Antidiabetic drug-1

anti diabetic drug description

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. 
5Non-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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11. Antidiabetic Drug 2019 
 
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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13. Antidiabetic Drug 2019 
 
●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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