Patented vs. Generic Antidiabetic Drug: Which Is Better?

 I received a request from Dr Jasmine on the 5^th December. 2024 who wrote:

Good evening, Dr Lim 

I need your help as you are the best person I can rely on for scientific and medical explanation. 

Recently I had an Indian patient who was diabetic. I prescribed metformin for her as this was what she has been taking all along. But she insisted that metformin does not work for her. She wanted a patented drug which she believed would work for her. I told her whether patented or generic they are the same thing. The only difference is patented antidiabetic drugs are much more expensive. 

Maybe you can write an article to explain all that so that when I get problems like this from stubborn unbelieving patients, I can ask them to refer to your article for the explanation. Compliance from many patients is headache    

JK

Thank you, Dr Jasmine, for your request and question

Sorry for this late reply because I have much more interesting articles about life and spiritual mysteries  awaiting to be posted here than on medicine which is very boring subject for me now after retiring from this field long ago.

But since you requested, I shall oblige. But what can I do if your patient does not believe that generic drugs are the same as the original patented drugs. They are your patients, not mine. If you cannot explain to them, what can I do?

The best I can do here is to explain the difference, not just for patients and doctors, but  for everybody, the differences  between Metformin, the generic version of this antidiabetic drug, and the original patented version called Glucophage.

 I can write a little bit more than this -  how this antidiabetic drug works (if your patients can understand simple pharmacology). If they cannot, what can I do?

Let me try to explain the differences between the original patented Glucophage and the current generic Metformin

(Later, I shall write a more detailed essay between patented vs generic drugs, plus biosimilar analogues – how they are manufactured plus a contrast between their mode of actions). But let me tackle Metformin you asked first.  

Generic vs. Patented Status the patented name and status of Metformin:

Metformin is currently a generic drug, widely available and manufactured by multiple pharmaceutical companies globally. It was first synthesized in the 1920s but was not used clinically until much later. The original patented name of metformin was Glucophage, developed and marketed by the French company Laboratoires Aron in 1957. The patent for Glucophage expired long ago, allowing metformin to become a widely used generic medication for type 2 diabetes mellitus.

Thus, I am sorry to say that you,  Dr Jasmine, as well as your patient are both wrong to believe that Glucophage (brand name)  which used to be the patented version of metformin  is more expensive than the generic version metformin. Both are the same metformin chemically, structurally and pharmacologically. They act exactly the same way.

To be more precise, Metformin hydrochloride is the same as Glucophage, namely,  1,1-dimethylbiguanide hydrochloride, with the molecular formula C4H11N5 • HCl and a molecular weight of 165.62 g/mole. Maybe you should educate your patient on this. It is also wrong for your patient to believe that the original patented Glucophage is more suitable for her that can ‘cure’ her diabetes. Diabetes is an incurable disease that no pharmaceutical drug, whether  patented, or the generic equivalent can permanently  ‘cure ‘ except controlled by dietary approaches,  and lifestyle modification with one of the antidiabetic agents such as sulfonylureas, meglitinides, biguanides (like metformin), thiazolidinediones (TZDs), alpha-glucosidase inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter (SGLT2) inhibitors, and of course  insulins, an injectable drug for type I and type II diabetes as  well as for gestational diabetes added if necessary.

Pharmacology of Metformin as an Antidiabetic Drug:

Metformin is a biguanide class drug, and its pharmacodynamics and pharmacokinetics make it unique among oral antidiabetic agents.

Pharmacodynamics primary mechanisms of Metformin:

In simple language, this antidiabetic drug works by  acting on its inhibition on hepatic gluconeogenesis.

In even simpler language, this means it blocks sugar production in the liver. If patients still cannot understand this, what can I do?

In technical  language, Metformin reduces the production of glucose in the liver by suppressing mitochondrial respiration, which leads to decreased energy (ATP) production. This inhibits gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase.

It works by improvement in insulin sensitivity by increasing insulin-mediated glucose uptake in skeletal muscle and adipose tissues, likely by activating the AMP-activated protein kinase (AMPK) pathway. AMPK activation is critical for improving metabolic homeostasis. This explanation, and all the rest of the explanations  below are meant only for pharmacologists who know more about drug actions.  

Metformin also increases GDF15 (Growth Differentiation Factor 15) secretion. This hormone reduces appetite and caloric intake, which may aid in weight management in patients with type 2 diabetes.

The secondary mechanism of Metformin is the reduction in lipogenesis and fatty acid synthesis. This means that Metformin inhibits lipogenic enzymes in the liver, such as acetyl-CoA carboxylase, reducing lipid accumulation.

It also enhances fatty acid beta-oxidation by promoting AMPK activation, metformin increases the breakdown of fatty acids in the mitochondria.

Recent studies suggest metformin alters gut microbiota composition, contributing to its glucose-lowering effects and systemic metabolic benefits, such as it decreases glucose absorption in the intestine. Thus, Metformin slightly reduces intestinal glucose absorption, although this is not its primary mechanism.

Pharmacokinetics of Metformin:

Metformin is absorbed in the small intestine, primarily via organic cation transporter 1 (OCT1). Its bioavailability is approximately 50-60%.

Distribution:

It is distributed to tissues through transporters such as OCT1 and OCT2, with high concentrations in the liver and gastrointestinal tract.

Metabolism:

Metformin is not metabolized by the liver or other enzymes, which is unique compared to many drugs.

Excretion:

It is eliminated unchanged by the kidneys via active tubular secretion. Its half-life is approximately 4-8 hours, and dose adjustment is required in renal impairment.

Additional Pharmacological Effects:

Metformin has been shown to reduce levels of inflammatory cytokines such as TNF-α and IL-6, potentially improving outcomes in chronic low-grade inflammation seen in type 2 diabetes.

Anticancer Properties:

Ongoing research suggests that metformin may reduce cancer risk by inhibiting mTOR (mammalian target of rapamycin) signalling via AMPK activation. This is of interest in breast, prostate, and colorectal cancers.

Cardiovascular Benefits:

Metformin improves lipid profiles by reducing LDL cholesterol and triglycerides. It also enhances endothelial function and may reduce the risk of atherosclerosis.

Neuroprotective Effects:

Studies suggest metformin may have a role in reducing cognitive decline and neurodegenerative diseases, possibly through its effects on mitochondrial function and insulin sensitivity in the brain.

Anti-Aging Effects:

Metformin is being investigated for its potential role in slowing aging by influencing pathways involved in metabolism, cellular senescence, and inflammation.

Clinical Considerations:

Advantages of Metformin is, it does not cause hypoglycaemia due to its non-insulinotropic nature. Weight neutrality or modest weight loss, making it ideal for overweight diabetic patients.

Long-standing safety profile and limitations is that  Metformin common side effects are  gastrointestinal symptoms (e.g., diarrhoea, nausea, and abdominal discomfort). Rare but serious: lactic acidosis in patients with significant renal impairment, liver dysfunction, or other conditions causing hypoxia.

Here are some useful information on the pharmacology (mode of action) of metformin:

1.      Mechanism of Action: Metformin primarily works by reducing hepatic glucose production through the inhibition of gluconeogenesis, largely mediated by the activation of the AMPK (AMP-activated protein kinase) pathway. It also enhances insulin sensitivity and promotes glucose uptake in peripheral tissues like muscles while reducing intestinal glucose absorption.

2.      Pharmacokinetics: After oral administration, metformin exhibits 50–60% bioavailability. It is not metabolized by the liver but is excreted unchanged via the kidneys. This emphasizes its safety in patients without renal impairment and highlights the risk of lactic acidosis in those with compromised renal function

3.      Clinical Applications Beyond Diabetes: While primarily used to manage type 2 diabetes mellitus, metformin has shown promise in other areas, including polycystic ovary syndrome (PCOS), cardiovascular risk reduction, and even potential neuroprotective effects in conditions like Alzheimer’s and Parkinson’s diseases

Side Effects: Gastrointestinal issues (e.g., nausea, diarrhoea) are common but manageable. The risk of lactic acidosis is rare but serious, especially in patients with kidney dysfunction

Closing Thoughts:

Finally, as a closing note, there are actually many other types of antidiabetic drugs, not just Glucophage  or metformin.  The major classes of oral antidiabetic medications include biguanides, sulfonylureas, meglitinide, thiazolidinedione (TZD), dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter (SGLT2) inhibitors, and α-glucosidase inhibitors. Some common antidiabetic agents used in Malaysia and in other countries under different brand names include:

alpha-glucosidase inhibitors (acarbose, miglitol), amylin analogues (pramlintide),

dipeptidyl peptidase 4 inhibitors (alogliptan, linagliptan, saxagliptin, sitagliptin), incretin mimetics (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide), insulin, meglitinides (nateglinide, repaglinide), non-sulfonylureas (metformin), SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin), sulfonylureas (chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), and thiazolidinediones (rosiglitazone, pioglitazone).

One very popular and effective antidiabetic medication used in Malaysia is Dyanil which is Glibenclamide 5mg.  Glibenclamide is an adopted name for glyburide, a member of the sulfonylurea class of drugs. Dyanil is produced by Dynapharm (M) Sdn Bhd, a member of DNG Corp., 

Recent antidiabetic drugs include glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i)

A new trend has been getting a lot of attention from people using the diabetes drug Ozempic for weight loss. Ozempic, known generically as semaglutide, was approved in 2017 by the U.S. Food and Drug Administration (FDA) for use in adults with type 2 diabetes. However, Ozempic has a lot of side effects. Reducing caloric intake and changing our dietary lifestyles is the only safe and permanent way of reducing body weight, not using all kinds of drugs.

 References:

For further reading, consider the following articles:

A comprehensive review on metformin’s cellular and molecular mechanisms in Endocrine Reviews link here

Insights into its therapeutic benefits beyond glucose regulation, particularly in neurodegenerative disorders, published in MDPI Pharmaceuticals link here.

Historical and clinical perspectives in the JAMA Network Open review link here