Cardiovascular disease & Diabetes

Anatomy of Heart

Reference
 Chambers of the Heart

• 2 Atria – receive blood from

veins
• Auricles – expanded areas of
atria that can fill with blood
from vena cava (major
veins to heart)

• 2 Ventricles – pump blood into

arteries
• Apex – Tip of the heart formed
by the left ventricle
• Changes position as person
ages

Reference
 Structure of Blood Vessel

• The blood vessels are the part of the circulatory system that transports blood
throughout the human body

• There are three major types of blood vessels

• Arteries
• Which carry the blood away from the heart
• Veins
• Which carry blood toward the heart
• Capillaries
• Which enable the actual exchange of water and chemicals between the blood and the
tissues

Reference
 Great Vessels of the Heart

• Arteries: Carry blood away from heart

• Pulmonary artery (trunk): To lungs (pulmonary circulation)
• Aorta: To body (systemic circulation)

• Veins: Return blood to heart

• Pulmonary veins: From lungs (pulmonary circulation)
• Superior & inferior vena cava (systemic circulation)
• Coronary sinus (coronary circulation)

Reference
 Atria & Atrioventricular Valves

• Atrioventricular (AV) valves

• Allow blood to flow from atria to ventricles when latter are relaxing
• Prevent flow from ventricles to atria when ventricles are contracting
• Mitral or bicuspid valve
• Allow blood to flow from
left atria to left ventricles

• Tricuspid valve
• Allow blood to flow from
right atria to right ventricles

Reference
 Ventricles & Semilunar Valves

• Semilunar (SL) valves

• Allow blood to flow from ventricles to arteries when ventricles are contracting
• Prevent back flow from arteries to ventricles when ventricles relax

Reference
 Blood Flow Through the Heart
• Two circuits:
• Pulmonary: To and from capillary beds
associated with alveoli of lungs where
gas exchange between blood and air
takes place
• Brings deoxygenated blood to lungs;
returns oxygenated blood to heart

• Systemic: To and from capillary beds of

the rest of the body where gas
exchange between blood and tissues
takes place
• Brings oxygenated blood to tissues; returns
deoxygenated blood to heart

Reference
 Blood Circulation
SVC/IVC Right auricle Right
ventricle

Lungs for
Veins
purification

Venules Left auricle

Capillaries (gas Left

exchange) Ventricle

Arterioles Arteries Aorta

Reference
Oxygen Transfer

Reference
 Coronary Circulation:
Disorders

• Occlusion – blockage; in a vessel, tissue downstream will be deprived of oxygen

and nutrients

• Ischemia – transient state of oxygen deficit leading to reversible changes in cell

structure and function

• Infarction – localized area of cell death (necrosis) resulting from anoxia.

Reference
 Cardiac Circulation:
Disorders

• Angina (most common-imbalance between myocardium oxygen supply and

demand)

• Myocardial infarction (MI - death of myocardium due to complete occlusion /

blockade of a coronary artery)

• Heart failure (failure of heart to pump blood)

• Arrhythmia (abnormalities of heart rhythm and conduction of impulses)

Reference
 Blood Pressure
• Blood Pressure
• It is the pressure exerted by the flowing blood on the walls of the blood vessels (Normal =
130/80 mm Hg)
• Depends on cardiac output and peripheral resistance
• BP = Cardiac output (CO) x Peripheral Resistance (PR)

• Systolic pressure
• It is the blood pressure in blood vessels during contraction or systole of the heart (Normal =
130 mm Hg)

• Diastolic pressure
• It is the blood pressure in blood vessels during the relaxation or diastole of the heart
(Normal = 80 mm Hg)
Reference
 JNC 8-Hypertension

Persistent elevation of blood pressure

BP ≥ 140/90 mm Hg

With an average of 2 readings per visit

Reference
 Determinants of BP

• BP = CO × PR

• CO = HR (×) SV

• BP = HR (×) SV × PR

• PR reflects relative tone of the arterioles

Reference
 Cardiac Output (CO)

• Volume of blood ejected from each ventricle per minute

• At rest, normally 5 L / min

• Cardiac output (CO) = Stroke volume (SV) × Heart rate (HR)

• Heart rate (HR)
• Number of beats per minute

• Stroke volume (SV)

• Amount of blood ejected per beat

Reference
 Peripheral Resistance

• It is the pressure exerted by blood vessel walls on the flowing blood

• It depends on diameter of blood vessel

• Bigger the diameter, less is peripheral resistance (PR)

• Smaller the diameter , more is the PR
Reference
 Vasoconstriction & Vasodilation

• Vasoconstriction
• Contraction of blood vessels, leading to decrease in diameter and increase in
peripheral resistance

• Vasodilation
• Relaxation or expansion of blood vessels leading to increase in diameter and
decrease in peripheral resistance

Reference
 Types of Hypertension

• Essential or Primary or Idiopathic Hypertension

• 90-95% of all cases
• So called because the raised blood pressure is essential to maintain adequate
tissue perfusion

• Secondary hypertension
• 5-10% of all cases
• Secondary to other disease, drugs, etc.

Reference
 Consequences of Hypertension

• Hypertension is a significant risk factor for:

• Cerebrovascular disease
• Coronary artery disease
• Angina
• MI

• Left ventricular hypertrophy

• Congestive heart failure
• Renal failure
• Peripheral vascular disease

Reference
 Left Ventricular Hypertrophy

Preload Afterload

• Preload
• Load or pressure on the heart due to vasoconstriction in veins and
increased venous return.

• Afterload
• Load or pressure on the heart due to vasoconstriction in arterioles
and arteries

Reference
Left Ventricular Hypertrophy
al
rm
No

hyp
tro
er
yp
rH
ula
ric
nt
Ve
ft
Le
Reference
 Angina

• Angina pectoris ~ chest pain

• Major CAD complication

• Symptom associated with myocardial ischemia

• Occurs when myocardial oxygen demand exceeds supply

Reference
 Signs and Symptoms

Shortness
Chest Pain
Of Breath

Signs &
Symptoms

None

Reference
Signs and Symptoms

Reference
 Myocardial Ischemia

• Myocardial ischemia (MI) is inadequate blood supply to myocardium

characterized by ST segment depression on ECG
• May or may not manifest as angina

• Death of myocardium due to complete occlusion / blockade of coronary arteries

• Infarction (necrosis of a tissue resulting from a sudden insufficiency of arterial or

venous blood supply)

Reference
Signs and Symptoms

Reference
 Angiotensin II is Central to
CVD Progression

Myocardial infarction
Remodelling

Atherosclerosis Ventricular dilation

and
left ventricular CV High-Risk
hypertrophy
Congestive heart
Hyper- failure
tension HF
Risk factors
Angiotensin II Death Death

Adapted from: Dzau VJ, et al. Circulation 2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E.
Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet 2004;364:937–952
Drugs for Hypertension

Reference
 Classes of Antihypertensives
for Initial Therapy
• Diuretics
• E.g.: Hydrochorthiazide, Chlorthalidone

• Angiotensin covering enzyme (ACE) inhibitors

• E.g.: Captopril, Enalapril, Lisinopril

• Angiotensin II receptor blockers

• E.g.: Telmisartan, Losartan, Candesartan

• Calcium Channel blockers

• E.g.: Amlodipine, Verapamil, Nifedipine

• Beta blockers
• E.g.: Metaprolol, Propanolol, Atenolol

• Alpha blockers
• E.g.: Prazosin, Terazosin

• Alpha-beta blockers
• E.g.: Carvedilol Reference
 Anti-hypertensive Drugs:
Sites of Action

Blood Cardiac Total Peripheral

Pressure = Output × Resistance

β-Blockers ACE Inhibitors

CCBs* ARBs
Diuretics CCBs
Diuretics
Vasodilators

Reference
 Mechanism of Action of RAS/RAAS
and Actions of Angiotensin II
Reduced glomerular filtration

Reduced Na+ in distal tubule­

Renin release

Angiotensinogen Angiotensin I

Bradykinin
ACE
Inactive
metabolites Angiotensin II

Direct Fluid Tissue Increased Decreased

vasoconstriction retention growth Sympathetic Glomerular
promotion activity filtration
pressure

Reference
 Sites of Actions of
ARBs Vs. ACEIs

Angiotensinogen
ACE inhibitor
i.e. Captopril Renin

Chymases
Angiotensin I
Bradykinin
ACE
Inactive
Angiotensin II AT1 receptor
metabolites
antagonist
i.e Telmisartan
Angiotensin II subtype 1
receptor sites

Direct Fluid Tissue Increased Decreased

vasoconstriction retention growth Sympathetic Glomerular
promotion activity filtration
pressure
ACE-Angiotensin converting enzyme; Drugs. 1996;51/5:825.
ARBs-Angiotensin receptor blockers
Angiotensin II Receptor Blockers:
Mechanism of Action

Angiotensin II

Telmisartan A-II Blockade

Angiotensin II Receptors
(subtype AT1)

 Aldosterone secretion
 Vasoconstriction
 Sympathetic Activation

Blood Pressure
Reference
ACE Inhibitor or ARB / Diuretic
Combinations

Diuretics ACE Inhibitors/ ARBs

  Fluid volume   PVR via inhibition of

  Renin release formation or action of
AT II at the receptor
level
  RAAS function

Reference
 Benefits of Combinations of Diuretics
Plus RAAS-Regulating Drugs

• Complementary mechanisms of action

• Reduction of fluid volume with diuretics
• Reduction in PVR with RAAS inhibitors

• RAAS inhibitors counteract relative increase in blood pressure related

to diuretic-induced renin secretion
• Generally, amelioration of diuretic-induced hypokalemia

Reference
 Highlights of Properties of
Telmisartan / HCTZ

• Complementary mechanisms of action

• Reduced PVR with angiotensin II receptor blocker
• Reduced fluid volume with diuretic

• Telmisartan’s 24-hour dosing period may be supported by its 24-hour half-life

• Substantial reductions in SBP (mean reduction >18 mmHg in a clinical trial)
• Blood pressure response in ~80% of patients with mild-to-moderate hypertension
in a clinical trial (where placebo response rate ~30%)
• Well tolerated with few treatment-related side effects and a low incidence of
cough
Reference
 Diuretics

• Drugs that accelerate the rate of urine formation

• In the nephron, where sodium goes, water follows
• 20% to 25% of all sodium is reabsorbed into the bloodstream in the ascending
loop of Henle
• 5% to 10% in the distal convoluted tubules
• 3% in collecting ducts

• If water is not absorbed, it is excreted as urine

• Result: Removal of sodium and water
Reference
 Classifications of Diuretics

• Loop diuretics
• Thiazide and thiazide-like diuretics
• Osmotic diuretics
• Potassium-sparing diuretics
• Carbonic anhydrase inhibitors

Reference
 Diuretics & Site of Action
Thiazide
diuretics

Potassium
sparing
diuretics

Osmotic
Osmotic Carbonic
anhydrase
diuretics
diuretics
inhibitors

Loop
diuretics

Reference
 Thiazide Diuretics

Thiazide diuretics Thiazide-like diuretics

• Hydrochlorothiazide • Chlorthalidone
• Chlorothiazide • Metolazone
• Bendroflumethiazide • Indapamide
Lack the
benzothiadiazine
structure

Reference
 Thiazide and Thiazide-like Diuretics

• Inhibit sodium transport in the distal portion of the nephron, causing

substantial loss of sodium and water
• Produce intense diuresis
• Useful in treatment of mild to moderate uncomplicated hypertension

Reference
Site of Action Of Thiazide Diuretic
• Chlorthalidone
• Thiazide like diuretic
• Uniquely long acting
• T1/2 = 50 to 60 hrs
• Large Vd->partioning into
erythrocytes->reservoir-
>constant seeping back to
plasma

• Advantageous in patients who

occasionally miss doses
• Retain measurable efficacy when
given less frequently than once daily
Reference
 Thiazide and Thiazide-like Diuretics
• Indications:
• Hypertension:
first line drug
for HTN

Reference
CONCLUSIONS – Messerli meta-analysis
“If a clinical indication calls for a thiazide-type diuretic,
chlorthalidone or indapamide remain the drugs of choice”

Messerli FH et al. J Am Coll Cardiol. 2011;57:590-600.

 Conclusion

• Diuretics to continue as first line therapy, specially in uncomplicated

hypertensive patients, where all the other classes will have some
acceptability issues

• Not all diuretics are same

• Choose diuretic with best supportive evidence of CV benefits

• Chlorthalidone is one such diuretic in Indian conditions

Reference
 Amlodipine
A typical modern long acting Ca2+ channel blocker with significant antihypertensive
effect

Reference
 Calcium Channel Blocker
• Amlodipine: A typical modern long acting Ca2+ channel blocker
with significant antihypertensive effect.

Reference
 Mechanism of Action: Amlodipine
• The contractile processes of cardiac muscle and vascular smooth muscle are dependent
upon the movement of extracellular calcium ions into these cells through specific ion
channels

• Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater
effect on vascular smooth muscle cells than on cardiac muscle cells

• Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth

muscle to cause a reduction in peripheral vascular resistance and reduction in blood
pressure

Reference
 Calcium Channels
Closed calcium channels
Extra cellular calcium
on membrane

Endoplasmic
reticulum

Intra cellular
calcium Actin-myosin contractile fibers
 Role of Calcium
3. Extra cellular calcium enters 2. Calcium channels open

1. Signal arrives at cell 4. Calcium stimulates ER

5. ER releases
more calcium
6. Actin-myosin fibers
contract after interacting
with calcium causing
vasoconstriction
Reference
 Mode of Action: Amlodipine
1. Amlodipine blocks
4. Extra cellular calcium
channel
cannot enter 3. Calcium channels
2. Signal arrives at does not open
cell

5. ER releases
less calcium

6. Actin-myosin
fibers contract
weakly reducing
vasoconstriction
Reference
 Why Telmisartan+ Amlodipine

• Highly effective in controlling the blood pressure for 24 hrs in patients with
diabetes, obese and elderly. DUAL BLOOD PRESSURE CONTROL

• Decreases insulin resistance, blocks the hyperactive RAAS and SNS activity

• The peripheral oedema caused by the amlodipine is counter acted by telmisartan

RAAS-Renin angiotensin aldosterone system

SNS- Sympathetic nervous system

Reference
 Alpha1-Adrenergic Blockers
• Alpha1-adrenergic receptors are found on vascular smooth muscle
where they mediate vasoconstriction

Reference
 Alpha1-Adrenergic Blockers

• Side effects
• Orthostatic (postural) hypotension
• Reflex tachycardia

• Blockade of the alpha1-adrenergic receptors results in vasodilation of

both the arterial and venous beds
• Prototype: Prazosin

Reference
 Beta Blockers
• The β1 receptors are predominantly present on the heart & kidney. On Stimulation by the
sympathetic nervous system they increase the rate and force of contraction of the heart.

• The β2 receptors are predominantly present on bronchi of respiratory tract. On stimulation

it causes broncho-dilation

• The drugs that block β1 receptors are known as cardio selective beta-blockers. e.g.
Metoprolol and Atenolol

• Drugs, which act on both the beta-receptors, are known as non-selective beta-blockers e.g.
Propranolol

• Cardio selective beta- blockers block the β1 receptors and reduce the rate and force of
contraction of the heart. This results in the decrease of cardiac output and lowering of BP

Reference
 Minoxidil-As an Antihypertensive Therapay
• Minoxidil is a direct vasodilator introduced in the early 1970s for the treatment of hypertension.

• It is capable of reducing blood pressure in most persons with resistant hypertension where therapy has
failed with multidrug regimens.

• Minoxidil's effect can be limited because of an increase in pulse rate and/or sodium (and water) retention.
The latter may prove quite debilitating in some patients. Thus, minoxidil is generally administered with
both a diuretic and an agent that can keep pulse rate in check, such as a beta blocker or a combined
alpha-beta blocker.

• The use of this medication should be limited in view of the availability of effective agents with fewer side
effects. There is, however, a place for minoxidil in the treatment of resistant hypertension especially in
patients with advanced renal disease.
 Classification and Management
of BP for Adults
Initial Drug Therapy
BP SBP* DBP* Lifestyle Without compelling With compelling
classification mm Hg mm Hg modification indication indications

Normal <120 and <80 Encourage

No antihypertensive drug Drug(s) for compelling
Pre-hypertension 120–139 or 80–89 Yes indicated. indications.‡

Thiazide-type diuretics for Drug(s) for the

Stage 1 most. May consider ACEI, compelling indications.‡
Hypertension 140–159 or 90–99 Yes ARB, BB, CCB, or
combination.

Two-drug combination for Other antihypertensive

Stage 2 most† (usually thiazide- drugs (diuretics, ACEI,
Hypertension >160 or >100 Yes type diuretic and ACEI or ARB, BB, CCB) as
ARB or BB or CCB). needed.

*Treatment determined by highest BP category.

†
Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.
‡
Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.

Reference
JNC 8 - Guidelines Ease Up on BP
Thresholds, Drug Choices

Reference
 JNC VIII Recommendations

Patient subgroup Target systolic Target diastolic

BP (mm Hg) BP (mm Hg)
≥60 years < 150 < 90
<60 years < 140 < 90
>18 years with CKD < 140 < 90
>18 years with diabetes < 140 < 90

CKD – Chronic kidney diseases

James PA, et al. JAMA. 2014;311(5):507-520.

 JNC VIII Recommendations

• General population
• Thiazides, CCB, ACEI or ARB initially

• CKD
• Treatment should include ACEI or ARB

• Up-titrate or add therapy after 1 month if BP goal not achieved

• Don't use ACEI and ARB together
• If > 3 drugs needed refer to hypertension specialist

James PA, et al. JAMA. 2014;311(5):507-520.

 Treatment Algorithm
Adult aged ≥18 years with hypertension

Implement lifestyle interventions (continue throughout management)

Set blood pressure goal and initiate BP lowering medications based on age, diabetes
and chronic kidney diseases (CKD)

General population (no diabetes or CKD) Diabetes or CKD present

Age ≥60 years Age <60 years All ages diabetes All ages CKD present
present no CKD with or without diabetes

BP goal BP goal BP goal BP goal

SBP <150 mm Hg SBP <140 mm Hg SBP <140 mm Hg SBP <140 mm Hg
DBP <90 mm Hg DBP <90 mm Hg DBP <90 mm Hg DBP <90 mm Hg

Initiate thiazide-type diuretic Initiate thiazide-type Initiate ACEI or ARB,

or ACEI or ARB or CCB, diuretic or CCB, alone or alone or in combination
alone or in combination in combination with other drug class
James PA, et al. JAMA. 2014;311(5):507-520.
 Treatment Algorithm
Select drug treatment titration strategy
A. Maximum first medication before adding second or
B. Add second medication before reaching maximum dose of first medication or
C. Start with 2 medication classes separately or as fixed dose combination

YES
At goal BP
NO

Reinforce medication and lifestyle adherence

For strategies A and B add and titrate thiazide-type diuretic or ACEI or ARB or CCB
(use medication class not previously selected and avoid combined use of ACEI and
ARB)
For strategy C titrate doses of initial modifications to maximum
YES
At goal BP
NO

Reinforce medication and lifestyle adherence

Add and titrate thiazide-type diuretic or ACEI or ARB or CCB (use medication class not
previously selected and avoid combined use of ACEI and ARB)
YES
At goal BP
NO

James PA, et al. JAMA. 2014;311(5):507-520.

 Treatment Algorithm

Reinforce medication and lifestyle adherence

Add additional medication class (e.g. beta blockers, aldosterone antagonist or others)
and/or refer to physician with expertise in hypertension management.

NO YES
At goal BP Continue current
treatment and
monitoring

James PA, et al. JAMA. 2014;311(5):507-520.

 Summary:
JNC 8 Recommendations

• In patients 60 years or over, start treatment in blood pressures >150 mm Hg systolic

or >90 mm Hg diastolic and treat to under those thresholds.

• In patients < 60 years, treatment initiation and goals should be 140/90 mm Hg, the same
threshold used in patients > 18 years with either chronic kidney disease (CKD) or
diabetes.

• In nonblack patients with hypertension, initial treatment can be a thiazide-type diuretic,

CCB, ACE inhibitor, or ARB

• In patients >18 years with CKD, initial or add-on therapy should be an ACE inhibitor or
ARB, regardless of race or diabetes status
James PA, et al. JAMA. 2014;311(5):507-520.
 Compelling Indications for
Individual Drug Classes
Compelling Indication Initial Therapy Options

Heart Failure THIAZ,BB, ACEi, ARBs, ALDO ANT

Post myocardial infarction BB, ACEi,ALDO ANT
High CVD risk THIAZ, BB,ACEi, CCB
Diabetes THIAZ, BB,ACEi, ARBs, CCB
Chronic kidney disease ACEi, ARB
Recurrent stroke prevention THIAZ, ACEi

Key THIAZ = thiazide diuretic, ACEI angiotensin converting enzyme inhibitor, ARB = angiotensin receptor blocker, BB =
beta blocker, CCB = calcium channel blocker, ALDO Ant – aldosterone antagonist

Reference
 Lipoprotein Particles

• Very low-density lipoprotein (VLDL)

• Intermediate-density lipoprotein (IDL)

• Low-density lipoprotein (LDL)

• High-density lipoprotein (HDL)

 Good and Bad Lipoprotein

• LDL-C
• Leads to atherosclerosis
• Bad Cholesterol

• HDL
• Picks up excess cholesterol & delivers to liver
• Reduces LDL-C levels
• Good Cholesterol
Cholesterol Synthesis

3-Hydroxy 3-Methyl Glutaryl Coenzyme A reductase

Lipoproteins Metabolism
Reverse cholesterol transport by HDL
 Management

• HMG CoA reductase inhibitors or statins

• Atorvastatin, Lovastatin, Simvastatin

• Bile acid sequestrants-cholestyramine, colestipol, and colesevelam

• Cholestyramine & Colestipol

• Cholesterol Absorption Inhibitors- Ezetimibe

• Niacin (nicotinic acid)

• Fibric acid derivatives

• Gemfibrozil, Fenofibrate & Clofibrate
 Drug Therapy

• HMG CoA Reductase Inhibitors (Statins)

• Reduce LDL-C 18-55% & TG 7-30%

• Raise HDL-C -15%

• Major side effects

• Myopathy
• Increased liver enzymes

• Contraindications
• Absolute: Liver disease
• Relative: Use with certain drugs
 Drug Therapy

• Fibric Acid
• Major actions
• Lower LDL-C 5-20% (with normal TG)
• Lower TG 20-50%
• Raise HDL-C 10-20%

• Side effects : dyspepsia, gallstones, myopathy

• Contraindications : Severe renal or hepatic disease

 Mechanisms of Hypolipidaemic
Agents

Bile
Niacin
Acid
Binding
Agents
Fibrates

Statins

Reference
 Mechanism of Action

HMG CoA

Inhibits
HMG CoA reductase ROSUVASTATIN

Mevalonic Acid

Cholesterol
 Lowers LDL-C levels

Decreased Cholesterol synthesis in liver

Increased Hepatic LDL receptors

Increased LDL uptake by liver

Decreased Circulating LDL

AACE/ACE Glycemic Control Algorithm
AACE/ACE Profiles of Antidiabetic
Medications
 Mechanism of action

• The primary effect is to reduce hepatic glucose production through

activation of the enzyme
AMP-activated protein kinase (AMPK)*
• Other mechanisms of action include:
• Increased glucose removal from blood (improves insulin sensitivity)
• Direct stimulation of glycolysis in tissues
• Impairment of renal gluconeogenesis
• Slowing of glucose absorption from the gastrointestinal tract
• Increased glucose to lactate conversion by intestinal cells
• Reduction of plasma glucagon levels
* AMP: Adenosine Mono-phosphate
Mechanism of action (contd…)
 SUs - Mechanism of Action

Pancreatic actions

Mechanism of action

Extra-pancreatic
actions
 Mechanism of action
A. Pancreatic actions
Binding to the
sulfonylurea receptor

Inhibition of K+ efflux

Depolarization

Opening of voltage-
sensitive Ca2+ channel

Intracellular (Ca2+)
increase

Triggering of insulin
Reference
secretion
 Mechanism of action
B. Extra-pancreatic actions (contd…)

• Maintains ischaemic preconditioning (cardio-protective effect)

• Ischaemic preconditioning is the process by which the heart prepares itself to
face an ischaemia (decreased blood supply)
 Rationale for Combining
Metformin and Glimepiride

• 20-25% of newly diagnosed diabetes patients fail to respond to initial SU therapy

(primary failure)

• Among 75% of those who achieve good control, 3-5% will lose responsiveness
each year (secondary failure)

• Glimepiride and metformin act as sequential anti-diabetic agents :

• Glimepiride increases the secretion of insulin
• Metformin increases the insulin sensitivity in the peripheral tissues
 Rationale for Combining
Metformin and Glimepiride

• The combination of glimepiride and metformin can be used in obese individuals

with lesser risk of weight gain

• Long duration of action allows single daily dose and increases patient compliance

• Metformin is the ideal drug for combination therapy in T2DM patients who are
obese, insulin-resistant and at increased risk of atherosclerosis
 Brand Positioning
For people with type 2 diabetes uncontrolled with glimepiride
or metformin monotherapy

Features Benefits
Sequential anti-diabetic agents: - Achieves optimal glycemic control
Insulin Secretagogue + Insulin - Lesser insulin dose requirements
Sensitizer - Lesser weight gain
 What is α-glucosidase?

• An enzyme located on the surface of the intestinal epithelium

Polysaccharides,
• Breaks down complex carbohydrates to glucose
oligosaccharides Glucose
 Mechanism of Action of AGIs
Carbohydrates in diet

Competitive inhibition of
AGI
α-glucosidase

α-glucosidase

Glucose

Delays glucose absorption in

Glucose absorbed in intestine
the intestine

Glucose reaches the blood vessels Decreases PPG peaks

Hirose T, et al. Diabetes Res Clin Pract. 2001;54(1):9-15
DPP-4 inhibitors and incretin mimetics
address a core defect in a unique way
Inadequate Acute Chronic
Glucose Insulin glucagon β-Cell
absorption resistance β-Cell
suppression dysfunction insufficiency

DPP-4 DPP-4
inhibitors and inhibitors and
incretin incretin
TZDs2 mimetics3 Sulfonylurea1 mimetics4
α-Glucosidase
inhibitors1 Metformin1 Glinide1

Blood glucose
1. Inzucchi SE. JAMA. 2002;287-360–372. 2. DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24–S40.
3. Nauck MA. Am J Med. 2011;124(1 Suppl):S3-18. 4. Garber AJ. Diabetes Care. 2011; 34(Suppl 2):S258-S263
 What DPP4 inhibitors Add to
T2DM therapy
• Comprehensive mechanism of action
• Targeting multiple levels in T2DM pathophysiology
• Dual targeting of α cell and β cell

• Improvement in Disposition/Adaptation Index

• Improvement in both Insulin secretion & Insulin sensitivity

• Glucose dependent secretion of Insulin secretion

• Lesser risk of hypoglycemia

• Preservation of Beta cells

• Stimulate β cell neo-genesis
• Reduce β cell apoptosis
Br J Diabetes Vasc Dis.  2006;6(5):207-215
Fred F Ferri, Practical guide to the care of the medical patient, Sixth edition, 2004
Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940
DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24-S40