sulfonylureas for four and even five decades with no significant side effects. The recent Carolina trial has proved the cardiovascular safety of glimepiride while the Advance and Steno-2 trials have conclusively shown the safety of gliclazide. Finally, sulfonylureas are very popular because they are inexpensive. It is fair to state that sulfonylureas and metformin continue to be the most widely presented antidiabetic drugs in the world today.

The wonder drug insulin, which celebrates the centenary of its discovery this year, remains the sheet anchor for treatment of any form of diabetes and at any stage of the disorder. With continuous improvement in the types of insulin produced over the last one hundred years, insulins have become more effective, faster in action, and longer in their duration of action. Insulin has virtually no side effects except for hypoglycemia and some degree of weight gain. There is an unfounded fear among people in India that once insulin is taken, it is “addicting” and one cannot stop taking it. This is not true. We prescribe insulin for a short period of time during an acute emergency like heart attack or stroke; if there is an acute infection; pre-operatively; at the onset of type 2 diabetes if there is evidence of glucotoxicity and lipotoxicity; and, finally, during pregnancy. In every one of these situations, we stop the insulin after giving it for a few days, weeks or months. The belief that insulin use leads to “addiction” is a myth.

DPP4 inhibitors have been around for more than a decade. DPP4 inhibitors have emerged as the “gentlest” of the antidiabetic drugs and can be used safely even in the elderly. Except for saxagliptin, which was associated with increased risk of hospitalization for heart failure, others in this class such as sitagliptin and linagliptin have demonstrated their safety through the CardioVascular OutcomeTrials (CVOT’s). Except for a very low risk of pancreatitis, there are very few other side effects reported with the DPP4 class of drugs. There are reports that these drugs can be safely used during the COVID-19 pandemic.

SGLT2 inhibitors are a relatively more recent addition to the list of antidiabetic drugs armamentarium. At least three drugs in this class (canagliflozin, dapagliflozin and empagliflozin) have undergone extensive CVOT trials and demonstrated remarkable “extra” benefits: Apart from impressive glucose lowering, other features include reducing weight and blood pressure, and, most importantly, providing significant cardiovascular and renal protection. Hence, these drugs have emerged as the “whiz kids” in the antidiabetic drug armamentarium. They do have some side effects, such as genital and urinary tract infections (and occasionally euglycemic ketosis), and should also be used with care in the elderly due to possible electrolyte disturbances. However, the benefits of these drugs far exceed these possible side effects and they are now used by cardiologists and nephrologists in patients without diabetes.

GLP1 receptor analogs, like the SGLT2 group, have become popular because of their additional cardiovascular protection and weight loss benefits. They do have some relatively minor side effects (such as nausea) and present a very small risk of pancreatitis or gall stone formation, but these benefits far outweigh the risks.

The thiazolidinedione group (pioglitazone) is the drug class among antidiabetic agents which does have significant side effects including weight gain, heart failure, bone fractures and possibly macular edema and bladder cancer. They do produce good glycemic control and help to reduce hepatic fat, but their popularity has declined over time.

What Evidence Do We Have That Long-Term Use of These Drugs Is Safe?

In 2013, my colleagues and I reported on long term survival of patients with type 2 diabetes. Some of these patients had lived with diabetes for more than fifty or even sixty years, taking their antidiabetic drugs throughout and with virtually no complications even at the end of decades of taking anti-diabetic drugs. This proved to us the safety of anti-diabetic drugs beyond doubt. Moreover, it was heartening to note that the older antidiabetic (and less expensive) drugs like sulfonylurea and metformin were used by majority of these patients because the newer ones were simply not available.

More recently, we published a report of our elderly type 2 diabetes patients who had completed 90 and some even 100 years of age! Many of them had lived with diabetes for three or four decades while continuously using their anti-diabetic drugs, further proving their safety. Landmark studies like the UKPDS trial and the Steno 2 diabetes trial have also shown that virtually all complications of diabetes can be avoided by good control of diabetes.

Follow Your ABCDs

It is important to follow the ABCDs of diabetes control:

A: Keep the A1c (glycated hemoglobin) less than seven percent (7%)

B: Stands for blood pressure at or under 140/90

C: Stands for LDL cholesterol less than 100g/dL

D: Discipline in living through a healthy diet, sufficient physical exercise, reducing stress, avoiding smoking and tobacco, and moderation in alcohol intake.

Finally, regular follow-up is also important. But if the ABCD mantra is followed carefully, people can have long and healthy life despite diabetes.

Most Important Drug Ingredient: Compliance

Don’t worry about taking anti-diabetic drugs on a long-term basis. It is more important to keep your sugars under control. Undoubtedly, there may be some minor side effects. But this can happen not just with medicines but with foods, which some may be allergic to. If you simply avoid medicines not suitable for your particular diabetes (which I am sure your diabetes specialists would do), you need not worry about taking these medicines in the long term.

It is evident that various antidiabetic drugs have been used in millions of patients, and often for several decades. Hence, the common notion among the public that antidiabetic drugs are dangerous and can lead to serious side effects, (including damage to the kidney) is a myth which needs to be debunked by creating more awareness about their safety and efficacy. Doctors should reassure people that, if anything, these drugs help to prevent the various complications of diabetes — including complications of the kidney, eye, nerve and heart. It is therefore our duty as clinicians to raise awareness about the benefits of these drugs and about the need for their regular, and continued, use. We can help ensure drug compliance, the most important ingredient for preventing the long-term complications of diabetes, but our time to act is NOW!