Glimepiride 1/2 mg + Metformin SR 1000mg + Pioglitazone 15 mg

MEDICAL PRESENTATION
OVERVIEW OF PRESENTATION

 Background

 Unmet need of triple drug combination

 Rationale of triple drug combination

 Molecular profiles of : Metformin, Glimepiride and Pioglitazone

 Clinical evidence

 Summary
DIABETES MELLITUS

Diabetes is a chronic, metabolic disease characterized by elevated levels of blood

glucose, which leads over time to serious damage to the heart, blood vessels, eyes,
kidneys and nerves.
 Characterized by chronic hyperglycemia.

 Generally arises from a combination of insulin resistance and -cell dysfunction.

~90% of people with type 2 diabetes are obese.

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
INSULIN RESISTANCE AND -CELL DYSFUNCTION ARE CORE
DEFECTS OF TYPE 2 DIABETES

Genetic susceptibility,
obesity, Western lifestyle

Insulin
resistance IR  b-cell
dysfunction

Type 2 diabetes

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
WHAT IS INSULIN RESISTANCE ?

 Major defect in individuals with type 2 diabetes 1

 Reduced biological response to insulin 1–3

 Strong predictor of type 2 diabetes4

 Closely associated with obesity5 IR

1
American Diabetes Association. Diabetes Care 1998; 21:310–314.
2
Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:1714–1721. 3Bloomgarden ZT. Clin Ther 1998; 20:216–231.
4
Haffner SM, et al. Circulation 2000; 101:975–980. 5Boden G. Diabetes 1997; 46:3–10.
INSULIN RESISTANCE – REDUCED RESPONSE TO
CIRCULATING INSULIN

Insulin
resistance IR

Liver Muscle Adipose

tissue

 Glucose output  Glucose uptake  Glucose uptake

Hyperglycemia
 WHAT IS -CELL DYSFUNCTION?

 Major defect in individuals with type 2 diabetes

 Reduced ability of -cells to secrete insulin in

response to hyperglycemia 



DeFronzo RA, et al. Diabetes Care 1992; 15:318–354.

LOSS OF -CELL FUNCTION OCCURS BEFORE
DIAGNOSIS
100
Up to
80 Diagnosis 50%
-cell function (%)

loss
60

40

20

0
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 1 2 3 4 5 6
Time from diagnosis (years)

Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25.

MORE THAN 80% OF PATIENTS PROGRESSING TO TYPE 2
DIABETES ARE INSULIN RESISTANT
Insulin sensitive;
low insulin secretion (16%)

Insulin sensitive;
good insulin Insulin resistant;
secretion (1%) low insulin secretion (54%)

83%
Insulin resistant;
good insulin secretion (29%)

Haffner SM, et al. Circulation 2000; 101:975–980.

INSULIN RESISTANCE IS CLOSELY LINKED TO
CARDIOVASCULAR DISEASE

Present in> 80% of people with

type 2 diabetes1

Insulin Approximately doubles the risk of

resistance IR a cardiac event2

Implicated in almost half of CHD

events in individuals with type 2 diabetes2

1
Haffner SM, et al. Circulation 2000; 101:975–980.
2
Strutton D, et al. Am J Man Care 2001; 7:765–773.
UNMET NEED OF TRIPLE DRUG COMBINATION
T2DM: A DIRE EPIDEMIOLOGY!

77 million
Diagnosed
cases in
India

425
million

IDF DIABETES ATLAS Ninth

edition 2019
TYPICAL INDIAN PHENOTYPE WILL ALWAYS NEED GLIMEPIRIDE +
METFORMIN + PIOGLITAZONE
High BMI
High
visceral
fat Increases Insulin Sensitivity
Insulin
Resistance Preserve B-cell function
Early
High LDL
decline
Low HDL
in Beta
cells Increases Anti-Inflammatory markers

High CV risk
High risk of Provides CV Protection
complicatio
ns
RATIONALE OF TRIPLE DRUG COMBINATION

 T2DM – A PROGRESSIVE DISEASE

 GUIDELINES RECOMMENDATION
 AACE GUIDELINES
 RSSDI-ESI INDIAN GUIDELINES

 ADVANTAGES OF TRIPLE DRUG COMBINATION

 DIABETES PATIENT JOURNEY – A PROGRESSIVE DESPAIR…
By 3 years , up to 50% of Diabetic patients are
uncontrolled & require additional pharmacological
70-80% of B-cell agent
function is lost & 50 %
insulin sensitivity is lost

Metformin Metformin + 1 OAD

Dual Drug Therapy +

Gets Diagnosed Monotherapy + Lifestyle
Modification Lifestyle Modification

Inevitable Progression towards

Triple drug combination!!
Dual Drug Triple Drug Therapy+ Drug Therapy
Therapy Lifestyle Modification + Injectable
Metformin + 1 OAD
Metformin + 2 OAD

By 10-15 years , < 10% of endogenous

By 3 years , up to 50% of Diabetic insulin is present & exogenous insulin
patients are uncontrolled & require therapy becomes essential
additional pharmacological agent
GUIDELINES RECOMMENDATION OF TRIPLE
DRUG COMBINATION

• AACE GUIDELINE RECOMMENDATIONS 2020

• RSSDI-ESI CLINICAL RECOMMENDATIONS FOR THE MANAGEMENT OF TYPE 2 DIABETES
MELLITUS 2020
GUIDELINE RECOMMENDATION: AACE 2020

At Entry A1C ≥ 7.5

% - Triple
Therapy Is The
Need Of Indian
T2DM Patients

Diabetes management algorithm, Endocr Pract. 2020;26(no.1) 137

 Patient-centric approach recommendation in RSSDI –ESI Guideline
Initial therapy Metformin + Life style Interventions
Dual therapy If glucose control targets are not
achieved: Add sulfonylurea or
thiazolidinediones (TZDs) or sodium-
glucose cotransporter 2 inhibitors
(SGLT2) inhibitor, or DPP-4 inhibitor, or
AGI

Triple Therapy If glucose targets are not achieved with

two agents: start third oral agent TZDs,
DPP-4 inhibitor, SGLT2 inhibitor, or -
AGI (depending on second-line agent
used) or start insulin or glucagon-like
peptide 1 (GLP-1) agonists

Consider initiating combination therapy if the HbA1c >1.5 above the

Indian J Endocr Metab 2020;24:1-122. target initial therapy
ADVANTAGES OF TRIPLE DRUG
COMBINATION
COMPLEMENTARY MECHANISM OF ACTION OF TRIPLE
THERAPY
FDC acts by different mechanisms thereby targeting multiple pathophysiological targets

SULFONYLUREA

Increase insulin
secretion
Keep
Hyperglycemia
METFORMIN
under control
PIOGLITAZONE Decrease hepatic
glucose output
Decrease insulin
resistance Increase insulin
sensitivity

ICMR GUIDELINES FOR THE MANAGEMENT OF DIABETES MELLITUS, 20

PIOGLITAZONE WHEN COMBINED WITH SU & METFORMIN…

METFORMIN
GLIMEPIRIDE
Covers
maximum
METFORMIN
aspects of
Ominous
octet
PIOGLITAZONE
PIOGLITAZONE
METFORMIN
MOLECULAR PROFILE OF INDIVIDUAL DRUGS
METFORMIN SR 1000MG + GLIMEPIRIDE 1 / 2 MG + PIOGLITAZONE 15 MG
 METFORMIN
Belongs to the class biguanides, which improves glucose tolerance in patients with type 2 diabetes,
lowering both basal and postprandial plasma glucose.

FDA LABEL : METFORMIN

 GLIMEPIRIDE
Sulfonylurea class, insulin-secretagogue appears to be dependent on stimulating the release of insulin
from functioning pancreatic beta cells.

Binding of
sulfonylurea to
beta cell (SU
Opening of Ca+ Stimulates insulin
receptors) reduces
channels and rapid containing
the rate of K+ ions
entry of calcium secretory granules
across the cell
into the cell to release insulin
membrane leading
to closure of K+
channels

FDA LABEL : GLIMEPIRIDE

 PIOGLITAZONE
Class thiazolidinedione that acts primarily by decreasing insulin resistance.

THIAZOLIDINEDIONES
(Pioglitazone)

Decreases TNF-alpha levels in the endothelium

Decreases hepatic
• Decreased monocyte adhesion gluconeogenesis
Increases glucose
• Decreased foam cell formation uptake

• Decreased atherosclerosis
• Decreased inflammation
Cardiovascular protection

Aust Prescr 2004;27:67-70 1 June 2004,Thiazolidinediones - mechanisms of action,Jerry R. Greenfield

Adiponectin: action, regulation and association to insulin sensitivity A S Lihn etalObes Rev 2005 Feb;6(1):13-2
PHARMACOKINETIC PROFILE

DAILY DOSAGE PREDOMINANT

DURATION OF FREQUENCY MODE OF
DRUG NAME RANGE (MIN-MAX) ACTION PER DAY EXCRETION
MG

Urine (15-30%)
PIOGLITAZONE 7.5 - 30 16-24 Hrs 1 remaining in the
faeces

METFORMIN SR 250-2500 4-8 Hrs 1-3 Urine

16-24 Hrs Urine 60%

GLIMIPIRIDE
GLIMEPIRIDE 1-8 1 Bile 40%

ICMR GUIDELINES FOR THE MANAGEMENT OF DIABETS MELLITUS,

CLINICAL EVIDENCE OF TRIPLE DRUG
COMBINATION
METFORMIN SR 1000MG + GLIMEPIRIDE 1 / 2 MG + PIOGLITAZONE 15 MG
1

Objective: Assess the long-term glycaemic effects and the safety profile of triple therapy with the addition of
pioglitazone vs. placebo in patients with Type 2 diabetes treated with combined metformin–sulphonylurea therapy in the
PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive).

Study design:
A randomized, double-blind, multi-centre study in 5328 patients aged 35–75 years with Type 2 diabetes and a
history of macrovascular disease. Identified patients who treated with metformin + sulfonylurea combination
therapy and not receiving insulin at baseline (n=1314)

Methods :
Group 1: Metformin + Sulfonylurea + Pioglitazone (15mg Titrated To 45mg) Mean followup for 34.5
Group 2: Metformin + Sulfonylurea + Placebo } months

Diabet. Med. 26, 1033–1039 (2009)

 Significantly greater reductions in HbA1c and greater proportions of patients
with HbA1c at target were noted with pioglitazone when compared to placebo.

There was an approximate twofold increase in progression to

permanent insulin use in the placebo group vs. the pioglitazone
group: 31.1 vs. 16.1%, respectively,

Adding pioglitazone to the classical metformin–sulphonylurea combination resulted

in sustained improvements in glycaemic control and reduced progression to insulin
therapy.

Diabet. Med. 26, 1033–1039 (2009)

 2

Objective: To study the effect of different daily doses of pioglitazone on glycemic control and weight gain in newly-
diagnosed type 2 diabetes mellitus (DM) patients.

Study design: Retrospective study

Study location: India

Patients: Recently-diagnosed (<24months) type 2 DM patients receiving oral therapy including pioglitazone.

Methods: A total of 237 patients, of which

77 received 7.5 mg/day of pioglitazone (Group A)
80 received 15 mg/day of pioglitazone (Group B) and
80 received 30 mg/day of pioglitazone (Group C)

Treatment period: 6 months

J Assoc Physicians India. 2015 Nov 1;63(11):36-9.
 Weight gain was
Greatest in Group C (2.72 kg), Intermediate
in Group B (1.62 kg) and Least in Group A
(0.88 kg).

There was no difference between HbA1c lowering in the three groups (P>0.05)

Pioglitazone when used at low doses (7.5mg/day) have similar

HbA1c reduction as 15mg or 30mg with less weight gain.

J Assoc Physicians India. 2015 Nov 1;63(11):36-9.

SUMMARY
 T2DM is a progressive disease with beta cell dysfunction and insulin resistance are
core defects.
 Triple drug combination therapy is a need of the hour in Indian T2DM patients due to
typical Indian phenotypes.
 Guidelines recommend use of triple drug combination therapy in T2DM patients with
HbA1c between ≥7.5 to 9%.
 Triple combination therapy mainly covers maximum aspects of Ominous octet in
T2DM management.
 Clinical evidence proves the efficacy, safety and tolerability of 7.5 mg pioglitazone
triple drugs combination regimen in patients with T2M.