Antidiabetic Drugs

Haftom G. (MSc.)
Fig: Regulation of glucose homeostasis. The organs shown contribute to glucose utilization, production, or storage.
 Introduction

• Diabetes mellitus (DM) is a group of metabolic disorders

characterized by hyperglycemia.

• DM is caused by derangements in the secretion of insulin, glucagon

and other hormones and results in abnormal carbohydrate and fat
metabolism.
 Introduction
• Fasting state: 75% of total body glucose disposal occurs in tissues, including the
brain and peripheral nerves that do not require insulin.

• Brain glucose uptake occurs at the same rate during fed and fasting periods.

• The remaining 25% of glucose metabolism takes place in the liver and muscle,
which is dependent on insulin

• In the fasting state, approximately 85% of glucose production is derived from the
liver, and the remaining amount is produced by the kidney.
 Introduction
• Glucagon, produced by pancreatic α cells, is secreted in the fasting state to oppose
the action of insulin and stimulate hepatic glucose production and glycogenolysis.

• Glucagon and insulin secretion are closely linked. Appropriate secretion of both
hormones is needed to keep plasma glucose levels normal.

• In the fed state: carbohydrate ingestion increases the plasma glucose concentration
and stimulates insulin release from the pancreatic β-cells→ hyperinsulinemia
 Introduction
• Although fat tissue is responsible for only a small amount of total body glucose
disposal, it plays a very important role in the maintenance of total body glucose
homeostasis.

• Small increases in the plasma insulin concentration exert a potent antilipolytic effect,
reducing plasma-free fatty acid levels.

• The decline in plasma-free fatty acid concentrations results in an increased glucose

uptake in muscle and indirectly reduces hepatic glucose production.
 Introduction

• Amylin is a hormone that is cosecreted from the pancreatic β-cell

with insulin.

• Amylin is also deficient in patients with type 1 DM secondary to the

destruction of β-cells.

• Amylin suppresses inappropriate glucagon secretion, slows gastric

emptying, and causes central satiety
 Types Diabetes Mellitus

2 major categories:
I. Type- I or Insulin Dependent Diabetes Mellitus (IDDM)
 Selective B cell destruction and severe or absolute insulin deficiency.

II. Type- II or Non-Insulin Dependent Diabetes Mellitus (NIDDM)

 Insulin is produced by the B cells, it is inadequate to overcome the resistance, and the
blood glucose rises.

III. Gestational Diabetes (GDM) is defined as any abnormality in glucose levels

noted for the first time during pregnancy.

IV. Other
 Diabetes Mellitus Type- I

 Results from pancreatic β-cell failure with “absolute” deficiency of insulin secretion.

 Most often this is due to immune-mediated destruction of pancreatic β-cells, but rare unknown
or idiopathic processes may also contribute.

 There often is a long preclinical period of positive autoimmune markers which progress to
immune-mediated β-cell destruction with resultant hyperglycemia when 80% to 90% of the β-
cells have been destroyed.

 After the initial diagnosis there is occasionally a period of transient remission called the
“honeymoon” phase before β-cell destruction requires lifelong insulin therapy
• Scheme of the natural history of the β-cell defect in type 1 diabetes mellitus. (Copyright© 2008
American Diabetes Association. From Medical Management of Type 1 Diabetes, Fifth Edition.
 Diabetes Mellitus Type- II

• Type 2 diabetes is caused by multiple defects including:

1. Impaired insulin secretion
2. Deficiency and resistance to incretin hormones
3. Insulin resistance involving muscle, liver, and adipocytes
4. Excess glucagon secretion and
5. Sodium-glucose cotransporter upregulation in the kidney
Fig: In Type 2 diabetes there is a progressive decline in β-cell function and insulin secretion. As a result,
most patients with type 2 DM will eventually need insulin. Adapted from Kendall et al (2009).
 Diabetes Mellitus Type- II

 Impaired Insulin Secretion

• The pancreas in people with a normal-functioning β-cell is able to adjust its secretion of insulin to
maintain normal plasma glucose levels.

• In nondiabetic individuals, insulin increases in proportion to the severity of the insulin resistance and
plasma glucose remains normal.

• Impaired insulin secretion is a hallmark finding in type 2 DM.

• When the insulin released is no longer sufficient to normalize plasma glucose, dysglycemia, including
prediabetes and diabetes can ensue.
 Diabetes Mellitus Type- II

 Impaired Insulin Secretion

• β-Cell mass and function in the pancreas are both reduced. β-Cell failure is
progressive, and starts years prior to the diagnosis of diabetes.

• People with type 2 DM lose approximately 5% to 7% of β-cell function per year.

• The β-cell is unable to maintain sufficient insulin secretion and, paradoxically,

releases less insulin as glucose levels increase
 Diabetes Mellitus Type- II

 Impaired Insulin Secretion

• The reasons for decreased insulin release are likely multifactorial including

• Glucose toxicity: when glucose levels chronically exceed 140 mg/dL (7.8
mmol/L)

• Lipotoxicity;

• Insulin resistance;

• Age: Age results in declining β-cell responsiveness

• Genetics: High-risk ethnicity/races are predisposed to β-cell failure

• Incretin deficiency
 Incretin Hormone Deficiency/Resistance

• Type 2 DM: decreased postprandial insulin secretion is a result of both impaired

pancreatic β-cell function and reduced stimulus from gut hormones to secrete insulin.

• The role gut hormones play in insulin secretion is best shown by comparing the insulin
response to an oral glucose load versus an isoglycemic intravenous glucose infusion.

• In individuals who do not have diabetes, 73% more insulin is released in response to an
oral glucose load compared to an intravenous (IV) glucose load given to mimic plasma
glucose levels achieved during the oral glucose load.

“the incretin effect”

 Incretin Hormone Deficiency/Resistance

• In patients with type 2 patients, this “incretin effect” is blunted

• Two hormones are responsible for over 90% of the increased insulin secretion seen in
response to an oral glucose load,

Glucagon-like peptide-1 (GLP-1) and

Glucose-dependent insulinotropic polypeptide (GIP)

• Patients with type 2 DM remain sensitive to GLP-1 but GIP levels are normal or
elevated in type 2 DM, which suggests that some individuals may be resistant to its
effect
Why do we care about hyperglycemia?
 Acute complications
 Chronic complications
Fig: Sequence of metabolic derangements underlying the clinical manifestations of diabetes.
Fig: Pathogenesis and clinical features of acute hyperglycaemia and ketoacidosis.
 Pathogenesis of Chronic Complications

• Four distinct mechanisms have been implicated in the deleterious effects of persistent hyperglycemia

I. Formation of Advanced Glycation End Products (AGEs): are formed as a result of

nonenzymatic reactions between intracellular glucose derived dicarbonyl precursors (glyoxal,
methylglyoxal, and 3-deoxyglucosone) with the amino groups of both IC and EC proteins.

• The natural rate of AGE formation is greatly accelerated in the presence of hyperglycemia.

• AGEs bind to a specific receptor (RAGE) that is expressed on inflammatory cells (macrophages and T cells),
endothelium, and vascular smooth muscle.

• RAGE Antagonists????
 Pathogenesis of Chronic Complications

ii. Activation of Protein Kinase C.

iii. Oxidative Stress and Disturbances in Polyol Pathways.

iv. Oxidative Stress and Disturbances in Polyol Pathways

Fig: Possible pathogenetic mechanisms of chronic diabetic complications. The central box lists the clinical features.
Fig: Polyol pathway and effects of polyol accumulation.
Fig: Relationship of glycemic control and diabetes duration to diabetic retinopathy
 Treatment Goals of DM

 To achieve best possible control of plasma glucose level

 To relieve the immediate signs and symptoms of diabetes

 Normalize nutrition and achieve ideal body weight.

 Improve quality and quantity of life by preventing and/or slowing the onset and

progression of the diabetes-associated complications.

 Antidiabetic agents
Insulin and its analogs
Oral hypoglycemic agents
Insulin and its analogs
 Insulin receptor
• Its cytoplasmic domain contains tyrosine kinase.

• Its contains two alpha sub-units and two beta sub-units; the tyrosine kinase
resides within the beta sub-units.

• The extracellular domain, ie, that part of the receptor which projects into the ECF,
combines with the ligand (eg.insulin) ----- this results in autophosphorylation of
the receptor and tyrosine kinase becomes active ------- eventually the
physiological-pharmacological actions (eg. Entry of glucose molecule from the ECF
into the inside of the cell) occur.
Fig : - Insulin receptor
 Insulin release
• Insulin release from the pancreatic B cell by glucose and by sulfonylurea drugs.

• In the resting cell with normal (low) ATP levels, potassium diffuses down its
concentration gradient through ATP-gated potassium channels, maintaining the
intracellular potential at a fully polarized, negative level. Insulin release is minimal.

• If glucose concentration rises, ATP production increases, potassium channels close, and
depolarization of the cell results.

• As in muscle and nerve, voltage-gated calcium channels open in response to

depolarization, allowing more calcium to enter the cell. Increased intracellular calcium
results in increased insulin secretion.
Fig: Insulin signal transduction pathway in skeletal muscle
Glucose Transporters
 Glucose Transporters

Table: Insulin requirement and transporters for glucose uptake into different tissues
 Insulin…
Pharmacodynamics

Liver
I. Inhibits glucose production and increases glycolysis
II. Inhibits glycogenolysis and stimulates glycogen synthesis
III. Increases the synthesis of triglycerides
IV. Increases protein synthesis
Pharmacodynamics cont’d…

Muscle cells
I. Increases glucose transport and glycolysis

II. Increases glycogen deposition

III. Increases protein synthesis

Adipose tissue
I. Increases glucose transport

II. Increases lipogenesis and lipoprotein lipase

III. Decreases intracellular lipolysis

**Net effect is….
Table: Metabolic effects of insulin
 Insulin….

 Pharmacokinetics
• Ineffective orally

• Given parenterally; SC or I/M; I/V in emergency, (inhalational?)

• Plasma t½ : 5-9 mins???

• Metabolized in liver (primarily) and kidney & muscles ( small extent)

 Sources of commercial insulin
• Animal (beef or pork)

• Human (recombinant )
 Goal of subcutaneous insulin therapy

 To mimic both the normal prandial (mealtime) insulin secretion and the basal
(overnight, fasting, and between meal) between-meal insulin levels as close as possible

 To accomplish this goal most current regimens use at least four different insulin
analogs:

Long-acting or Intermediate acting insulins are used to provide basal insulin levels

Rapid or Short-acting insulins are used to correct the transient (prandial)

hyperglycemia associated with meals.
Fig: Schematic representation of normal diurnal variations in blood glucose and plasma insulin levels. As the blood glucose level rapidly
rises after a meal, it is closely followed by an increase in insulin level to limit the rise. The insulin returns towards the basal level as blood
glucose reaches the normal fasting level once more. Note how the two substances follow almost parallel curves, the insulin a little later
than the glucose. The small but positive constant basal insulin level emphasizes that insulin has functions other than just dealing with
dietary glucose. Note: this diagram does not differentiate the two phases of insulin release
 Goal of subcutaneous insulin therapy…

 Several different regimens have been developed involving multiple subcutaneous

injections per day when insulin is used alone in the treatment of Type 1 diabetes

 Another available option is the use of an insulin pump, in the form of a battery
powered pump controlled by a microprocessor
 Principal Types and Duration of Action of Insulin Preparations

• Four principal types :

I. Rapid-acting: with very fast onset and short duration;

II. Short-acting: with rapid onset of action;

III. Intermediate-acting: and

IV. Long-acting: with slow onset of action

 Types of Insulin….
• Rapid-acting: Insulin Lispro, Insulin aspart and, insulin glulisine

• Short-acting: Regular, semilente

• Intermediate acting: NPH (Neutral Protamine Hagedorn) and Lente

• Long-acting: Ultralente, glargene

Fig: Subtypes and approximate DOA of different insulin formulations. The DOA of regular & NPH insulin
increases at higher doses. Adapted from Kennedy & Masharani (2015).
Fig: A) Once-daily long-acting insulin glargine B) Intermediate-acting NPH is the oldest basal insulin that is still
in common use. Figure adapted from DeWitt & Hirsch (2003).
Fig: Examples of physiologic insulin delivery.
Fig: Insulin stacking. The combination of intermediate-acting NPH and short-acting regular insulin were used to mimic the
physiologic time course of insulin secretion by the normal pancreas.
Fig: Insulin infusion protocol for patients using a computerized, battery operated
insulin pump. Adapted from Kroon et al. (2009).
Insulin pump
 Picture: Insulin pump. Patient with Type 1 diabetes
wearing a Medtronic Paradigm insulin pump.

 The device contains an insulin reservoir connected

to a SC catheter.

 A battery powered pump and microprocessor are

used to provide both a basal infusion of insulin, as
well as pre-mealtime boluses (the size of the pre-
meal insulin bolus is varied to match the amount
of carbohydrate to be consumed).
 Insulin Regimens for type 1 DM

• Overall, patients using insulin analogues (lispro, aspart, glargine) in physiologic

regimens, including patients with hypoglycemia unawareness, have fewer hypoglycemic
episodes than patients using traditional insulins (regular and NPH).

• It may be that the main impact of physiologic insulin regimens and insulin glargine, in
particular, is that the separation of prandial and basal components improves our
understanding of insulin use, simplifies dosing adjustments, and allows patients more
flexibility in meal timing.
 Pharmacokinetics of Insulin Preparations

• Commercial insulin preparations differ in a number of ways, such as

differences in the recombinant DNA production techniques, amino
acid sequence, concentration, solubility, and the time of onset and
duration of their biologic action.
Pharmacokinetics of Insulin Preparations…
Pharmacokinetics of Insulin Preparations…
Table: Pharmacologic Properties of Insulin analogs
 Insulin Regimens

• Choice of regimen depends on desired degree of glycemic control, the

patients lifestyle, and his or her ability to adjust insulin dose.

• Once daily injections are rarely satisfactory.

 Insulin Regimens
• 2 shots: most commonly used regimen

• Rapid + intermediate acting (1:2)

• 2/3rd of dose to be given in the morning and the remaining in the evening.

e.g -10 units of regular and 15 units of NPH insulin in the morning and 5 units of
regular and 5 units of NPH in the evening.
Representative Plasma Insulin Times
• Advantages:

Controls Postprandial glycaemia at breakfast and dinner.

• Disadvantages:

 Pre-breakfast hyperglycemia is common.

Increased risk of nocturnal hypoglycemia in attempt to control pre-breakfast

hyperglycemia.
 Intensive Insulin therapy (3 shots & 4 shots)

• 3 shots
• Rapid/short + intermediate at breakfast
• Rapid/short acting at supper (evening meal)
• Intermediate at bedtime
e.g. 10 units of regular insulin mixed with 10 units of NPH in the morning, 8 –
10 units of regular insulin before the evening meal, and 6 units of NPH insulin
at the bedtime.
Representative Plasma Insulin Times
 Insulin Regimens

• 4 shots
• Rapid/short acting at breakfast, lunch and supper

• Long acting at bedtime

 Intensive Insulin therapy (3 shots & 4 shots)

• Advantages:

- Controls PP glycemia. Allows flexibility of meal schedule and quantity.

- Tight glycemic control possible with least risk of hypoglycemia.

• Disadvantages

- Pumps( insulin syringe) are expensive, add risk of skin infections and pump failure.
 Some important guidelines for insulin therapy

• Initiate with the daily dose with 0.3 U/kg (16 – 20 U/d), increasing to 1 U/kg

• Adjust the dose according to the usual monitoring of blood glucose

• Daily increment should not be more than 4 Units

• Peak action of insulin injected should coincide with the postprandial rise in blood
glucose.
• Aim of therapy:

* Blood glucose level of 90 – 130 mg/dl before meal, and after overnight fast

* ≤ 180 mg/dl 1 hr after meal & 150 mg/dl 2 hr after meal

 Factors Affecting Absorption

• Absorption depends on :

• Blood flow to site,

- Site of injection,

Abdomen>Arm>Buttock>Thigh

• Exercise will increase absorption, as will local massage

 Therapeutic Uses of Insulin

• Type I diabetes

• Type II diabetes when pregnant

• Type II diabetes under stress

• Type II diabetes poorly controlled by diet and oral agents

• Complications of diabetes (ketoacidosis)

 Complication of Insulin Therapy

I. Hypoglycemia : Rapid development of hypoglycemia causes signs of autonomic

hyperactivity—both sympathetic (tachycardia, palpitations, sweating,
tremulousness) and parasympathetic (nausea, hunger)—and may progress to
convulsions and coma if untreated

 They usually result from inadequate carbohydrate consumption, unusual physical

exertion, or too large a dose of insulin
 Complication of Insulin Therapy

I. Treatment of Hypoglycemia

• All the manifestations of hypoglycemia are relieved by glucose administration.

• To expedite absorption, simple sugar or glucose should be given, preferably in

liquid form.

• Dextrose tablets, glucose gel, or any sugar-containing beverage or food may

be given.

• Unconsciousness or stupor: 20–50 mL of 50% glucose solution by IV infusion

over a period of 2–3 minutes.
 Complication of Insulin Therapy
I. Treatment of Hypoglycemia

• 1 mg of glucagon injected either SC or IM

• If the patient is stuporous and glucagon is not available, small amounts of honey
or syrup can be inserted into the buccal pouch.

• In general, however, oral feeding is contraindicated in unconscious patients.

• Emergency medical services should be called immediately for all episodes of

severely impaired consciousness.
• If no response is shown, it may be due to cerebral edema treat with iv dexamethasone or mannitol
 Complication of Insulin Therapy….

ii. Lipodystrophy  atrophy of subcutaneous fatty tissue leading to depressed areas

at the site of injection.
result from an immune reaction

iii. Lipohypertrophy (accumulation of extra fat) (local)

 seen as a consequence of pharmacological effect of insulin

iv. Insulin allergy  rare with human insulin  mainly due to contaminating proteins
in the preparation  hypersensitivity reactions such as local or systemic urticaria,
rarely anaphylaxis reaction antihistamines, corticosteroids may be required
 Complication of Insulin Therapy….

V. Hypokalemia??????

VI. Weight gain

Other:
• Insulin resistance

• Peripheral oedema

• Insulin antibody formation

• Increased Cancer Risk???

 How Much Insulin Does the patient Need?

• Different in different individuals.

• Amount depends on
• Body weight

• Level of physical activity

• Daily food intake

• Other medicines
 Insulin…

Drug interactions
• β – blockers (prolong hypoglycemia)

• Alcohol (precipitate hypoglycemia)

• Salicylates, lithium & theophylline (accentuate hypoglycemia)

Oral Hypoglycemic Agents
 Oral hypoglycaemic agents
1. Sulfonylureas 2. Biguanides: Metformin
• First generation?? 3. Meglitinide analogues: Repaglinide,
• Tolbutamide Nateglinide
• Chlorpropamide 5. Thiazolidinediones: Rosiglitazone,
• Tolazamide Pioglitazone
• acetohexamide
6. Αlpha glucosidase inhibitors: Acarbose,
• Second generation Miglitol
• Glibenclamide
7. Dipeptidyl peptidase-4 inhibitors:
• Glipizide Saxagliptan, Linagliptan
• Gliclazide
8. SGLT-2 Inhibitors: Dapagliflozin
• Glimepiride
 1. Sulfonylureas

• Classified as insulin secretagogues

Promote insulin release from the β-cells of the pancreas.

• The sulfonylureas in current use are the

Second-generation drugs: glyburide, glipizide, and glimepiride

• All are orally active

• All bound to plasma protein (90-99%)

 Sulfonylureas…
Mechanism of action

Bind with the receptors present close to the ATP sensitive K+ channels on
pancreatic β cell membrane → inhibits the channel → no K+ efflux
(accumulation of K+) → depolarization → opens Ca2+ channel → entry of
Ca2+ → degranulation → release of insulin
 Extra-pancreatic action of sulfonylureas

 These agents increase sensitivity to insulin, perhaps by increasing the

number of insulin receptors.
However, sulfonylureas do not decrease the insulin requirements of patients
with type I diabetes.

 Sulfonylureas decrease serum glucagon, which opposes the action of

insulin.
Mechanism of action of sulfonylureas
 Sulfonylureas…
• Pharmacokinetics

• Good oral bioavailability

• ≥ 90% plasma protein bound

• Metabolised in liver

• Excreted via urine

• Once daily dosing??

 Use: Type-II DM only

Table: pharmacokinetics of sulfonylureas
• Glyburide exerts a mild diuretic effect

• Long-acting sulfonylureas cause adverse effects more frequently than

other sulfonylureas.

• Water retention is common, and alcohol consumption produces a

disulfiram-like reaction in some patients.
 Sulfonylureas…
 Adverse effects
• Weight gain

• Hyperinsulinemia and Hypoglycemia

• Use with caution in hepatic or renal insufficiency

• Renal impairment is a particular problem for glyburide

• Glipizide or glimepiride are safer options in renal dysfunction and in elderly

patients.

• Glyburide has minimal transfer across the placenta -

 2. Biguanides
• Drugs: Metformin and phenformin (withdrawn due to serious lactic acidosis)

• Metformin: insulin sensitizer; ↑es glucose uptake and use

• It does not stimulate insulin release or cause hypoglycemia

o Hyperinsulinemia is not a problem: risk of hypoglycemia is far less than that with
sulfonylureas.

• Does not bind plasma proteins

• Excreted unchanged in urine

• Often combined with sulfonylurea drugs

 Biguanides…
- Mechanism of action

- Reduce hepatic production of glucose

- Other minor actions may include

- Increases glucose uptake by skeletal muscle and

- Increase peripheral utilization of glucose by enhancing anaerobic glycolysis.

- Slows down GI absorption of glucose and increase uptake by skeletal muscles.

- reduction of plasma glucagon levels

- Weight loss may occur because metformin causes loss of appetite.

Fig: Metformin acts primarily to suppress glucose production in the liver.
 Biguanides…
Use: Type II DM
o Drug often preferred for obese patient as it stimulates weight loss in patients
not controlled by diet and exercise

• Other use: Metformin is effective in the treatment of polycystic ovary syndrome.

o It lowers insulin resistance seen in this disorder and can result in ovulation

o It lowers serum androgens and restores normal menstrual cycles and

ovulation.
 Biguanides…

 Adverse effects
• Nausea, abdominal discomfort, diarrhea, metallic taste, anorexia are more common

• Lactic acidosis (rare)  contraindicated in renal dysfunction

• Vitamin B12 deficiency: interfere with absorption

 Biguanides are contraindicated in patients with renal disease, alcoholism, hepatic

disease, or conditions predisposing to tissue anoxia (eg, chronic cardiopulmonary
dysfunction) because of the increased risk of lactic acidosis induced by these drugs.
 3. Meglitinide (glinides)
• Drugs: repaglinide and nateglinide
• Insulin secretagogues: Have rapid onset & short duration

• Used to control postprandial glucose levels if diet and exercise fail.

• Should not be combined with sulfonylureas: increased the risk of serious hypoglycemia.

• They bind to an ATP-dependent K+ (KATP) channel on the cell membrane of

pancreatic beta cells in a similar manner to Sulfonylureas but have a weaker binding

affinity and faster dissociation from the SUR1 binding site.

 Meglitinide (glinides)….

• Glinides should be taken prior to a meal

• Well absorbed after oral administration.

• Both glinides are metabolized to inactive products by cytochrome P4503A4 in the

liver and are excreted through the bile.
 Meglitinide (glinides)….
• Adverse effects:

• Although glinides can cause hypoglycemia and weight gain, the incidence is lower than
that with sulfonylureas.
• Note: Drugs that inhibit CYP3A4, such as itraconazole, fluconazole, erythromycin,and clarithromycin, may
enhance the glucose lowering effect of repaglinide. Drugs that induce CYP3A4, such as barbiturates,
carbamazepine, and rifampin, may have the opposite effect.]

• By inhibiting hepatic metabolism, the lipid-lowering drug gemfibrozil may significantly

increase the effects of repaglinide, and concurrent use is contraindicated.

• These agents should be used with caution in patients with hepatic impairment.
 Repaglinide
• Short acting Insulin secretagogue

• Acts similar to sulfonylureas

• Administered before each major meal

• Can be used with metformin

• Used only in Type II DM

• Adverse effects
• Headache, dyspepsia, arthralgia & weight gain; lower risk of serious hypoglycemia
 Nateglinide

• Stimulates insulin secretion →rapid onset & shorter duration of action than repaglinide

• Administer 10-30 mins before meal

• Adverse effects
• Dizziness, Nausea, flu like symptoms & joint pain; less frequent episodes of
hypoglycemia
 4. Thiazolidinediones (Glitazones)

• Drugs: Rosiglitazone and Pioglitazone

• They are insulin sensitizers.

• Used where there is insulin resistance and when other oral agents fail

• Reduce blood glucose without increasing circulating insulin.

• Although insulin is required for their action, the TZDs do not promote its release
from the βcells, so hyperinsulinemia is not a risk.
 Thiazolidinediones…
• MOA

• Thiazolidinediones or TZDs act by activating PPARs (peroxisome

proliferator-activated receptors), a group of nuclear receptors ( Adipocytes).

• They may act to stimulate production of proteins that increase insulin

sensitivity, such as adiponectin.

• They may also act by blocking transcription of other proteins responsible

for insulin resistance ( e.g. Resistin )
 Thiazolidinediones…
Pharmacokinetics

• Pioglitazones: taken orally with or w/o food

• Plasma levels peak about 3 hr

• Plasma half-life is 3-7 hr; active metabolites (t1/2= 16-24 h)

• Liver metabolism by CYP2C8 and CYP3A4 and excreted in feces (2/3) and urine (1/3)

• Rosiglitazone is well absorbed; with or w/o food

• Plasma levels peak about 1 hr

• t1/2 is 3-4 hr

• Liver metabolism via CYP2C8

 Thiazolidinediones…

 Adverse effects
• Edema
• Both drugs tend to cause increase in body weight, causes peripheral edema and
can also precipitate or worsen congestive heart failure.

• Plasma volume expansion

• Dose-related weight gain
• Headache, myalgia & mild anaemia
* Do not cause lactic acidosis, even in patients with renal impairment
 5. Alpha-Glucosidase Inhibitors
• Drugs: Acarbose, Miglitol

• Taken orally to act on gut

• Small reductions in blood glucose

• Will not cause hypoglycemia in monotherapy.

• Competitive inhibitors, so take before meals.

• Mechanism of action: Reversible inhibitors of pancreatic α-amylase and intestinal

α-glucosidase enzymes on intestine.
 Alpha-Glucosidase Inhibitors cont’d…

• Miglitol is a more potent inhibitor of sucrase and maltase than is acarbose.

• Unlike acarbose, miglitol does not inhibit pancreatic α-amylase but does
inhibit isomaltose.

• These drugs are usually combined with a sulfonylurea or another oral

hypoglycemic agent.

• α-Glucosidase inhibitors rarely cause hypoglycemia

 Alpha-Glucosidase Inhibitors cont’d….

 Adverse effects

• Flatulence, bloating, diarrhea, and abdominal cramping

 Contraindications

• Patients with major GI disorders including inflammatory bowel disease,

chronic ulcers, malabsorption, or intestinal obstruction.
 Dipeptidyl peptidase-4 inhibitors
• Alogliptin, linagliptin, saxagliptin, and sitagliptin are orally active dipeptidyl
peptidase-4 (DPP-4) inhibitors used for the treatment of type 2 diabetes.

• Mechanism of action: inhibit the enzyme DPP-4, which is responsible for the
inactivation of incretin hormones such as GLP-1.
• Prolonging the activity of incretin hormones increases insulin release in response to meals and
reduces inappropriate secretion of glucagon.

• May also improve β-cell function

• DPP-4 inhibitors may be used as monotherapy or in combination with other

hypoglycemic agents.
 SGLT-2 Inhibitors
• SGLT-2 is a sodium-glucose low affinity & high-capacity co-transporter that is
expressed in the proximal renal tubule and mediates reabsorption of ~90% of
filtered glucose into blood.

• SGLT-1 is a second transporter expressed in a distal segment of the proximal

tubule that acts in concert with SGLT-2.

• Together these two transporters produce a relatively complete reabsorption of

glucose from the renal tubules, so that glucose is barely detectable in the urine of
healthy adults.
 SGLT-2 Inhibitors
• Mutations in the SGLT-2 gene cause renal glycosuria and urinary glucose
excretion.

• SLGT-2 inhibitors reduce glucose reabsorption, resulting in increased urinary

glucose excretion, and lower plasma glucose.

• SGLT-2 inhibitors efficiently lower plasma glucose levels independently of insulin

action and secretion.
 SGLT-2 Inhibitors

• Efficacy depends on renal function.

• Canagliflozin can be prescribed to patients with normal or moderate

renal function (GFR above 45 ml/min).

• However, dapagliflozin is not recommended in patients with even

moderate to severe renal dysfunction (if the GFR is below 60 ml/min).
Fig: ~ 90% of glucose reabsorption is produced by a sodium-glucose transporter (SGLT-2). Its inhibition
results in increased glucose in the urine (glycosuria) and a lowering of plasma glucose level in patients
with type 2 diabetes.
 SGLT-2 Inhibitors…

• Drugs:
Canagliflozin
Dapagliflozin
Empagliflozin

• Side effects: genito-urinary infections, hypotension, dehydration,

potential for weight loss.
 Bile acid sequestrants
• Drugs: Colesevelam

• Mechanism of action: lowers LDL cholesterol in patients with primary

hypercholesterolemia.

• Colesevelam's MOA to improve glycemic control is uncertain.

• One possibility is that bile acid sequestrants act in the GIT to reduce glucose
absorption.

• Side Effects: N, dyspepsia, constipation, interference with absorption of other

oral meds increase in triglycerides
 Dopamine agonists
• Drugs: Bromocriptine
• MoA: Type 2 Diabetes: Decreased dopaminergic tone in the hypothalamus related to a
dysfunction circadian rhythm is involved in the pathogenesis of insulin resistance.

• This can contribute to increased glucose, triglyceride & fatty acid levels in both the
fasting and postprandial state in patients with insulin resistance.

• A daily morning dose of bromocriptine can reset the circadian rhythm, and improves
glycemic control, lowering A1C levels by 0.3 to 0.5 percent when taken alone or in
combination with a sulfonylurea
 Bromocriptine
• Indications:
• Parkinson's disease

• Type II Diabetes

• Certain endocrinologic disorders, especially hyperprolactemia

• Contraindications:
• History of psychotic illness, recent myocardial infarction or peptic ulceration

• Avoid in patients with peripheral vascular disease

• Side Effects:
• D2 agonists can have more limited adverse effects compared to levodopa

• Has a lower incidence of response fluctuations & dyskinesias compared to long-term therapy with levodopa
in treating Parkinson's disease.
 Injectable non-insulin hypoglycemics

 GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS

• Drugs:
• Exenatide

• Lixisenatide

• Liraglutide

• Albiglutide

• Dulaglutide
 Injectable non-insulin hypoglycemics

 GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS….

• Stimulates insulin secretion; suppresses glucagon secretion; Slows

down GI absorption rate; reduces appetite; and reduces liver fat.

• These drugs decrease prandial glucose excursions by increasing

glucose-mediated insulin secretion & decreasing glucagons levels.
 Side Effects of Exenatide:
• Most common:
• Mild & mainly GI (nausea in 44%; vomiting & diarrhea); nausea decreases with
ongoing usage

• A steady weight loss occurs in some patients over 2 years (may be related to nausea
& CNS-mediated loss of appetite)

• There is an increased risk of hypoglycemia when exenatide is used with a

sulfonylurea: reduce dose of the sulfonylurea

• Most serious: rare & sometimes fatal necrotizing or hemorrhagic pancreatitis

 GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS

• Liraglutide has been found to cause a dose-dependent and treatment-duration-

dependent thyroid C-cell tumors at clinically relevant exposures in both genders of
rats and mice.

Whether it produces similar carcinogenic effects in humans is unknown, and can

not be ruled out with available data.

Liraglutide is contraindicated in patients with a personal or family history of

medullary thyroid carcinoma (MTC) and in patients with Multiple Endocrine
Neoplasia syndrome type 2 (MEN 2).
 Injectable non-insulin hypoglycemics
 AMYLIN ANALOG

 Drugs: Pramlintide

 Amylin can suppress appetite via hypothalamic receptors (different receptors than for
GLP-1), Suppresses glucagon secretion and slows gastric emptying.

 Pramlintide acts to slow gastric emptying, decrease glucagon secretion, and decreases
appetite.
 Administered SC, typically with insulin. Common side effects are hypoglycemia and nausea.
 Injectable non-insulin hypoglycemics
Pramlintide

• Indications: approved for:

• Amylin is approved for “adjunct” therapy in combination with insulin:

• Type 1 diabetes - as an adjunct treatment in patients who use mealtime insulin therapy but
have failed to achieve desired glucose control despite optimal insulin therapy

• Type 2 diabetes - as an adjunct treatment in patients who use mealtime insulin therapy but
have failed to achieve desired glucose control despite optimal insulin therapy, with or without
concurrent use of a sulfonylurea and/or metformin.
 Injectable non-insulin hypoglycemics
Pramlintide

• Pharmacokinetics: administered by subcutaneous injection immediately before eating

• rapidly absorbed (SC): with peak levels within 20 mins & duration of action less than 150 minutes

• undergoes renal metabolism & excretion

• Side Effects:
• Risk of hypoglycemia exists, so that doses of mealtime rapid- or short-acting insulin should be
reduced by ~50% or more

• A similar reduction in secretagogue doses may also be necessary in patients with Type 2 diabetes.

• Modest weight loss

Summary….
Summary….
Summary….
Summary….
Summary….
Summary….
Thank you!