Diabetes drugs by mechanism: where each class acts
Every antidiabetic drug lowers glucose, but each one acts at a different site and carries its own signature side effect. Sort them by mechanism and the side effects follow.
Classify antidiabetic drugs (metformin, sulfonylureas, GLP-1 agonists, DPP-4 inhibitors, SGLT2 inhibitors, thiazolidinediones, insulin) by mechanism and signature adverse effect.
The short version
- Think of six places to act: the liver, the beta cell, the gut hormones, the kidney, fat and muscle, and insulin itself.
- Drugs that supply insulin or force it out regardless of glucose, insulin itself and the sulfonylureas, carry the hypoglycaemia risk.
- Metformin acts on the liver and rarely causes hypoglycaemia on its own; it is avoided when the eGFR is below 30 mL/min/1.73 m².
- GLP-1 agonists and DPP-4 inhibitors work through incretins, and GLP-1 agonists are contraindicated with medullary thyroid cancer or MEN2.
- SGLT2 inhibitors bring genital mycotic infections and euglycaemic ketoacidosis; thiazolidinediones bring fluid retention.
Two diabetes drugs: why can only one push glucose too low?
Two women with type 2 diabetes catch a stomach bug and eat almost nothing for a day. The first takes metformin and feels fine. The second takes a sulfonylurea, and by evening she is sweating, shaking and confused, with a glucose of 44 mg/dL.
Both drugs lower glucose, so why can only one of them push it too low? Answering that is the point of learning diabetes drugs by mechanism: sort each class by where it acts, and pin to it its signature side effect.[1][2]
The frame is six places to act: the liver, the beta cell, the gut hormones, the kidney, fat and muscle, and insulin itself.
Metformin: the liver
Metformin acts on the liver. It reduces hepatic glucose production, mainly by suppressing gluconeogenesis.[1][3]
It does not stimulate insulin release, so on its own it rarely causes hypoglycaemia, and it is weight neutral.[2]
Its signature problems are gastrointestinal upset, vitamin B₁₂ deficiency and, rarely, lactic acidosis. For that reason it is avoided when the eGFR is below 30 mL/min/1.73 m².[1][2]
Sulfonylureas: the beta cell
Sulfonylureas bind the sulfonylurea receptor and close the K-ATP channel (the ATP-sensitive potassium channel). The cell depolarises, calcium enters, and insulin is released.[3][5]
That does not depend on glucose, so insulin keeps coming even when glucose is low. Hypoglycaemia and weight gain are the signature effects.[2]
The gut hormones: GLP-1 agonists and DPP-4 inhibitors
After a meal the gut releases GLP-1, which raises insulin only when glucose is high, lowers glucagon, and slows gastric emptying.[1][2]
GLP-1 agonists mimic it. Weight falls, nausea and vomiting are the common problems, and pancreatitis has been reported. They are contraindicated with a personal or family history of medullary thyroid cancer, or MEN2, because of thyroid C cell tumours in rodents.[1][2]
DPP-4 inhibitors block the enzyme that breaks down native GLP-1. The effect is smaller, they are generally well tolerated, and the one to remember is a slight increase in pancreatitis risk.[1][2]
SGLT2 inhibitors: the kidney
SGLT2 inhibitors act in the proximal tubule. They block glucose reabsorption, so glucose is lost in the urine.[1][2]
The signature effects are genital mycotic infections, volume depletion, and euglycaemic ketoacidosis. In that last one, glucose and insulin fall while glucagon rises, which favours hepatic ketogenesis.[1][2][4]
Thiazolidinediones: PPAR-gamma in fat and muscle
Thiazolidinediones, such as pioglitazone, bind the nuclear receptor PPAR-gamma, mainly in fat cells, and improve insulin sensitivity.[1]
Their signature effects are fluid retention, oedema, weight gain, fractures, and worsening heart failure.[1][2]
Insulin itself, and the rule for hypoglycaemia risk
Insulin replaces or supplements the patient's own insulin. Hypoglycaemia is the most common effect, and weight gain is common in type 2 diabetes.[1][2]
So the rule: drugs that supply insulin, or force it out, regardless of glucose, insulin itself and the sulfonylureas, carry the hypoglycaemia risk. Metformin and the incretin drugs do not, on their own.
| Class | Where it acts | Signature effects |
|---|---|---|
| Metformin | Liver: less hepatic glucose production | GI upset, vitamin B₁₂ deficiency, rare lactic acidosis; avoid if eGFR < 30 mL/min/1.73 m² |
| Sulfonylureas | Beta cell: close the K-ATP channel | Hypoglycaemia, weight gain |
| GLP-1 agonists | GLP-1 receptor: mimic the gut hormone GLP-1 | Weight loss, nausea and vomiting, pancreatitis reported; contraindicated with medullary thyroid cancer or MEN2 |
| DPP-4 inhibitors | Block the enzyme that degrades GLP-1 | Well tolerated; slight increase in pancreatitis risk |
| SGLT2 inhibitors | Proximal tubule: block glucose reabsorption | Genital mycotic infections, volume depletion, euglycaemic ketoacidosis |
| Thiazolidinediones | PPAR-gamma, mainly in fat cells | Fluid retention, oedema, weight gain, fractures, worsening heart failure |
| Insulin | Replaces or supplements insulin | Hypoglycaemia (most common), weight gain |
Practice question
Original · USMLE styleA 63-year-old woman with type 2 diabetes mellitus comes to the emergency department with 2 days of vomiting, abdominal pain and deep, rapid breathing. She has had poor oral intake for the past week. Her medications are metformin and a once-daily oral drug that was added 5 weeks ago. Laboratory studies show:
| Glucose | 154 mg/dL |
|---|---|
| Arterial pH | 7.17 |
| Bicarbonate | 8 mEq/L |
| Sodium | 135 mEq/L |
| Chloride | 96 mEq/L |
| Serum beta-hydroxybutyrate | 6.2 mmol/L |
| Serum lactate | 1.6 mmol/L |
Common questions
Why do sulfonylureas cause hypoglycaemia but metformin rarely does?
Sulfonylureas close the K-ATP channel and release insulin regardless of glucose, so insulin keeps coming when glucose is low. Metformin acts on the liver and does not stimulate insulin release, so on its own it rarely causes hypoglycaemia.
What is the mechanism of metformin?
Metformin reduces hepatic glucose production, mainly by suppressing gluconeogenesis. It is avoided when the eGFR is below 30 mL/min/1.73 m² because of the risk of lactic acidosis.
When are GLP-1 agonists contraindicated?
They are contraindicated with a personal or family history of medullary thyroid cancer, or MEN2, because of thyroid C cell tumours in rodents.
What are the signature side effects of SGLT2 inhibitors?
Genital mycotic infections, volume depletion and euglycaemic ketoacidosis. Glucose and insulin fall while glucagon rises, which favours hepatic ketogenesis.
What are the signature side effects of thiazolidinediones?
Fluid retention, oedema, weight gain, fractures and worsening heart failure. They bind PPAR-gamma, mainly in fat cells.
Transcript
Read the full narration, by chapter678 words
0:00Two women, one puzzle: why only one goes low
Two women with type two diabetes catch a stomach bug and eat almost nothing for a day. The first takes metformin and feels fine. The second takes a sulfonylurea, and by evening she is sweating, shaking and confused, with a glucose of 44. Both drugs lower glucose. So why can only one of them push it too low? Today: sort the antidiabetic drugs by mechanism, and pin to each its signature side effect. Think of six places to act: the liver, the beta cell, the gut hormones, the kidney, fat and muscle, and insulin itself.
0:38Metformin: the liver
Metformin acts on the liver. It reduces hepatic glucose production, mainly by suppressing gluconeogenesis. It does not stimulate insulin release, so on its own it rarely causes hypoglycaemia, and it is weight neutral. Its signature problems: gastrointestinal upset, vitamin B12 deficiency, and, rarely, lactic acidosis, so it is avoided when the eGFR is below 30.
1:08Sulfonylureas: the beta cell
Sulfonylureas act on the beta cell. They bind the sulfonylurea receptor and close the KATP channel, the cell depolarises, calcium enters, and insulin is released. That does not depend on glucose, so insulin keeps coming even when glucose is low. Hypoglycaemia and weight gain are the signature effects.
1:31GLP-1 and GLP-1 agonists
After a meal the gut releases GLP-1, which raises insulin only when glucose is high, lowers glucagon, and slows gastric emptying. GLP-1 agonists mimic it. Weight falls, nausea and vomiting are the common problems, and pancreatitis has been reported. They are contraindicated with a personal or family history of medullary thyroid cancer, or MEN2, because of thyroid C cell tumours in rodents.
2:02DPP-4 inhibitors
DPP-4 inhibitors block the enzyme that breaks down native GLP-1. The effect is smaller, they are generally well tolerated, and the one to remember is a slight increase in pancreatitis risk.
2:17SGLT2 inhibitors: the kidney
SGLT2 inhibitors act in the proximal tubule. They block glucose reabsorption, so glucose is lost in the urine. The signature effects: genital mycotic infections, volume depletion, and euglycaemic ketoacidosis, because glucose and insulin fall while glucagon rises.
2:38Thiazolidinediones: PPAR-gamma
Thiazolidinediones, such as pioglitazone, bind the nuclear receptor PPAR gamma, mainly in fat cells, and improve insulin sensitivity. Their signature effects: fluid retention, oedema, weight gain, fractures, and worsening heart failure.
2:58Insulin itself, and the rule: who carries the hypoglycaemia risk
Insulin itself replaces the missing hormone. Hypoglycaemia is the most common effect, and weight gain is common in type two diabetes. So the rule: drugs that supply insulin, or force it out, regardless of glucose, insulin itself and the sulfonylureas, carry the hypoglycaemia risk. Metformin and the incretin drugs do not, on their own. That is our second woman, in the evening.
3:26Practice question
Your turn. A 63-year-old woman with type two diabetes has 2 days of vomiting, abdominal pain and deep, rapid breathing, after a week of poor intake. She takes metformin, and a once-daily oral drug that was added five weeks ago. Glucose is 154 mg/dL, pH 7.17, bicarbonate eight, sodium 135, chloride 96. Beta-hydroxybutyrate is 6.2 mmol/L, and lactate 1.6. The drug most likely responsible acts by which of the following mechanisms? A, closing ATP sensitive potassium channels in beta cells. B, inhibiting glucose reabsorption in the proximal tubule. C, inhibiting hepatic gluconeogenesis. D, activating PPAR gamma in adipose tissue. E, inhibiting the enzyme that degrades incretin hormones. Pause here and decide.
4:34Answer and explanation
A is out: a sulfonylurea causes hypoglycaemia, not ketoacidosis. C is out: metformin is the lactic acidosis drug, and her lactate is normal. D is out: a thiazolidinedione causes fluid retention and heart failure, not an anion gap acidosis. E is out: a DPP-4 inhibitor acts only when glucose is high, and has no urinary glucose loss to set up this picture. So the answer is B. An SGLT2 inhibitor with poor intake can cause euglycaemic ketoacidosis: glucose near normal, a gap of 31, and ketones high.
5:18Recap: three things to keep, then thyroid next
Three things to keep. One: metformin acts on the liver and rarely causes hypoglycaemia; sulfonylureas and insulin do. Two: GLP-1 agonists and DPP-4 inhibitors work through incretins, and GLP-1 agonists are contraindicated with medullary thyroid cancer or MEN2. Three: SGLT2 inhibitors bring mycotic infections and euglycaemic ketoacidosis, and thiazolidinediones bring fluid retention. Next, thyroid hormone synthesis, step by step.
Sources
Numbers in the text, e.g. [1], point here- Drug treatment of diabetes mellitus. MSD Manual Professional Edition. msdmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/drug-treatment-of-diabetes-mellitus
- Davies MJ, et al. Management of hyperglycaemia in type 2 diabetes, 2022: ADA/EASD consensus report. Diabetologia 2022. pmc.ncbi.nlm.nih.gov/articles/PMC9510507/
- Metformin; Sulfonylurea. Wikipedia (secondary). en.wikipedia.org/wiki/Metformin · en.wikipedia.org/wiki/Sulfonylurea
- SGLT2 inhibitors and euglycaemic diabetic ketoacidosis. pmc.ncbi.nlm.nih.gov/articles/PMC13284666/ · pmc.ncbi.nlm.nih.gov/articles/PMC11343900/
- Sulfonylurea mechanism. pmc.ncbi.nlm.nih.gov/articles/PMC4892884/
- Further sources: pmc.ncbi.nlm.nih.gov/articles/PMC11445387/ · pmc.ncbi.nlm.nih.gov/articles/PMC4166864/ · pmc.ncbi.nlm.nih.gov/articles/PMC12889352/
The hook patients and the question are invented teaching cases with synthetic values.
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (cropped, recoloured, outlined): glucometer, woman, islet of Langerhans, cell membrane, liver, stomach, intestine, kidney, syringe, thyroid, tablet, body, fat cell, heart. Oedema illustration by Servier via Bioicons (bioicons.com), CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/), adapted (cropped, recoloured, outlined). The glucose curves, channel, scissors and nephron schematics and all handwriting are drawn in code (original).
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-ENDO-013.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01Hypothalamic-pituitary axes and feedback: primary, secondary, tertiary5:05
- EP 02Primary vs secondary endocrine disorders: paired hormone levels5:13
- EP 03Insulin secretion in the beta cell: from glucose to granule5:06
- EP 04Insulin vs glucagon signalling: receptors and effects5:19
- EP 05DKA vs HHS pathophysiology: why only one makes acid5:58
- EP 06Diabetes drugs by mechanism: where each class acts5:58
- EP 07Thyroid hormone synthesis, step by step5:14
- EP 08Calcium homeostasis: PTH, vitamin D and calcitonin5:28
- EP 09Adrenal steroidogenesis: zones, enzymes and the 17α-hydroxylase fork5:29
- EP 10Congenital adrenal hyperplasia: three enzymes, three patterns5:44
- EP 11Cushing syndrome: the dexamethasone suppression test and ACTH5:29
- EP 12Primary hyperaldosteronism: high aldosterone, low renin5:27
- EP 13SIADH vs diabetes insipidus: central vs nephrogenic DI5:44
- EP 14MEN1, MEN2A and MEN2B: match the gene to its tumours5:13