Oral Hypoglycaemic Drugs

These drugs lower blood glucose levels and are effective orally, The chief draw back of insulin is—
it must be given by injection, Orally active drugs have always been saught.

Classification
A. Enhance Insulin Secretion
1. Sulfonylureas (KATP Channel blockers)
First generation: Tolbutamide
Second generation: Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepiride
2. Meglitinide/phenylalanine analogues : Repaglinide, Nateglinide
3. Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable drugs) : Exenatide, Liraglutide
4. Dipeptidyl peptidase-4 (DPP-4) inhibitors : Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin,
Linagliptin
B. Overcome Insulin Resistance
1. Biguanide (AMPK activator): Metformin
2. Thiazolidinediones (PPARγ activator) : Pioglitazone
C. Miscellaneous Antidiabetic Drugs
1. α-Glucosidase inhibitors : Acarbose, Miglitol, Voglibose
2. Amylin analogue : Pramlintide
3. Dopamine-D2 receptor agonist : Bromocriptin
4. Sodium-glucose cotransport-2 (SGLT-2)inhibitor : Dapagliflozin

Sulfonylureas (KATP Channel Blockers)

All SUs have similar pharmacological profile, their sole significant action being lowering of blood
glucose level in normal subjects and in type 2 diabetics, but not in type 1 diabetics.
#Being more potent and clinically superior, only the second generation SUs are employed now.

Mechanism of action :
Sulfonylureas provoke a brisk release of insulin from pancreas, the mechanism of which is detailed
in Fig. 19.6 , The rate of insulin secretion at any glucose concentration is increased, i.e. insulin release
is provoked even at low-glucose concentration risking production of severe and unpredictable
hypoglycaemia. In type 2 DM the kinetics of insulin release in response to glucose or meals is
delayed and subdued.
#A minor action reducing glucagon secretion, probably by increasing insulin and somatostatin
release has been demonstrated, Hepatic degradation of insulin is also slowed.
1
#they should be used cautiously in patients with liver or kidney dysfunction.
Interactions
Drugs that enhance SU action (may precipitate hypoglycaemia) are :
(a) Displace from protein binding : Phenylbutazone, sulfinpyrazone, salicylates, sulfonamides.
(b) Inhibit metabolism/excretion: Cimetidine ketoconazole, sulfonamides, warfarin,
chloramphenicol, acute alcohol intake (also synergises by causing hypoglycaemia).
(c) Synergise with or prolong pharmacodynamics action: Salicylates, propranolol (cardioselective
β1 blockers are less liable), sympatholytic antihypertensives, lithium, theophylline, alcohol (by
inhibiting gluconeogenesis).
Drugs that decrease SU action (vitiate diabetes control) are :
(a) Induce metabolism: Phenobarbitone, phenytoin, rifampicin, chronic alcoholism.
(b) Opposite action/suppress insulin release: Corticosteroids, thiazides, furosemide, oral
contraceptives.

Adverse effects : Incidence of adverse effects is quite low (3–7%).

1. Hypoglycaemia : It is the commonest problem, may occasionally be severe and rarely fatal, It is
more common in elderly, liver and kidney disease patients and when potentiating drugs are
added.
#Tolbutamide carries lowest risk due to its low potency and short duration of action.
2. Nonspecific side effects : Majority of diabetics started on SUs tend to gain 1–3 kg weight, This
may be a consequence of their insulinaemic action.
#Nausea, vomiting, flatulence, diarrhoea or constipation, headache and paresthesias are generally
mild and infrequent.
3. Hypersensitivity : Rashes, photosensitivity, purpura, transient leukopenia, rarely agranulocytosis.
#Flushing and a disulfiram-like reaction after alcohol is reported to occur in some individuals taking
SUs.
#Tolbutamide reduces iodide uptake by thyroid but hypothyroidism does not occur.
#Safety of SUs during pregnancy is not established, Change over to insulin is advised.

Meglitinide/D-Phenylalanine Analogues (KATP Channel Blockers)

These are KATP channel blockers with a quick and short lasting insulinemic action.
Repaglinide : This meglitinide analogue oral hypoglycaemic is designed to normalise mealtime
glucose excursions, Though not a sulfonylurea, it acts in an analogous manner by binding to SUR →
closure of ATP dependent K+ channels → depolarisation → insulin release
#It is administered before each major meal to control postprandial hyperglycaemia; the dose
should be omitted if a meal is missed.

2
#Because of short lasting action it may have a lower risk of serious hypoglycaemia.
#Side effects are mild headache, dyspepsia, arthralgia and weight gain.
Repaglinide is indicated only in selected type 2 diabetics who suffer pronounced post prandial
hyperglycaemia, or to supplement metformin/long-acting insulin.
#It should be avoided in liver disease.
Nateglinide : principally stimulates the 1st phase insulin secretion by closing β cell KATP channels
resulting in faster onset and shorter lasting hypoglycaemia than repaglinide.
#Ingested 10 min before meal, it limits postprandial hyperglycaemia in type 2 diabetics without
producing late phase hypoglycaemia, Episodes of hypoglycaemia are less frequent than with SUs.
#Side effects are dizziness, nausea, flu like symptoms and joint pain.
#It is used in type 2 DM along with other antidiabetics, to control postprandial rise in blood glucose.

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

GLP-1 is an important incretin released from the gut in response to ingested glucose.
#It induces insulin release from pancreatic β cells, inhibits glucagon release from α cells, slows
gastric emptying and suppresses appetite by activating specific GLP-1 receptors.
#Characteristically GLP-1 induces insulin release only at high glucose concentration.
#The incretin system appears to promote β cell health as well, Failure of incretins has been
implicated in the pathogenesis of β cell dysfunction of type 2 DM, particularly progression of the
disease.
#GLP-1 based therapy appears to be the most effective measure for preserving β cell function in
type 2 DM, GLP-1 itself is not suitable for clinical use because of rapid degradation by the enzyme
dipeptidyl peptidase-4 (DPP-4) which is expressed on the luminal membrane of capillary endothelial
cells, kidney, liver, gut mucosa and immune cells.
#Another incretin glucose-dependent insulinotropic peptide (GIP) also induces insulin release, but
in human beings GLP-1 is the more important incretin and GIP has poor action in type 2 diabetics.

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4), They can be
used to treat diabetes mellitus type 2.
Sitagliptin : This is the first DPP-4 inhibitor introduced in USA in 2006 and now available world
wide.
#It is a competitive and selective DPP-4 inhibitor which potentiates the action of GLP-1 and GIP,
boosts post prandial insulin release, decreases glucagon secretion and lowers meal-time as well
as fasting blood glucose in type 2 diabetics.
#No effect on gastric emptying and appetite have been noted, It is body weight neutral and carries
low risk of hypoglycaemia unless combined with SUs or insulin.

3
#The HbA1c lowering caused by sitagliptin is equivalent to that with metformin.
#Further lowering of HbA1c occurs when it is added to pioglitazone/SUs/insulin with or without
metformin.
#However, sitagliptin monotherapy is recommended only when metformin cannot be used.
#Most professional guidelines recommend DPP-4 inhibitors primarily as adjuvant drugs in type 2
diabetics not well controlled by metformin/SUs/pioglitazone or insulin.
#Dose reduction is needed in renal impairment, but not in liver disease.
#Side effects are nausea, loose stools, headache, rashes, allergic reactions and edema,
Nasopharyngitis and cough occurs in some patients.
Vildagliptin : This is the second DPP-4 inhibitor , longer duration of action (12–24 hours) despite
short plasma t½ (2–4 hours). The major route of elemination is by hepatic metabolism; only 20–
25% is excreted unchanged in urine, Vildagliptin is less selective than sitagliptin for DPP-4.
#Dose reduction is needed in moderately severe liver and kidney disease.
#No significant drug interactions have been reported.
#The tolerability of vildagliptin is similar to that of sitagliptin, but hepatotoxicity has been reported.
Saxagliptin : Like vildagliptin, it binds covalently with DPP-4 and acts for 24 hours despite a
plasma t½ of 2–4 hours, It is metabolized by CYP3A4 and generates an active metabolite that has a
t½ of 3–7 hours.
#Drug interactions with CYP3A4 inhibitors are possible.

Biguanide (AMPK Activator)

Two biguanide antidiabetics, phenformin and metformin.
#Because of higher risk of lactic acidosis, phenformin was withdrawn and has been banned.
Metformin : It differs markedly from SUs: causes little or no hypoglycaemia in nondiabetic
subjects, and even in diabetics, episodes of hypoglycaemia are rare. It does not stimulate pancreatic
β cells, Metformin is reported to improve lipid profile as well in type 2 diabetics.
Mechanism of action : Biguanides do not cause insulin release, but presence of insulin is essential
for their action, Metformin is not effective in pancreatectomized animals and in type 1 diabetics.
The key features of which are :
1. Suppresses hepatic gluconeogenesis and glucose output from liver : This is the major action
responsible for lowering of blood glucose in diabetics.
2. Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat, Insulin
resistance exhibited by type-2 diabetics is thus overcome.
#Metformin also retards intestinal absorption of glucose, other hexoses, amino acids and Vit B12.
#Clearance of metformin approximates GFR, It accumulates in renal failure and increases the risk
of lactic acidosis.

4
Side effects with metformin : are frequent, but generally not serious,
1- Abdominal pain, anorexia, bloating, nausea, metallic taste, mild diarrhoea and tiredness are the
usual complaints, which tend to subside with time.
#Metformin does not cause hypoglycaemia except in overdose.
2- metformin is contraindicated in hypotensive states, heart failure, severe respiratory, hepatic
and renal disease, as well as in alcoholics because of increased risk of lactic acidosis.
3- Drugs (cimetidine, furosemide may compete with metformin excretion → enhance its toxicity.

Uses
Metformin is now established as a first choice drug for all type 2 DM patients, except when not
tolerated or contraindicated.
Advantages of metformin are:
1- nonhypoglycaemic
2- weight loss promoting
3- has potential to prevent macrovascular as well as microvascular complications of diabetes
4- no acceleration of β cell exhaustion/ failure in type 2 DM.
5- antihyperglycaemic efficacy (HbA1c reduction by 0.8–1.2%) equivalent to other oral drugs.
6- can be combined with any other oral or injectable antidiabetic, if one drug is not adequate.
#The limiting feature is GI intolerance, especially at higher doses.
#Infertility: Metformin has been found to improve ovulation and fertility in some infertile women
with polycystic ovary.

Thiazolidinedione (PPARγ agonist)

Only one thiazolidinedione Pioglitazone is currently available.
#Rosiglitazone, the other member, is banned in India has been withdrawn in Europe due to
unacceptable increase in risk of myocardial infarction, CHF, stroke and death.
#This class of oral antidiabetic drugs are selective agonists for the nuclear peroxisome proliferator-
activated receptor γ (PPARγ) which is expressed mainly in fat cells, but also in muscle and some
other cells.
#Entry of glucose into muscle and fat is improved, Hepatic gluconeogenesis is also suppressed,
Thus, fatty tissue is a major site of their action.
#The magnitude of blood glucose reduction is somewhat less than SUs and metformin, Improved
glycaemic control results in lowering of circulating HbA1C and insulin levels in type 2 DM
patients.
#Pioglitazone, in addition, lowers serum triglyceride level and raises HDL level without much
change in LDL level.

5
Adverse effects :
1- plasma volume expansion, edema, weight gain, headache, myalgia and mild anaemia.
2- Few cases of hepatic dysfunction have been reported; CHF may be precipitated or worsened, So It
is contraindicated in liver disease and in CHF.
#Glitazones increase the risk of fractures, especially in elderly women.
3- Failure of oral contraception may occur during pioglitazone therapy.
4- Ketoconazole inhibits and rifampin induces metabolism of pioglitazone.
#Pioglitazone is indicated in type 2 DM, but not in type 1 DM, It reduces blood glucose and HbA1c
(by 0.5–1.2%) without increasing circulating insulin.
#About 25% patients may not respond (nonresponders), probably due to low baseline insulin levels.
#It should be stopped if HbA1c reduction is < 0.5% at 6 months.
#Pioglitazone is primarily used to supplement SUs/metformin and in case of insulin resistance, It
may also be used as monotherapy (along with diet and exercise) in mild cases.
#Several reports describe greater fluid retention, weight gain and precipitation of CHF after
combined use of glitazones with insulin.
#Pioglitazone should not be used during pregnancy.
#The Diabetes Prevention Programme (2005) has shown that glitazones have the potential to delay
progression of prediabetics to overt type 2 DM.

α-Glucosidase Inhibitors
Acarbose : It slows down and decreases digestion and absorption of polysaccharides (starch, etc.)
and sucrose, In addition, GLP-1 release is promoted which may contribute to the effect.
#Postprandial glycaemia is reduced without significant increase in insulin levels.
#long-term acarbose treatment in prediabetics reduces occurrence of type 2 DM as well as
hypertension and cardiac disease, In diabetics, it reduces cardiovascular events.
#Acarbose is a mild antihyperglycaemic and not a hypoglycaemic; may be used as an adjuvant to
diet (with or without metformin/SU) in obese diabetics.
#Dose 50–100 mg TDS is taken at the beginning of each major meal.
#Adverse Effects : Flatulence, abdominal discomfort and loose stool are produced in about 50%
patients due to fermentation of unabsorbed carbohydrates.
#Hepatic transaminases may rise, but liver damage is rare.
Miglitol : It has a smaller molecule than acarbose, and it is a stronger inhibitor of sucrase. Potency for other α-
glucosidases is equivalent to acarbose, Absorption of miglitol is substantial, but variable, The absorbed drug is
excreted by the kidney, No systemic toxicity is known.
Voglibose : Has properties, use and side effects similar to that of acarbose

6
Amylin analogue
Amylin, also called ‘islet amyloid polypeptide’ (IAP), is produced by pancreatic β cells and acts in the brain to
reduce glucagon secretion from α cells, delay gastric emptying, retard glucose absorption and promote
satiety.
Pramlintide : It is a synthetic amylin analogue which on s.c. injection before meal attenuates postprandial
glycaemia and exerts a centrally mediated anorectic action, It has been used as an adjuvant to meal time insulin
injection to suppress the glycaemic peak in both type 1 and type 2 diabetics. Reduction in body weight is an
additional benefit.
Dopamine D2 agonist
Bromocriptine : a quick release oral formulation of bromocriptine has been approved by US-FDA for adjunctive
treatment of type 2 DM, Taken early in the morning it is thought to act on the hypothalamic dopaminergic
control of the circadian rhythm of hormone (GH, prolactin, ACTH, etc.) release and reset it to reduce insulin
resistance.
#can be taken alone to supplement diet+exercise or added to metformin or SU or both, Started at 0.8 mg OD
and increased upto 4.8 mg OD (as needed) it has been shown to marginally improve glycaemic control and
lower HbA1c by up to 0.5%.

Sodium-Glucose Co-Transport-2 (SGLT-2) Inhibitor

Practically all the glucose filtered at the glomerulus is reabsorbed in the proximal tubules, The
major transporter which accomplishes this is SGLT-2, whose inhibition → induces glucosuria and
lowers blood glucose in type 2 DM, as well as causes weight loss.
Dapagliflozin : This SGLT-2 inhibitor has been recently tested in type 2 DM patients, After single
daily dose it produces round-the-clock glucosuria and lowers blood glucose levels,The concerns
which appear inbuilt due to its mechanism of action are—glycosuria which can predispose to urinary
and genital infections, electrolyte imbalance and increased urinary frequency.

Status Of Oral Hypoglycaemics In Diabetes Mellitus

The University Group Diabetes Programme (UGDP) of USA (1970) presented findings that
cardiovascular mortality was higher in patients treated with biguanides and SUs than in those
treated with diet and exercise alone or with insulin.
The controversy has been settled by the UK PDS trial which found that both SUs and metformin did
not increase cardiovascular mortality over > 10 years observation period.
#Both insulin and SUs reduced microvascular complications (retinopathy, neuropathy,
nephropathy) in type 2 DM, but did not have significant effect on macrovascular complications
(coronary artery disease, stroke, etc).
#Oral hypoglycaemics are indicated only in type 2 diabetes, in addition to diet and exercise, They
are most effective in patients with :
1. Age above 40 years at onset of disease. 2. Obesity at the time of presentation.
3. Duration of disease < 5 years when starting treatment.
4. Fasting blood sugar < 200 mg/dl. 5. Insulin requirement < 40 U/day.
6. No ketoacidosis or a history of it, or any other complication.

7
#Oral hypoglycaemics should be used to supplement dietary management and not to replace it.
#Metformin may delay progression of diabetic severity, It is especially valuable for obese patients;
may also aid weight reduction, Further, it has the potential to reduce the risk of myocardial
infarction and stroke.
#Thus,unless contraindicated/not tolerated, metformin is prescribed to all type 2 diabetics,
despite its inferior patient acceptability due to GI side effects.
#Many type 2 DM patients do not attain desired level of glycaemia control and HbA1c reduction (to <
7%) with metformin alone, and a second drug is needed, SUs are the most commonly selected 2nd
drug, They have good patient acceptability, convenient dosing and high efficacy, but can cause
weight gain and hypoglycaemia.
#There is some evidence that SUs given over longterm (2–10 years) expedite β cell apoptosis and failure.
#Patients with near normal fasting blood glucose but prominent post-prandial hyperglycaemia, or those
experiencing late postmeal hypoglycaemia may do better with a premeal meglitinide/phenyl alanine
analogue

#Pioglitazone is usually the 3rd choice drug; may be added to metformin or a combination of
metformin + SU , Though it reduces insulin resistance, tends to preserve β cell function and does
not cause hypoglycaemia, it is infrequently selected for monotherapy, Its major limitations are—
tendency to fluid retention, weight gain, increased risk of heart failure and fractures, need to
monitor liver function and inefficacy in a significant number of patients.
#Acarbose-like drugs are mild anti-hyperglycaemics, mostly used as supplementary drugs to a
combination hypoglycaemic regimen, They are disliked by many patients because of bloating,
indigestion and other abdominal symptoms.
#The latest hypoglycaemics gaining popularity are the DPP-4 inhibitors, Their favourable features
are:
• Insulin release is glucose dependent; therefore not likely to induce hypoglycaemia.
• Suppress glucagon release, thus lowering fasting blood glucose as well.
• Improve β cell health and retard progression of β cell failure.
• Body weight neutral.
• Mostly single daily dose, well tolerated with few side effects, no serious toxicity, no drug
interactions, except with saxagliptin.
#Up to 50% patients of type 2 DM initially treated with oral hypoglycaemics ultimately need insulin.
#Moreover, when a diabetic on oral hypoglycaemics presents with infection, severe trauma or stress,
pregnancy, ketoacidosis or any other complication, or has to be operated upon— switchover to
insulin.

8
 Fig. 19.7: Simplified flow chart of management approaches in diabetes mellitus.
Note: A meglitinide drug is indicated only in patients with predominant postprandial hyperglycaemia.

Glucagon
It is secreted by the α cells of the islets of Langerhans.
Regulation of Secretion : Its secretion is regulated by glucose levels, other nutrients, paracrine
hormones and nervous system, Glucose has opposite effects on insulin and glucagon release, i.e.
high glucose level inhibits glucagon secretion.
#The incretin GLP-1, FFA and ketone bodies also inhibit glucagon release.
#Amino acids, however, induce both insulin and glucagon secretion.
#Sympathetic stimulation consistently and parasympathetic stimulation under certain conditions
evokes glucagon release.
Actions :
1- Glucagon is hyperglycaemic; most of its actions are opposite to that of insulin, Glucagon causes
hyperglycaemia primarily by enhancing glycogenolysis and gluconeogenesis in liver; suppression
of glucose utilization in muscle and fat contributes modestly.
2- Its secretion is increased during fasting, and is largely responsible for the high fasting blood
glucose levels in type 2 diabetics.

9
3- It plays an essential role in the development of diabetic ketoacidosis.
4- Increased secretion of glucagon has been shown to attend all forms of severe tissue injury.
5- Glucagon increases the force and rate of cardiac contraction and this is not antagonized by β
blockers.
6- It has a relaxant action on the gut and inhibits gastric acid production.

Uses
1. Hypoglycaemia (0.5–1.0 mg i.v. or i.m.) : due to insulin or oral hypoglycaemics; use of glucagon
is; only an expedient measure for the emergency, and must be followed by oral glucose/sugar given
repeatedly till the blood glucose level stabilizes.
#It may not work if hepatic glycogen is already depleted.
2. Cardiogenic shock : to stimulate the heart in β adrenergic blocker treated patients, However,
action is not very marked.
3. To facilitate radiographic examination of upper/lower GI tract by relaxing stomach and
intestines.

Other Hyperglycaemics
Diazoxide : it inhibits insulin release from β cells and causes hyperglycaemia lasting 4–8 hours, It
has been used to prevent hypoglycaemia in insulinomas, Other actions are vasodilatation, fall in
BP and antidiuresis.
Somatostatin : It causes hyperglycaemia primarily by inhibiting insulin release.
Streptozocin : Causes selective damage to insulin secreting β cells, It has been used to produce
experimental diabetes in animals and to treat insulin secreting tumours of pancreas.

11