ORAL HYPOGLYCEMIC

AGENTS
Oral Hypoglycaemic agents
• Diabetes mellitus is a spectrum of metabolic disorders arising from
myriad pathogenic mechanisms, all resulting in hyperglycemia.
• These drugs lower blood glucose levels and are effective orally.
 Classification of drugs
A. Enhance Insulin secretion
1. Sulfonylureas (KATP Channel blockers) B. Overcome Insulin resistance
First generation: Tolbutamide, Chlorpropamide 1. Biguanide (AMPK activator) Metformin
Second generation: Glibenclamide (Glyburide), 2. Thiazolidinediones (PPARγ activator)
Pioglitazone
Glipizide, Gliclazide, Glimepiride C. Miscellaneous antidiabetic drugs
2. Meglitinide/phenylalanine analogues 1. α-Glucosidase inhibitors
Repaglinide, Nateglinide Acarbose, Miglitol, Voglibose
3. Glucagon-like peptide-1 (GLP-1) receptor 2. Amylin analogue: Pramlintide
agonists (Injectable drugs) 3. Dopamine-D2 receptor agonist
Exenatide, Liraglutide Bromocriptin
4. Dipeptidyl peptidase-4 (DPP-4) inhibitors 4. Sodium-glucose cotransport-2 (SGLT-2)
Sitagliptin, Vildagliptin, Saxagliptin, Inhibitor Dapagliflozin
Alogliptin, Linagliptin
 Sulfonylureas (KATP Channel blockers)
• These agents are classified as insulin secretagogues, because they
promote insulin release from the β cells of the pancreas.
Mechanism of action:
• The main mechanism of action includes stimulation of insulin release
from the β cells of the pancreas. Sulfonylureas block ATP-sensitive K+
channels, resulting in depolarization, Ca2+ influx, and insulin
exocytosis.
• In addition, sulfonylureas may reduce hepatic glucose production and
increase peripheral insulin sensitivity.
 ATP-sensitive 3. Raised ATP levels and
2. Glucose metabolism results in K+ Channel binding of SUs to the SUR-1
a rising ATP/ADP ratio. lead to closure of the ATP-
sensitive K+ Channel.
Increased ATP/ADP SUs
Ratio
1. Glucose enters the B- SUR-1
cell via GLUT-2
transporter K+

GLUT-2
Glucose Membrane
depolarization

Ca2+
Influx

Voltage gated
Insulin Ca2+ channel
secretion 4. Raising intracellular K+ levels
leads to membrane
5. Raising intracellular Ca2+ levels results depolarization, which causes
in activation of protein kinases leading to Ca2+ influx via a voltage-gated
exocytosis of insulin. Ca2+ channel
 Sulfonylureas- Pharmacokinetics
• Absorption- effectively absorbed from the GI tract. Food and
hyperglycemia can reduce absorption.
• Distribution- all body fluids, placenta & breast milk.
PPB- 90-99%(Albumin), VD- 0.2L/kg.
• Metabolism: liver
• Excretion: Kidney
• t1/2- 3-5hrs Duration: 12-24hrs
• Contraindication: Pregnancy, lactation, renal & hepatic insufficiency,
T1DM
 Sulfonylureas- ADRs
• Hypoglycaemia- common in elder, liver & kidney disease.
• 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.
• 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.
 Sulfonylureas- Drug interactions
I. Drugs that enhance SU action (may precipitate hypoglycaemia) are—
(a) Displace from protein binding: Phenylbutazone, sulfinpyrazone, salicylates,
sulphonamides.
(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).
II. 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.
Meglitinide/phenylalanine analogues (KATP
Channel blockers)
• Glinides are also considered insulin secretagogues.
• Mode of Action: Same as Sulfonylureas.
• In contrast to the sulfonylureas, the glinides have a rapid onset and a
short duration of action. They are particularly effective in the early
release of insulin that occurs after a meal and are categorized as
postprandial glucose regulators.
 Nateglinide
• Nateglinide is an orally effective insulin secretagogue.
Repaglinide • The drug’s major therapeutic effect is reducing
• The drug is absorbed rapidly from the GI tract, and
postprandial glycemic elevations in patients with type
peak blood levels are obtained within 1 h. The t1/2 is
about 1 h. 2 diabetes.
• These features allow for multiple pre-prandial use. • Nateglinide is most effective when administered at a
Repaglinide is metabolized primarily by the liver dose of 120 mg, TID, 1–10 min before a meal.
(CYP3A4) to inactive derivatives. • It is metabolized primarily by hepatic CYPs (2C9,
• Because a small proportion (~10%) is metabolized by 70%; 3A4, 30%)
the kidney, dosing of the drug in patients with renal • About 16% of an administered dose is excreted by the
insufficiency also should be performed cautiously. kidney as unchanged drug.
• The major side effect of repaglinide is hypoglycemia. • Some drugs reduce the glucose-lowering effect of
Repaglinide also is associated with a decline in efficacy
nateglinide (corticosteroids, rifamycins,
(secondary failure) after initially improving glycemic
control. sympathomimetics, thiazide diuretics, thyroid
• Certain drugs may potentiate the action of repaglinide products); others (alcohol, NSAIDs, salicylates,
by displacing it from plasma protein-binding sites (β MAOIs, and nonselective β blockers) may increase the
blockers, chloramphenicol, coumarin, MAOIs, risk of hypoglycemia nateglinide.
NSAIDs, probenecid, salicylates, and sulfonamide) or • Nateglinide therapy may produce fewer episodes of
• altering its metabolism (gemfibrozil, itraconazole, hypoglycemia than other currently available oral
trimethoprim, cyclosporine, simvastatin, insulin secretagogues, including repaglinide.
clarithromycin).
Glucagon-like peptide-1 (GLP-1) receptor agonists
Synonym: incretin mimetics
Drugs- Exenatide, Liraglutide
• GLP-1 receptors are expressed by β cells, cells in the peripheral and
central nervous systems, the heart and vasculature, kidney, lung, and
GI mucosa.
GLP-1: glucose-dependent insulinotropic polypeptide, in response to a
meal. Incretin hormones are responsible for 60% to 70% of
postprandial insulin secretion.
Mode of action
• In β cells, the end result of these actions is increased insulin
biosynthesis and exocytosis in a glucose-dependent manner.
• These agents improve
glucose dependent insulin secretion,
slow gastric emptying time,
reduce food intake by enhancing satiety (a feeling of fullness),
decrease postprandial glucagon secretion, and
promote β-cell proliferation.
• Consequently, weight gain and postprandial hyperglycemia are reduced,
and HbA1c levels decline.
• 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
Exenatide
• It is a synthetic DPP-4(dipeptidyl peptidase-4 ) resistant analogue which
activates GLP-1 receptors and produces the same responses. Being a peptide, it
is inactive orally.
• After s.c. injection its plasma t½ is ~ 3 hours and duration of action 6–10 hours.
• It is marketed in USA, UK, Europe for use mainly as add-on drug to
metformin/SU or a combination of these or pioglitazone in poorly controlled
type 2 diabetics.
• Benefits noted are lowering of postprandial as well as fasting blood glucose,
HbA1c and body weight.
• The most important side effect is nausea and vomiting occurring in ~ 50%
recipients, but tolerance develops later.
Liraglutide
• This recently developed long-acting GLP-1 agonist is closely related to the
native peptide but its tight binding to plasma proteins extends t½ to > 12
hours and duration of action to > 24 hours.
• Injected s.c. once daily, alone or added to oral metformin ± SU or
pioglitazone, it has achieved improved glycaemic control in type 2 diabetics.
• Nausea and diarrhoea are the frequent side effects, but decrease in
incidence over time.
• Use of liraglutide is attended by weight loss, and it is being evaluated as an
antiobesity drug even for nondiabetics.
• Hypoglycaemia is rare with exenatide/liraglutide monotherapy, but can
occur when combined with SUs/metformin
 Dipeptidyl peptidase-4 (DPP-4) inhibitors
• Dipeptidyl peptidase IV is a serine protease that is widely distributed
throughout the body.
• Alogliptin, linagliptin,and sitagliptin are competitive inhibitors of DPP-4;
vildagliptin and saxagliptin bind the enzyme covalently.
• Elevation of plasma concentrations of active GIP and GLP-1 and is
associated with increased insulin secretion, reduced glucagon levels, and
improvements in both fasting and postprandial hyperglycemia.
• Inhibition of DPP-4 does not appear to have direct effects on insulin
sensitivity, gastric motility, or satiety; chronic treatment with a DPP-4
inhibitor also does not affect body weight.
Dipeptidyl peptidase-4 (DPP-4) inhibitors- Pharmacokinetics
Drugs Absorption Elimination ADRs
Sitagliptin Sitagliptin is well Little metabolized Unchanged in nausea, loose stools, headache,
absorbed from small urine. Dose reduction is needed in rashes, allergic reactions and
intestine orally, well renal impairment, but not in liver edema, Nasopharyngitis and
tolerated. disease. t½- 12 hours cough. Pancreatitis is rare.

Linagliptin Food does not affect binds extensively to plasma Does not require dose
absorption “ proteins and is cleared primarily by adjustment in renal dysfunction
the hepatobiliary system, with
little renal clearance

Alogliptin “ Excreted in unchanged form

Saxagliptin “ t½ of 2–4 hrs Duration-24hrs Drug interaction with CYPA4
Metabolite- 3-7 hrs inhibitors
Vildagliptin “ t½ :2–4 hours, Duration: 12-24hrs. Dose reduction is needed in
elemination is by hepatic, 20–25% moderately severe liver and
is excreted unchanged in urine. kidney disease
Hepatotoxicity were reported.
 Biguanide (AMPK activator)
• Activation of AMP dependent protein kinase (AMPK) to play a crucial role in
mediating the actions of metformin, 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.
3. Insulin resistance exhibited by type-2 diabetics is thus overcome. glycogen storage
in skeletal muscle reduced lipogenesis in adipose tissue and enhanced fatty acid
oxidation.
4. Interferes with mitochondrial respiratory chain and promotes peripheral glucose
utilization through anaerobic glycolysis.
• AMPK activation by metformin appears to be an indirect consequence of interference
with cellular respiration and lowering of intracellular ATP and other energy sources.
• Metformin also retards intestinal absorption of glucose, other hexoses, amino acids and
Vit B12.
Additional effects
• Metformin also inhibits the mitochondrial glycerol phosphate
dehydrogenase, thereby changing the redox state of the cell.
• blunting the effects of glucagon,
• Metformin has direct effects on GI function, including interference
with the absorption of glucose and bile salts.
• inhibiting conversion of lactate and glycerol to glucose, and shifting
the liver toward negative lipid balance.
 Biguanide (AMPK activator)
• Absorption- Small intestine
• Bioavilbilty – 70-80%, PPC- 2hrs, t1/2 is 4–5 h
• The drug does not bind to plasma proteins and is excreted unchanged in the
urine.
• The transport of metformin into hepatocytes is mediated primarily by OCT
1; renal uptake is mediated by OCT 2.
• Export into the urine is by MATE1/2 (multidrug and toxin extrusion
proteins).
• The maximum dose is 2550 mg.
• Hypoglycemia may occur when metformin is taken in combination with
insulin or insulin secretagogues, so adjustment in dosage may be required.
Biguanides- ADR
• Side effects with metformin are IMPORTANT NOTE:
frequent, but generally not serious. • It is important to assess renal function before
• Abdominal pain, starting metformin and to monitor function at
least annually.
• anorexia, • The ADA suggests that metformin may be
• bloating, used safely when the GFR is greater than 45
mL/ min/1.73 m2, and that the dose should be
• nausea,
reduced by 50%–75% when GFR is 30–45
• metallic taste, mL/min/1.73 m2.
• mild diarrhoea and • Metformin should be discontinued
preemptively if renal function could decline
• Tiredness precipitously, such as before radiographic
• Lactic acidosis and Vit B12 procedures that use contrast dyes and during
deficiency. admission to the hospital for severe illness.
 Indications Advantages of metformin are:
• first-line treatment of type 2 diabetes. • Non hypoglycaemic
• Mild weight reduction. • weight loss promoting has potential to
prevent macrovascular as well as
• Metformin is used to treat infertility microvascular complications of diabetes
bcz of PCOD (improves ovulation and • no acceleration of β cell exhaustion/
menstrual cyclicity and reduces failure in type 2 DM.
circulating androgens and hirsutism) • antihyperglycaemic efficacy (HbA1c
• Metformin inhibits UPR (Unfolded reduction by 0.8–1.2%) equivalent to
Protein Response) activity in stressed other oral drugs.
conditions, according to studies, and • can be combined with any other oral or
forces cancer cells to undergo injectable antidiabetic, if one drug is not
apoptosis and ultimately die. adequate.
Biguanide (AMPK activator)

contraindicated: IMP Note:

Lactic acidosis is common in Alcoholics,
• Hypotensive states, RF & poor tissue perfusion (e.g., sepsis,
• heart failure, myocardial infarction, and congestive
• severe respiratory, heart failure).

• hepatic and renal disease, as well as

• in alcoholics because of increased risk of lactic acidosis.
Drug Interactions: cimetidine, furosemide may compete with metformin
excretion and enhance its toxicity.
 Thiazolidinediones (PPARγ activator)
• The thiazolidinediones (TZDs) are also insulin sensitizers. Hyperinsulinemia is not a risk.
• 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.
• Glitazones tend to reverse insulin resistance by enhancing GLUT4 expression and
translocation. Entry of glucose into muscle and fat is improved.
• Effects of these drugs on cholesterol levels are of interest. Rosiglitazone increases LDL
cholesterol and triglycerides, whereas pioglitazone decreases triglycerides.
• Both drugs increase HDL cholesterol.
• The ADA recommends pioglitazone as a second- or third-line agent for type 2 diabetes.
Rosiglitazone is less utilized due to concerns regarding cardiac adverse effects.
Pharmacokinetics- IMP Note: It should be stopped if
HbA1c reduction is < 0.5% at 6 months

Absorption: well absorbed from gut.

Distributed: well distributed and extensively bond to serum
albumin.
Metabolism: CP450 isoenzymes, some metabolities are active.
Excretion: renal (Negligible), mostly by bile and fees.
• No dosage adjustment is required in renal impairment.
Contraindications: pregnancy and Lactation, CHF, Bladder
cancer
ADR:
• Weight gain can occur because TZDs may increase subcutaneous fat
and cause fluid retention.
• TZDs have been associated with osteopenia and increased fracture risk.
• plasma volume expansion, edema, weight gain, headache, myalgia and
mild anaemia
• Pioglitazone may also increase the risk of bladder cancer.
Drug Interactions:
• Failure of oral contraception may occur during pioglitazone therapy.
• Ketoconazole inhibits and rifampin induces metabolism of pioglitazone.
 α-Glucosidase inhibitors
Acarbose It is a complex oligosaccharide which reversibly inhibits α-
glucosidases, the final enzymes for the digestion of carbohydrates in the brush
border of small intestine mucosa.
• 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.
• Regular use lowers HbA1c modestly (by 0.4–0.8%), but change in body weight
and lipid levels is minimal.
• In diabetics, it reduces cardiovascular events.
 α-Glucosidase inhibitors
• 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.
• Only a small fraction of the dose is absorbed.
• Flatulence, abdominal discomfort and loose stool
• Patient acceptability of α-glucosidase inhibitors is poor due to
uncomfortable g.i. symptoms. Hepatic transaminases may rise, but
liver damage is rare.
 α-Glucosidase inhibitors
Note:
Miglitol It has a smaller molecule than acarbose, and it It is important that
hypoglycemia in this
is a stronger inhibitor of sucrase. Potency for other α- context be treated with
glucosidases is equivalent to acarbose. glucose rather than sucrose,
because sucrase is also
• Absorption of miglitol is substantial, but variable. inhibited by these drugs.
• The absorbed drug is excreted by the kidney. No
systemic toxicity is known.
• Dose: 25–100 mg TDS at beginning of each meal. Contraindication:
inflammatory bowel disease,
Voglibose Has properties, use and side effects similar to colonic ulceration, or
intestinal obstruction
that of acarbose.
• Dose: 200–300 mg TDS just before meals.
 Amylin analogue: Pramlintide
• 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.
• The duration of action is 2–3 hours.
• 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 receptor agonist: Bromocriptin
• Bromocriptine Recently (2009) 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.
• Bromocriptin 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 upto
0.5%.
Colesevelam- Oral hypolipidemic agent
 Sodium-glucose cotransport-2 (SGLT-2) Inhibitor Canagliflozin, dapagliflozin
MOA: The sodium–glucose cotransporter 2 (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.
• Therefore, SGLT2 inhibitors may reduce systolic blood pressure. (But not used in HTN)
Pharmacokinetics and fate:
• These agents are given once daily in the morning. Canagliflozin should be taken before the first meal of the
day.
• metabolized- glucuronidation to inactive metabolites, Excretion- feces, urine(1/3rd)
Contraindication: renal dysfunction.
• ADR: The most common adverse effects with SGLT2 inhibitors are female genital mycotic infections (for
example, vulvovaginal candidiasis), urinary tract infections, and urinary frequency.
• Hypotension has also occurred, particularly in the elderly or patients on diuretics.