Anti‐diabetic drugs →

Question 1

Type 2 diabetes

Answer 1

characterized by impaired glucose tolerance, decreased insulin sensitivity as well as β‐cell dysfunction

Question 2

Stepwise management of type 2 diabetes

Answer 2

Diet & exercise→Monotherapy with anti‐diabetic agents →→Combination of anti‐diabetic agents
→→→insulin ± anti‐diabetic agents

Question 3

Major categories of anti‐diabetic agents

Answer 3

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

Question 4

Effect, Name Insulin secretagogues: Sulphonylureas

Answer 4

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

Question 5

Clinical uses and adverse effect of Sulphonylureas

Answer 5

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

Question 6

Non‐sulfonylurea insulin secretagogues: Glinides

Answer 6

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

Question 7

Mechanism and effect of Metformin

Answer 7

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

Question 8

Adverse effects and contraindications of Metformin

Answer 8

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

Question 9

Mechanism and effect Thiazolidinediones (TZDs): Rosiglitazone and Pioglitazone

Answer 9

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

Question 10

α‐Glucosidase inhibitors: Acarbose and Miglitol

Answer 10

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.

Question 11

Incretin pathway as the therapeutic target for antidiabetic drugs

Answer 11

Incretin analogs (mimetics)

Incretin enhancers (DPP‐4 inhibitors)

Incretins→ Pancreas → increased Insulin

Question 12

The incretins (GLP‐1 and GIP)

Answer 12

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).

Question 13

Incretin Mimetics (GLP analogs and agonists) Exenatides

Answer 13

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

Question 14

DPP‐4 inhibitors

Answer 14

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.

Question 15

Sodium‐glucose cotransporter 2 (SGLT2) inhibitors

Answer 15

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

Question 16

Key action mechanisms of anti-diabetic agents

Answer 16

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.

Question 17

Anti‐obesity therapies

Answer 17

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)

Question 18

Mechanism, Recommeneded Dose Precautions and Adverse effect of Lorcaserin

Answer 18

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

Question 19

The mechanism, Recommeneded Dose Precautions and Adverse effect of Phentermine and Topiramate combination

Answer 19

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

Question 20

The mechanism, Recommeneded Dose Precautions and Adverse effect of
Liraglutide

Answer 20

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

Question 21

Orlistat

Answer 21

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

Question 22

Orlistat: mechanism of actions

Answer 22

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

Question 23

Challenges for anti‐obesity drug development

Answer 23

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