This document provides an overview of antidiabetic drugs, classifying them based on their mechanisms of action and summarizing their uses, side effects, and contraindications. The main classes described include biguanides (e.g. metformin), sulfonylureas, meglitinides, incretin mimetics, DPP-4 inhibitors, SGLT-2 inhibitors, alpha-glucosidase inhibitors, and thiazolidinediones. Metformin is noted as the first-line oral medication for type 2 diabetes due to its efficacy, safety profile, and cost-effectiveness. All antidiabetic drugs require careful consideration of risks like hypoglycemia and drug interactions when prescribing based on a

1. Antidiabetic Drug 2019
ANTIDIABETIC DRUG
1 Introduction​:
Anti-diabetic drug​, any ​drug​ that works to lower abnormally high ​glucose​ (​sugar​) levels in
the ​blood​, which are characteristic of the ​endocrine system​ disorder known as ​diabetes mellitus​.
Diabetes is caused by the body’s inability to produce or respond to the pancreatic
hormone ​insulin​. One of the important physiological actions of insulin is to control blood
glucose levels. Glucose is an important nutrient for cellular ​metabolism​, and ​cells​ must receive
neither too little nor too much. A deficiency in the pancreatic secretion of insulin, or lack of
tissue sensitivity to the hormone, leads to diabetes, the primary feature of which is elevated
blood glucose levels (​hyperglycemia​).
There are a number of different types of antidiabetic drug including:
1) Insulin
2) Pramlintide (Amylin)
3) GLP-1 receptor agonists (such as Byetta and Victoza)
4) Oral hypoglycemics (tablets)
2 Classification:
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2. Antidiabetic Drug 2019
2.1 Overview of Antidiabetic drug:
Class Mechanism of action Side effects Contraindications
Biguanide​ (​metformin​) Enhances
the effect of ​insulin
Lactic acidosis
Weight loss
Gastrointestinal
complaints are
common (e.g. ​diar
rhea​, abdominal
cramps)
Reduced ​vitamin
B12​absorption
Chronic kidney disease
Liver​ failure
Metformin​ must be
paused before
administration of
iodinated contrast
medium and major
surgery.
Sulfonylureas​ (e.g., ​glyburid
e​, glimepiride)
Increase ​insulin​ secr
etion
from ​pancreatic​β-cel
ls
Risk
of ​hypoglycemia
Weight gain
Hematological
changes: ​agranulo
cytosis​, ​hemolysis
Severe cardiovascular
comorbidity
Obesity
Sulfonamide​ ​allergy​ (par
ticularly long-acting sub
stances)
Meglitinides​ (​nateglinide​, ​rep
aglinide​)
Increase ​insulin​ secr
etion
from ​pancreatic​β-cel
ls
Risk
of ​hypoglycemia
Weight gain
Severe renal
or ​liver​ failure
DPP-4
inhibitors​ (​saxagliptin​, ​sitagli
ptin​)
Inhibit GLP-1 degra
dation →
promotes glucose-de
pendent ​insulin​ secre
tion
Gastrointestinal
complaints
Pancreatitis
Headache​,
dizziness
Arthralgia
Liver​ failure
Moderate to severe renal
failure
GLP-1 agonists​ (​incretin
mimetic
drugs​: ​exenatide​, ​liraglutide​,
albiglutide​)
Direct stimulation of
the GLP-1 ​receptor
Nausea
Increased risk
of pancreatitisand
possibly ​pancreati
c cancer
Preexisting,
symptomatic gastrointest
inal motility disorders
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3. Antidiabetic Drug 2019
SGLT-2
inhibitors​(​canagliflozin​, ​dapa
gliflozin​, ​empagliflozin​)
Increased glucosuria
through the
inhibition
of SGLT-2 in the
kidney
Genital ​yeast​ infe
ctions and ​urinary
tract infections
Polyuria and ​dehy
dration
Diabetic
ketoacidosis
Chronic kidney disease
Recurrent urinary tract
infections
Alpha-glucosidase
inhibitors​(​acarbose​)
Reduce intestinal
glucose absorption
Gastrointestinal
complaints
(flatulence, ​diarrh
ea​, feeling of
satiety)
Any preexisting
intestinal conditions
(e.g., inflammatory
bowel disease)
Severe renal failure
Thiazolidinediones​(​pioglitaz
one​)
Reduce insulin
resistance through
the stimulation of
PPARs (​peroxisome
proliferator-activated
​receptors​)
Increase ​transcriptio
n​ of adipokines
Weight gain
Edema
Cardiac failure
Increased risk of
bone ​fractures​ (​os
teoporosis​)
Congestive heart failure
Liver​ failure
Amylin
analogs (pramlintide)
Reduce glucagon rel
ease
Reduce gastric
emptying
Increase satiety
Risk
of ​hypoglycemia
Nausea
Gastroparesis
3 Common contraindications of antidiabetic agents
● Type 1 diabetes mellitus​: Patients require ​insulin therapy​ (see principles of ​insulin
therapy​).
● Pregnancy​ and breastfeeding (also see ​gestational diabetes​): All antidiabetic agents are
contraindicated. Antidiabetic drugs should be substituted with human ​insulin​ as early as
possible (ideally prior to the ​pregnancy​).
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4. Antidiabetic Drug 2019
● Renal failure : Antidiabetic drugs that may be administered if ​GFR​ < 30
mL/min include DPP-4 inhibitors, ​incretin mimetic drugs​, ​meglitinides​,
and ​thiazolidinediones​.
● Morbidity​ and surgery.
● Pause antidiabetic treatment in the following cases:
● Major surgery performed under general anesthesia.
● Acute conditions requiring hospitalization (infections, organ failure).
● Elective procedures associated with an increased risk of ​hypoglycemia​ (periods of
fasting, irregular food intake).
4 Insulinotropic agents
● Mechanism: stimulate the secretion of ​insulin​ from ​pancreatic​ ​β-cells​.
● Glucose-independent: ​Insulin​ is secreted regardless of the blood glucose level, even if
blood glucose levels are low → risk of ​hypoglycemia​.
● Sulfonylurea​, ​meglitinides​.
● Glucose-dependent: ​Insulin​ secretion is stimulated by elevated blood glucose levels
(postprandially). These antidiabetic agents depend on residual ​β-cell​function.
● GLP-1 agonists, DPP-4 inhibitors.
5 Non-insulinotropic agents
● Mechanism:These agents do not depend on residual ​insulin​ production.
● Effective in patients with nonfunctional endocrine ​pancreatic​ ​β-cells​..
● Biguanides​ (​metformin​), SGLT-2 inhibitor, ​thiazolidinediones​, alpha-glucosidase
inhibitors.
5.1 Biguanides (Metformin)
5.1.1 Mechanism of action​:
● enhances the effect of ​insulin​.
● Reduction in insulin resistance via modification of glucose metabolic pathways.
● Inhibits ​mitochondrial​ glycerophosphate dehydrogenase (mGPD)..
● Decreases hepatic ​gluconeogenesis​ and intestinal glucose absorption.
● Increases peripheral ​insulin​ sensitivity.
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5. Antidiabetic Drug 2019
● Lowers postprandial and fasting blood glucose levels.
● Reduces LDL, increases HDL.
5.1.2 Indications​:​ ​drug of choice in all patients with ​type 2 diabetes​.
5.1.3 Clinical characteristics:
● Glycemic efficacy: lowers ​HbA1c​ by 1.2–2% over 3 months.
● Weight loss or weight stabilization.
● No risk of ​hypoglycemia​.
● Beneficial effect on ​dyslipidemia​.
● Studies show ​metformin​ reduces the risk of macroangiopathic complications in diabetic
patients.
● Cost-effective.
5.1.4 Important side effects:
● Metformin-associated lactic acidosis.
● Incidence: ​∼​ 8 cases/100,000 patient years.
● Clinical features: frequently nonspecific.
● Gastrointestinal prodromal symptoms: nausea, vomiting, ​diarrhea​, abdominal ​pain​.
● Severe symptoms: muscle cramps, ​hyperventilation​, apathy, disorientation, ​coma​.
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● High-risk groups.
● Elderly individuals.
● Patients with cardiac or renal insufficiency.
● Diagnostics.
● Arterial blood gas​ (​ABG​): ​metabolic acidosis​ and ​anion gap​.
● ↑ Serum ​lactate​.
● Treatment: discontinue ​metformin​ and treat acidosis.
● Gastrointestinal complaints are common: nausea, ​diarrhea​, flatulence.
● Vitamin B12 deficiency​.
● Metallic taste in the mouth (dysgeusia).
5.1.5 Contraindications:
● Renal failure (if ​creatinine clearance​ < 30 mL/min).
● Severe ​liver​ failure.
● Intravenous iodinated contrast medium.
● Pause ​metformin​ prior to surgery.
● Chronic pancreatitis​, starvation ketosis, ketoacidosis, ​sepsis​.
● Heart failure​ (​NYHA​ III and IV), respiratory failure, ​shock​, ​sepsis​.
● Alcoholism​.
5.1.6 Important interactions​:​ ​sulfonylureas
5.2 Thiazolidinediones (glitazones, insulin sensitizers)
5.2.1 Active agents:
● Pioglitazone
● Rosiglitazone
5.2.2 Mechanism of action​:
● Activation of the ​transcription
factor​ PPARγ (​peroxisome​ proliferator-activated ​receptor​ of gamma type).
● ↑ ​Transcription​ of ​genes​involved in glucose and lipid metabolism.
● ↑ levels of adipokines such as adiponectin.
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● ↑ Storage of ​triglycerides​ and subsequent reduction of products of lipid metabolism (e.g.,
free ​fatty acids​) that enhance insulin resistance .
● Glucose utilization is increased and hepatic glucose production reduced.
5.2.3 Indications​:
May be considered as a monotherapy in patients with severe renal failure and/or
contraindications for ​insulin therapy​.
5.2.4 Clinical characteristics:
● Glycemic efficacy: lowers ​HbA1c​ by 1% in 3 months.
● Favorable effect on lipid metabolism: ↓ ​triglyceride​, ↓ LDL, ↑ HDL.
● No risk of ​hypoglycemia​.
5.2.5 Important side effects:
● Fluid retention and ​edema​.
● Weight gain.
● Increased risk of ​heart failure​.
● Increased risk of bone ​fractures​ (​osteoporosis​!).
5.2.6 Contraindications:
● Congestive heart failure​ (​NYHA​ III or IV).
● Liver​ failure.
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● Pioglitazone​: history of ​bladder cancer​ or active ​bladder
cancer​; macrohematuria of unknown origin.
5.3 Sulfonylureas
5.3.1 Active agents:
● Glyburide: the standard substance of this class with a relatively long ​half-life​.
● Glipizide: a short-acting agent.
5.3.2 Mechanism of action:
● Sulfonylureas block ​ATP​-sensitive potassium channels of the ​pancreatic​ ​β-cells​.
● Depolarization​ of ​the cell​ membrane.
● Calcium influx.
● Insulin​secretion.
● Extrapancreatic effect: decreases hepatic ​gluconeogenesis​ and increases
peripheral ​insulin​ sensitivity.
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9. Antidiabetic Drug 2019
5.3.3 Indications:
Particularly suitable for patients who are not overweight, do not consume alcohol, and adhere to
a consistent dietary routine.
5.3.4 Clinical characteristics:
● Glycemic efficacy: lowers ​HbA1c​ by 1.2% over 3 months.
● Long-term experience.
● Low-cost.
5.3.5 Important side effects:
● Life-threatening ​hypoglycemia​.
● Increased risk in patients with renal failure.
● Weight gain.
● Hematological changes: granulocytopenia, ​hemolytic anemia​.
● Allergic skin reactions.
● Alcohol intolerance.
● Compared to ​metformin​, ​sulfonylureas​ are associated with more cardiovascular
(macrovascular) complications.
5.3.6 Contraindications:
● Severe cardiovascular comorbidity.
● Obesity​.
● Sulfonamide​ ​allergy​ (particularly long-acting substances).
● Severe ​liver​ failure.
● Severe kidney failure.
5.4 Meglitinides (sulfonylurea analogue)
5.4.1 Active agents:
● Repaglinide: the leading agent in the class of ​meglitinides​, which is well tolerated by
patients with ​chronic kidney disease
● Nateglinide
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5.4.2 Mechanism of action:
● Enhances ​insulin​ secretion (similar mechanism of action to that of
the ​sulfonylureas​).
● Meglitinides​ should be taken shortly before meals.
5.4.3 Indications:​ particularly suitable for patients with postprandial peaks in blood glucose
levels.
5.4.4 Clinical characteristics:
● Glycemic efficacy: lowers ​HbA1c​ by 0.75% over 3 months.
● More expensive than ​sulfonylureas​.
5.4.5 Important side effects:
● Life-threatening ​hypoglycemia​ (less risky than ​sulfonylureas​).
● Increased risk in patients with renal failure.
● Weight gain.
● Hepatotoxicity (rare).
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5.4.6 Contraindications:
● Severe ​liver​ failure.
● Severe renal failure.
5.4.7 Interactions:​ ​Sulfonylureas​.
5.5 Incretinmimetics (GLP-1 receptor agonists)
5.5.1 Active agents:
● Exenatide.
● Liraglutide: rapid-release formula that is administered daily.
● Albiglutide: extended-release formula that is administered once weekly.
● Dulaglutide.
5.5.2 Mechanism of action:
● Incretin effect:
1. Food intake.
2. Activation of enteroendocrine cells in the ​gastrointestinal tract​.
3. Release of GLP-1.
4. GLP-1 degradation via the enzyme DPP-4.
5. End of the GLP-1 effect.
● Incretin mimetic drugs​ bind to the GLP-1 ​receptors​ and are resistant to
degradation by DPP-4 enzyme
● Increase ​insulin​ secretion, decrease glucagonsecretion, slow gastric emptying (↑
feeling of satiety, ↓ weight)
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5.5.3 Clinical characteristics:
● Glycemic efficacy: lowers ​HbA1c​ by 0.5–1.5% over 3 months
● Subcutaneous injection
● Weight loss
● No risk of ​hypoglycemia
5.5.4 Side effects:
● Gastrointestinal complaints (particularly impaired gastric emptying!)
● Increased risk of pancreatitis and potentially ​pancreatic cancer​ :
5.5.5 Contraindications:
● Preexisting symptomatic gastrointestinal motility disorders
● Chronic pancreatitis​ or a family history of ​pancreatic​ tumors
5.6 Dipeptidyl peptidase-4 inhibitors (gliptins)
5.6.1 Active agents:
● Sitagliptin
● Saxagliptin
5.6.2 Mechanism of action:
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● Gliptins​ indirectly increase the endogenous incretin effect by inhibiting the dipeptidyl
peptidase.
● 4 enzyme that breaks down glucagon-like peptide 1.
● Increased ​insulin​ secretion, decreased glucagon secretion, delayed gastric emptying.
5.6.3 Indications​:​ ​Antihyperglycemic therapy algorithm for type 2 diabetes​.
5.6.4 Clinical characteristics:
● Glycemic efficacy: lowers ​HbA1c​ by 0.5–0.75% over 3 months.No risk of
hypoglycemia unless ​insulin​ and/or insulinotropic drugs are used simultaneously.
5.6.5 Important side effects:
● Gastrointestinal complaints: ​diarrhea​, ​constipation​ (milder than
in GLP-1 agonist exposure).
● Nasopharyngitis and upper respiratory tract infection.
● Arthralgia.
● Headaches, dizziness.
● Urinary infections (mild).
● Increased risk of pancreatitis.
● Acute renal failure​.
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5.6.6 Contraindications:
● Hypersensitivity.
● Liver​ failure.
5.7 SGLT-2 inhibitors (gliflozins)
5.7.1 Active agents:
● Dapagliflozin
● Empagliflozin
● Canagliflozin
5.7.2 Mechanism of action:
● Reversible inhibition of the sodium-dependent glucose co-transporter (SGLT-2) in
the proximal tubule of the kidney.
● reduced glucose reabsorption in the kidney.
● glycosuria and polyuria.
5.7.3Indications:​ A treatment option used especially in young patients
with treatment-compliant ​type 2 DM​ without significant renal failure.
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5.7.4 Clinical characteristics:
● Glycemic efficacy: lowers ​HbA1c​ by 0.6% over 3 months.
● Promotes weight loss.
● Reduces blood pressure.
5.7.5 Important side effects:
● Urinary tract infections​, genital infections (​vulvovaginitis​, ​balanitis​).
● Dehydration​ as a result of polyuria.
● Severe ​diabetic ketoacidosis​.
5.7.6 Contraindications:
● Chronic kidney disease​.
● Recurrent urinary tract infections​ (e.g., in patients with anatomical or functional
anomalies of the urinary tract).
5.8 Alpha-glucosidase inhibitors
5.8.1 Active agents:
● Acarbose
● Miglitol
5.8.2 Mechanism of action:
● Inhibits alpha-glucosidase.
● Decreased intestinal glucose absorption.
● The drug is particularly effective in controlling postprandial blood glucose levels.
● The undigested ​carbohydrates​ reach the colon, where they are degraded by
intestinal bacteria, resulting in the production of intestinal gas.
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5.8.3 Clinical characteristics:
● Glycemic efficacy: lowers ​HbA1c​ by 0.8% over 3 months.
● No risk of ​hypoglycemia​.
5.8.4 Important side effects:​ gastrointestinal complaints (flatulence, abdominal
discomfort, ​diarrhea​).
5.8.5 Contraindications
● Inflammatory bowel disease.
● Conditions associated with ​malabsorption​.
● Severe renal failure.
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References:
1. https://www.amboss.com/us/knowledge/Antidiabetic_drugs
2. American Diabetes Association. Diabetes Basics. Accessed 11/5/2018
3. MIMS. 2013. [12 December 2013]. Available from: ​http://www​.mims.co.uk/
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