Antidiabetic drugs

1. Drugs for Diabetes
Subramani Parasuraman, M.Pharm., Ph.D.,
Associate Professor
Faculty of Pharmacy
AIMST University, Malaysia

2. Diabetes
• Diabetes is a chronic disease that occurs either when
the pancreas does not produce enough insulin or when
the body cannot effectively use the insulin it produces.
• Types:
• Type I: Insulin-dependent diabetes mellitus
(IDDM)/ juvenile onset diabetes mellitus
• Cause: Loss of β-cell function in type 1 diabetes
• Treatment: Exogenous insulin to control hyperglycemia
• Type II: Noninsulin-dependent diabetes mellitus
(NIDDM)/ maturity onset diabetes mellitus
• Cause: Lack of sensitivity of target organs to insulin
• Treatment: Weight reduction, exercise, dietary
modification, hypoglycemic agents, insulin therapy

3. Diabetes
• The incidence of diabetes is growing rapidly worldwide.
• Malaysia has the highest rate of diabetes in Western Pacific
region and one of the highest in the world and costing
around 600 million US dollars per year.
• The prevalence of diabetes raised from 11.2% in 2011 to
18.3% in 2019, with a 68.3% increase. According to a
national survey report, in Malaysia in 2019, 3.6 million
adults had diabetes. Diabetes is expected to affect 7 million
Malaysian adults aged 18 and older by 2025.
Ref: PMID: 35085366

4. Comparison of type 1 and type 2 diabetes

5. Insulin
• Insulin is a two-chain polypeptide having 51 amino acids
and MW about 6000. The A-chain has 21 while B-chain has
30 amino acids. Under basal condition ~1U insulin is
secreted per hour by human pancreas.
Human proinsulin

6. Insulin
• Mechanism of action: Exogenous insulin is administered to
replace absent insulin secretion in type 1 diabetes or to
supplement insufficient insulin secretion in type 2 diabetes.
• Pharmacokinetics: Insulin is a polypeptide; it is degraded in
the gastrointestinal tract if taken orally. Therefore, it is
generally administered by subcutaneous injection. Inhaled
insulin formulation is also available
• Adverse effects: Hypoglycemia, weight gain, local injection
site reactions, and lipodystrophy. Hypoglycaemia is
managed by administering glucose (or glucose yielding
carbohydrate, e.g., sugar) 15–20 g orally reverses the
symptoms.

7. Insulin preparations
• Rapid-acting and short-acting insulin preparations
• Intermediate-acting insulin
• Long-acting insulin preparations
• Insulin combinations
• Insulin delivery devices

8. Insulin preparations
• Rapid-acting and short-acting insulin preparations:
• Five preparations fall into this category: regular insulin, insulin
lispro, insulin aspart, insulin glulisine, and inhaled insulin.
• Regular insulin (peck level at 50 to 120 minutes) is a short-acting,
soluble, crystalline zinc insulin.
• Insulin lispro (peck level at 30 to 90 minutes), aspart, and glulisine
are classified as rapid- acting insulins.
• Inhaled insulin is also considered rapid-acting. This dry powder
formulation is inhaled and absorbed through pulmonary tissue,
with peak levels achieved within 45 to 60 minutes.
• Regular insulin should be injected subcutaneously 30 minutes
before a meal, whereas rapid-acting insulins are administered in
the 15 minutes proceeding a meal or within 15 to 20 minutes
after starting a meal.
• Rapid-acting insulin suspensions are commonly used in external
insulin pumps, and they are suitable for IV administration.

9. Insulin preparations
• Intermediate-acting insulin: Neutral protamine
hagedorn (NPH) insulin is an intermediate-acting insulin
formed by the addition of zinc and protamine to regular
insulin. NPH insulin is used for basal (fasting) control in
type 1 or 2 diabetes and is usually given along with
rapid- or short-acting insulin for mealtime control. NPH
insulin should be given only subcutaneously (never IV).
• Long-acting insulin preparations: It has a slower onset
than NPH insulin and a flat, prolonged hypoglycemic
effect with no peak. Eg: Insulin glargine, Insulin
degludec

10. Insulin preparations
• Insulin combinations: Various premixed combinations
of human insulins [70% NPH insulin + 30% regular
insulin/ 50% NPH insulin + 50% regular insulin]. Use of
premixed combinations decreases the number of daily
injections but makes it more difficult to adjust
individual components of the insulin regimen.
• Insulin delivery devices:
• Syringes
• Pens
• Durable pens
• Pumps
• Jet injectors
• Others

11. Oral antidiabetic drugs
• These drugs lower blood glucose levels in diabetics and
are effective orally. The main drawback of insulin is - it
must be given by injection.

12. Oral antidiabetic drugs

13. Sulfonylureas
• Sulfonylureas more potent and clinically superior. All first-
generation compounds have been discontinued except
tolbutamide which is infrequently used.
• Mechanism of action: Sulfonylureas bind to a specific
‘sulfonylurea receptor’ (SUR1) located on the pancreatic β cell
membrane and provoke a brisk release of insulin.
• Pharmacokinetics: All SUs are well absorbed orally and are 90%
or more bound to plasma proteins: have low volumes of
distribution (0.2–0.4 L/kg). Most sulfonylureas are extensively
metabolized in the liver, primarily by the CYP2C9 isoenzyme and
excreted in urine.
• Adverse effects: Incidence of adverse effects is quite low (3–7%).
Hypoglycaemia, hypersensitivity and nonspecific side effects such
as weight gain, Nausea, vomiting, flatulence, diarrhoea or
constipation, headache and paresthesias.

14. Meglitinide/D-phenylalanine analogues
• Drugs: Repaglinide, Nateglinide
• Mechanism of action: Like the sulfonylureas, the
glinides stimulate insulin secretion. These are KATP
channel blockers with a quick and short lasting
insulinemic action.
• Pharmacokinetics: Glinides should be taken prior to a
meal and are well absorbed after oral administration.
Both glinides are metabolized to inactive products by
cytochrome P450 3A4 (CYP3A4) in the liver and are
excreted through the bile.
• Adverse effects: Although glinides cause hypoglycemia
and weight gain, the incidence is lower than that with
sulfonylureas.

15. Dipeptidyl peptidase-4 (DPP-4) inhibitors
• Drugs: Sitagliptin, Vildagliptin, Saxagliptin, Teneligliptin
• Mechanism of action: These drugs inhibit the enzyme DPP-4,
which is responsible for the inactivation of incretin hormones
such as glucagon-like peptide (GLP-1). Prolonging the activity of
incretin hormones increases release of insulin in response to
meals and reduces inappropriate secretion of glucagon.
• Pharmacokinetics: The DPP-4 inhibitors are well absorbed after
oral administration. Food does not affect the extent of
absorption. Sitagliptin are mostly excreted unchanged in the
urine. Saxagliptin is metabolized via CYP450 3A4/5 to an active
metabolite. All DPP-4 inhibitors except linagliptin require dosage
adjustments in renal dysfunction.
• Adverse effects: DPP-4 inhibitors are well tolerated, with the
most common adverse effects being nasopharyngitis and
headache.

16. Biguanide (AMPK activator)
• Drugs: Metformin, Phenformin [Phenformin is banded in
many countries because of higher risk of lactic acidosis]
• Mechanism of action: Metformin is a complex drug with
multiple sites of action. Metformin acts directly or indirectly
on the liver to lower glucose production, and acts on the gut
to increase glucose utilisation, increase GLP-1 and alter the
microbiome.
• Pharmacokinetics: Metformin is well absorbed after oral
administration, is not bound to serum proteins, and is not
metabolized. Excretion is via the urine.
• Adverse effects: Side effects with metformin are frequent,
but generally not serious. Others: Diarrhea, nausea, and
vomiting, metallic taste, tiredness. Metformin does not
cause hypoglycaemia except in overdose.

17. Thiazolidinedione (PPARγ agonist)
• Drugs: Pioglitazone, Rosiglitazone
• Mechanism of action: The thiazolidinediones (TZDs) are also
insulin sensitizers. The TZDs lower insulin resistance by acting
as agonists for the peroxisome proliferator–activated
receptor-γ (PPARγ), a nuclear hormone receptor. Activation of
PPARγ regulates the transcription of several insulin-responsive
genes, resulting in increased insulin sensitivity in adipose
tissue, liver, and skeletal muscle. The TZDs can be used as
monotherapy or in combination with other glucose-lowering
agents or insulin.
• Pharmacokinetics: Oral administration, metabolized by CYP450,
Pioglitazone- excreted in the bile and eliminated in the feces,
Rosiglitazone - primarily excreted in the urine. No dosage
adjustment is required in renal impairment.
• Adverse effects: Liver toxicity, osteopenia, Pioglitazone may also
increase the risk of bladder cancer, rosiglitazone carries a boxed
warning about the potential increased risk of myocardial infarction
and angina.

18. α Glucosidase inhibitors
• Drugs: Acarbose, Miglitol, Voglibose
• Mechanism of action: These drugs reversibly inhibit α-
glucosidase enzymes and delay the digestion of
carbohydrates, resulting in lower postprandial glucose
levels. They do not stimulate insulin release or increase
insulin sensitivity; these agents do not cause
hypoglycemia when used as monotherapy.
• Adverse effects: The most common adverse effects are
flatulence, diarrhea, and abdominal cramping.

19. Dopamine D2 agonist
• Drugs: Bromocriptine. Used as adjunctive treatment of
type 2 DM.
• Mechanism of action: Bromocriptine is thought to act
on the circadian neuronal activities in the
hypothalamus, to reset an abnormally elevated
hypothalamic drive for increased plasma glucose, free
fatty acids, and triglycerides in insulin-resistant
patients. Contraindicated in patients with renal
insufficiency.

20. Sodium-glucose co-transport-2 (SGLT-2)
inhibitor
• Drugs: Dapagliflozin, Canagliflozin
• Mechanism of action: The SGLT2 is responsible for
reabsorbing filtered glucose in the tubular lumen of the
kidney. By inhibiting SGLT2, these agents decrease
reabsorption of glucose, increase urinary glucose excretion,
and lower blood glucose. Inhibition of SGLT2 also decreases
reabsorption of sodium and causes osmotic diuresis 
reduce systolic blood pressure (not indicated for the
treatment of hypertension).
• Pharmacokinetics: Before the first meal of the day,
metabolized by glucuronidation, avoided in patients with
renal dysfunction
• Adverse effects: Mycotic infections (in females), urinary
tract infections, and urinary frequency, hypotension
(elderly), Ketoacidosis

21. Bile acid sequestrant
• Drug: Colesevelam
• It is a bile acid binding resin which lowers cholesterol as
well as glucose levels in blood. It is approved as add-on
drug in type 2 DM patients who are not properly
controlled by other antidiabetic drugs. The mechanism
of action is not clear.

22. Oral hypoglycemic agents, dose range and dose frequency
MEDICINE USUAL DAILY DOSE FREQUENCY
Glibenclamide 5 mg 2.5–20 mg • Up to 10 mg as a single dose
• >10 mg in divided doses
• Taken with or immediately before food
Glipizide 5 mg 2.6–40 mg • Up to 15 mg as a single dose
• >15 mg in a twice daily dosage taken
• immediately before meals
Gliclazide 80 mg 30–120 mg • Daily
Glimepiride 1/ 2 mg 1–4 mg • 2–3 per day
Metformin 500 mg, 1g 0.5–1.5 g • 1–3 times/day taken with or immediately
after food
Repaglinide 0.5 mg, 1/ 2 mg 0.5–16 mg • 2–3 per day
Pioglitazone 15 mg, 30 mg 4–8 mg • Daily
Rosiglitazone 2 mg, 4 mg 4–8 mg • Daily
Acarbose 50/ 100 mg 50–100 mg • TDS with food thrice a day
Voglibose 0.2/ 0.3 mg 0.2–0.3 mg • TDS with food thrice a day
Sitagliptin 50/ 100 mg 100 mg per day in BD
regimen. In combination with
metformin, or a sulfonylurea
• With or without food
Vildagliptin 50 mg • With or without food

23. Ref: https://www.puremed.com.my/world-diabetes-day-5-minutes-read/ [last assessed on 25-12-2022]