Anti‐diabetic drugs → Flashcards
Type 2 diabetes
characterized by impaired glucose tolerance, decreased insulin sensitivity as well as β‐cell dysfunction
Stepwise management of type 2 diabetes
Diet & exercise→Monotherapy with anti‐diabetic agents →→Combination of anti‐diabetic agents
→→→insulin ± anti‐diabetic agents
Major categories of anti‐diabetic agents
Insulin secretagogues
→Sulfonylureas (Glipizide, Glimepiride)
→Meglitinide analogs (Repaglinide and Nateglinide)
Insulin sensitizers
→Biguanides (Metformin)
→Thiazolidinediones (Rosiglitazone, Pioglitazone)
α‐Glucosidase inhibitors (Acarbose and Miglitone)
Incretin mimetics
→Glucagon‐like peptide (GLP) analogs (Exenatide and Liraglutide)
Dipeptidyl peptidase‐4 (DPP‐4) inhibitors
→(Sitagliptin and Vidagliptin)
Sodium‐glucose cotransporter‐2 inhibitors
→canagliflozin, dapagliflozin, empagliflozin and ertugliflozin
Effect, Name Insulin secretagogues: Sulphonylureas
bind to a 140 kDa high‐affinity receptor that is associated with a β‐cell inward rectifier ATP‐sensitive potassium channel.
increase insulin secretion from β‐cells
long duration of action 12‐48 hours
1st generation sulphonylureas
(e.g. chlorpropamide, tolbutamide) not commonly used because of long duration
of action & adverse reactions.
2nd generation sulphonylureas, (e.g. glipizide, glyburide, glimepiride) more commonly used because of fewer adverse effects and drug
interactions
Clinical uses and adverse effect of Sulphonylureas
used in Type 2 patients with residual β‐cell function
ineffective where there is absolute deficiency of insulin
production such as in type 1 diabetes.
adjunctive to nutritional and exercise therapy
20‐25% of newly diagnosed patients will fail to respond to initial therapy (primary failure)
of the 75% who achieve good control, 3‐5% will lose
responsiveness each year (secondary failure
Adverse effects of Sulphonylureas
weight gain due to increased appetite
hypoglycaemia (esp. in hepatic & renal insufficiency)
potentially teratogenic and cannot be used in pregnancy or
in patients who may become pregnant
gastrointestinal upsets
Non‐sulfonylurea insulin secretagogues: Glinides
This class of agents includes Repaglinide and Nateglinide.
Meglitinides bind to a distinct site on the
sulfonylurea receptor of ATP‐sensitive K+
channels, thereby stimulating a very rapid and
transient insulin release.
In contrast to Sulfonylureas, Glinides have a rapid
onset and short duration of action (~2 hours).
Good for controlling postprandial glucose, but
has minimal effect on overnight and fasting
glucose levels.
The incidence of hypoglycemia is much lower
than sulfonylureas
Mechanism and effect of Metformin
Major mechanism: inhibits
hepatic glucose production
possibly by activation of AMPactivated protein kinase (AMPK)
also reduce hyperlipidemia
→ decreased fatty acid synthesis
→ increased fatty acid oxidation
recommended for obese patients or patients with insulin resistance
used alone does not cause
hypoglycaemia
can reduce risk of
cardiovascular complications
Adverse effects and contraindications of Metformin
most frequent adverse effects: GI upsets including
abdominal discomfort, nausea, and diarrhoea
The most serious side effect: lactic acidosis ‐ a rare (9 per
100,000) but potentially fatal complication
contraindicated in patients with renal disease,
alcoholism, hepatic disease and severe infection
long term use causes vitamin B12 deficiency
Adverse
Mechanism and effect Thiazolidinediones (TZDs): Rosiglitazone and Pioglitazone
Main action site: adipose tissue (fat), muscle
and liver
Major molecular target: peroxisome
proliferator‐ activated receptor γ (PPAR γ), a
nuclear hormone receptor
Possess anti‐inflammatory properties
and improve lipid profile
Major adverse effects: weight gain and
fluid retention
Should not be used in patients with heart disease
Can be potentially used for prevention of type 2 diabetes
α‐Glucosidase inhibitors: Acarbose and Miglitol
inhibit α‐glucosidase through competition with
the substrate of this enzyme
block postprandial digestion and absorption of
starch and disaccharides from small intestine
lower blood glucose and insulin levels after
meals
no effect on body weight
used alone does not cause hypoglycaemia
not absorbed into the bloodstream
major side effects are flatulence, diarrhoea,
and abdominal pain
relatively weak anti‐diabetic effect, usually used
in combination with other drugs.
Incretin pathway as the therapeutic target for antidiabetic drugs
Incretin analogs (mimetics)
Incretin enhancers (DPP‐4 inhibitors)
Incretins→ Pancreas → increased Insulin
The incretins (GLP‐1 and GIP)
Incretins are gut‐derived hormones that can enhance glucose‐dependent insulin
secretion and inhibit glucagon release.
The endogenous incretins include glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory peptide (also called glucose‐dependent insulinotropic peptide or GIP).
GLP‐1 and GIP have a very short half‐life due to the rapid degradation by dipeptidyl
peptidase‐4 (DPP‐4).
Incretin Mimetics (GLP analogs and agonists) Exenatides
Exenatides (a 39‐amino acid peptide)
It is a synthetic version of exendin‐4, a hormone found in the saliva of the Gila
monster
It is the first GLP‐1 agonist approved for the treatment of Type 2 diabetes
It has only 53% homology with GLP, which increases its resistance to degradation by
DPP‐4 and extends its half‐life
can cause weigh loss through slowing down gastric emptying time.
can also decrease fatty liver
Side effects: (1) GI disorders including acid or sour stomach, belching, diarrhea, and vomiting etc (2) dizziness, headache, and feeling jittery
Disadvantages: needs to be administered by injection.
Liraglutide
It is a long‐acting GLP‐1 analog that has been developed by Novo Nordisk
Recently approved by both EMEA and FDA, but has cancer concerns
DPP‐4 inhibitors
Sitagliptin phosphate (trade name: Januvia) is approved by FDA for use in 2006
works by blocking the activity of DDP‐4
can be used as a monotherapy or as combination therapy with metformin or a PPARgamma agonist.
provide a long‐term blood glucose control.
side effects include upper respiratory tract infection, sore throat and diarrhea.
Sodium‐glucose cotransporter 2 (SGLT2) inhibitors
SGLT2 inhibitors promote renal excretion of glucose
Sodium‐glucose cotransporter 2 (SGLT2) is a channel in the
proximal tubule responsible for 90% of glucose
reabsorption.
SGLT2 inhibitors: canagliflozin, dapagliflozin, empagliflozin
Side effects: UTIs, vulvovaginal candidiasis (vaginal yeast infections), glycosuria, renal failure, decrease blood
pressure, hyperkalemia, dehydration, substantial weight loss
Key action mechanisms of anti-diabetic agents
Sulphonylureas and Meglitinide analogs: bind to a receptor (K-ATP channel) in β-cells and cause membrane depolarization,
resulting in increased insulin secretion.
Biguanides (Metformin): activate AMPK in the liver tissue, which
in turn suppress glucose production.
α-glucosidase inhibitors (Acarbose and Miglitol): inhibit α-
glucosidase in gastrointestinal tract, thus blocking the absorption
of glucose.
TZDs (Pioglitazone and Rosiglitazone): bind PPARγ to increase insulin sensitivity in fat, muscle and liver.
DPP-4 inhibitors (Sitagliptin phosphate): inhibit DPP-4 activity and therefore decrease the degradation of incretins, which in turn
enhances glucose-mediated stimulation of insulin secretion.
GLP analogs and agonists (Exenatides and Liraglutide): mimic the effects of incretins to stimulate insulin secretion and inhibit glucagon production.
SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin): inhibit SGLT2 to decrease glucose reabsorption from the proximal tubules in kidney.
Anti‐obesity therapies
Diet, excise.
Anti‐obesity drugs
Suppression of appetite through central nerve system
(phentermine, sibutramine and rimonabant)
Interference with the body’s ability to absorb specific
nutrients in food (orlistat)
Surgery (gastric banding, liposuction)
Mechanism, Recommeneded Dose Precautions and Adverse effect of Lorcaserin
Mechanism of Action
Lorcaserin is used to decrease food consumption and promote satiety by selectively activating 5‐HT2c
receptors on anorexigenic pro‐opiomelanocortin neurons located in the hypothalamus. However the exact mechanism of action is still unknown. 1‐year weight loss: 3.0%‐3.6%
Recommended Dose
10mg, orally, bid
Precautions
Monitor for symptoms of serotonin toxicity and cognitive impairment. Monitor for signs and symptoms of valvular heart disease, heart rate decreases, pulmonary hypertension
Adverse events
Headache, dizziness, fatigue, nausea, dry mouth, constipation, cough, hypoglycemia in patients with diabetes
The mechanism, Recommeneded Dose Precautions and Adverse effect of Phentermine and Topiramate combination
Phentermine
↑catecholamines release in the hypothalamus →appetite ↓ food consumption↓
Topiramate
Activity of the neurotransmitter γ-aminobutyra↑
Modulation of voltage‐gated ion channels
Inhibition of AMPA/kainite excitatory glutamate receptors
Inhibition of carbonic anhydrase
→appetite ↓ satiety↑
Recommended dose
Phentermine/topiramate (3.75/23 mg extended‐release, once daily,14 days) 7.5/46 mg (extended‐release once daily) evaluates weight loss after 12 weeks of treatment.
Precautions
Fetal toxicity; increases in heart rate; suicidal behavior and ideation; mood and sleep disorder; glaucoma;
Adverse events
Paresthesia, headache, dizziness, insomnia, dysgeusia, constipation, dry mouth
The mechanism, Recommeneded Dose Precautions and Adverse effect of
Liraglutide
Mechanism of Action
Liraglutide is an acylated human GLP‐1 receptor agonist. It activates GLP‐1 receptor in pancreatic beta cells leading to insulin release. Liraglutide also decreases glucagon secretion. In 2014, the FDA approved it for chronic
weight management in obese and overweight adults with at least one‐weight related comorbidity. 1‐year weight
loss: 4.0%‐5.4%
Recommended dose
3mg, subcutaneous injection, once daily
Precautions
Waring: It causes thyroid C‐cell tumors at clinically relevant exposures in both genders of rats and mice. It
should be discontinued if pancreatitis is suspected.
Adverse events
Nausea, vomiting, diarrhea, constipation, dyspepsia, abdominal pain, headache, fatigue, hypoglycemia
Orlistat
A reversible inhibitor of lipases
→Works at lumen of the stomach and small intestine
→→Covalent bond with the active serine residue site of
gastric and pancreatic lipases
→→→Dietary fat in the form of triglycerides can not be hydrolyzed into absorbable free fatty acids and monoglycerides
→→→→Caloric deficiency and weight control (1‐year weight loss: ~3%)
Recommended dose
120mg, orally, tid
Precautions
Adhere to dietary guidelines
Gastrointestinal events ↑
Supplement with fat‐soluble vitamins to ensure adequate nutrition
Adverse events Oily Spotting Flatus with Discharge Fecal Urgency Fatty/Oily Stool Oily Evacuation Increased Defecation Fecal Incontinence
Orlistat: mechanism of actions
Orlistat inhibits gastric and pancreatic lipases, thus decreasing the
breakdown of dietary fat into smaller molecules
inhibits pancreatic and gastric lipases to digest fat
reduces absorption of fat in the small intestine by 30%
effects observed after 2 days of treatment
<1% absorbed from the GI tract, and primarily eliminated in the
feces
used for the treatment of significant obesity
Major side effects: GI symptoms (such as oily-spotting, fecal urgency, increased defecation and malabsorption of fat‐soluble
viatmins and carotenoids)
not recommended during pregnancy
Challenges for anti‐obesity drug development
Safety
Numerous withdrawals of anti‐obesity drugs (centrally‐acting) from the market is due to untoward effects (such as fenfluramine/phentermine combination). FDA requires anti‐obesity drugs
should not adversely affect cardiovascular functions.
Efficacy
FDA criteria for weight reduction (after 1 year drug treatment) is defined as ≥ 5% body weight.
The drug‐induced weight loss should be primarily due to a reduction in fat content , not lean‐body mass.
An effective product should also provide improvement in blood pressure, lipids, glycemia or other
metabolic complications.
Novel strategy:
focusing on not only central, but also peripheral targets governing energy expenditure
