Drive success from the start in

diabetes management: focus on

Linagliptin

A. MAKBUL AMAN MANSYUR

Devision of Endocrine and Metabolism, Department of Internal Medicine
Faculty of Medicine Hasanuddin University /
RS. UNHAS / RS Dr. Wahidin Sudirohusodo / RS.Grestelina /
RS.Akademis / RS. Ibnu Sina Makassar

TRA-TRD/034/FEB17/FY
 Diabetes related facts: huge and growing problem

The prevalence of diabetes 2015

One in 11 adults has diabetes

One in two adults with
Diabetes is undiagnoses
2040

One in 10 adults will have diabetes

IDF Diabetes Atlas 7th edition 2015. International Diabetes Federation
 The number of patients with diabetes
worldwide is expected to increase from 382
million in 2013 to 592 million in 2035
Country/ 2013 Country/ 2035
Territory Millions Territory Millions
China 98.4 China 142.7
India 65.1 India 109.0
United States of America 24.4 United States of America 29.7

Brazil 11.9 Brazil 19.2

Russian Federation 10.9 Mexico 15.7

Mexico 8.7 Indonesia 65%

IN JUST 22 YEARS
14.1
Indonesia 8.5 Egypt 13.1
Germany 7.6 Pakistan 12.8
Egypt 7.5 Turkey 11.8
Japan 7.2 Russian Federation 11.2

IDF Diabetes Atlas 6th edition. @International Diabetes Federation

 Every 10 seconds a person dies from diabetes
related complications
Diabetes significantly increases the risk of…

…stroke
…heart disease by to more than 2–4x
2–4x* the general population*

In 2005 – 2008: 655,000 In 2008: In 2006:

patients had advance 202,290 people with end 65,700 patients will have
diabetic retinopathy that stage kidney disease living an amputation*
could lead severe loss of on chronic dialysis*
vision

CDC 2011 National Diabetes Fact Sheet. http://www.cdc.gov/diabetes/pubs/estimates11.htm#12

 Approximately 40% of T2DM patients have renal
complications

• Typical progression of CKD†1

CKD
2
CKD CKD
1 3

CKD
4–5

No
CKD

* No signs of kidney damage

** Albuminuria – kidney damage

†Based on data from 1462 patients aged ≥20 years with T2DM who participated in the Fourth National Health and Nutrition Examination Survey .
(NHANES IV) in the years 1999 through 2004
1. Koro CE, et al. Clin Ther 2009;31:2608–17.
 Southeast Asia has one of the highest rates of end
stage renal disease (ESRD) in the world
Consequently, CKD in diabetes patient is associated with considerable morbidity and
cardiovascular related mortality

Chow F Cc, et all. J Diabetes Invest Doi:10.1111/jdi.12006, 2012.

 Risk for CV events are greater when both
Incidence per 100 patient-years diabetes and nephropathy are present

* CHF=congestive heart failure; AMI=acute myocardial infarction; CVA/TIA=cerebrovascular accident/transient ischemic attack;
PVD=peripheral vascular disease; ASVD=atherosclerotic vascular disease. aASVD was defined as the first occurrence of AMI, CVD/TIA, or PVD.
Foley RN, et al. J Am Soc Nephrol 2005;16:489–95.
 Effective control of T2D reduces risk of complications

1% decrease in HbA1c correlates with reduction in risk of…

Microvascular Peripheral Myocardial Stroke Heart Cataract Death
disease vascular failure extraction related to
disorders infarction diabetes
0
–37% –43% –14% –12% –16% –19% –21%
–15
Relative Risk (%)

p = 0.035 p = 0.016 p < 0.0001 p < 0.0001

–30

–45
p < 0.0001

Prospective observational analysis of UKPDS35 patients (n=4585, incidence analysis; n=3642, relative risk analysis).
Median 10.0 years of follow-up.

Adapted from Stratton IM, et al. BMJ. 2000;321:405–412.

 And yet…., many patients not have good
glycemic control
DiabCare Indonesia 2008 illustrated the need for more
intensive treatment to decrease FPG and PPG
n: 1.823 patients with diabetes The burden
mg/dl mg/dl
220 208 68% Have high
A1c>7%
200
180
160
mg/dl 32%
glycemic Control Level

144 140
140
120
100
100
80
60
A1c:
40
20
<7.0%
0

FPG (mg/dl) PPG (mg/dl)

Indonesia2

DiabCare 20081 PERKENI Guidelines

1. Soewondo P, et al. Diabcare Indonesia 2008, 2. Soewondo P, et al. Globalization and health 2013.
 Barriers to achieve glycemic goals

Disease Factors Patient

• Chronic condition • Non-adherence
• Progressive condition • Hypoglycemia
• Weight gain

Provider
• Clinical inertia
– Recognition of the problem but
failure to act or
– Failure to initiate or intensify
therapy appropriately
1. Liebl A, et al. Diabetologia. 2002
2. Harris SB, et al. Diabetes Res Clin Pract. 2005
3. Alvarez Guisasola F, et al. Diab Obes Metab. 2008
 11

Type 2 diabetes is a progressive disease

Progression of Type 2 Diabetes

Insulin resistance

Hepatic glucose
production

Insulin level

Beta-cell function

4–7 years Postprandial

glucose

Fasting plasma
glucose

Development of Microvascular Complications

Development of Macrovascular Complications

Impaired Glucose Tolerance Diabetes

Diabetes Diagnosis

Conceptual representation adapted from Ramlo-Halsted BA, Edelman SV. Prim Care 1999;26(4):771–789. © 1999 Elsevier
 Barriers to achieve glycemic goals

Disease Factors Patient

• Chronic condition • Non-adherence
• Progressive condition • Hypoglycemia
• Weight gain

Provider
• Clinical inertia
– Recognition of the problem but
failure to act or
– Failure to initiate or intensify
therapy appropriately
1. Liebl A, et al. Diabetologia. 2002
2. Harris SB, et al. Diabetes Res Clin Pract. 2005
3. Alvarez Guisasola F, et al. Diab Obes Metab. 2008
 Adherence to Medicine in Diabetes
• Most people with type 2 diabetes are prescribed multiple
medicines to improve metabolic control; lower serum glucose,
cholesterol and blood pressure.1,2

• is affected by the frequency of doses and the number of

medicines prescribed.3

• Once daily doses of OADs were associated with better adher-

ence than multiple daily doses.3,4

1.Morris AD. Int J Clin Pract Suppl 2001;(121):32-5.

2. Rosenstock J. Drugs Aging 2001;18:31-44.

3. Paes AH, et al.. Diabetes Care 1997;20:1512-17.

4. Donnan PT, et al. Diabet Med 2002;19:279-84.

 Non adherence to treatment leads to poor glycemic
control and outcome

28.9% Prevalence of non adherence* to oral glucose

lowering medication1

0.16%
HbA1c decrease for every 10% increase in
treatment adherence2

2.5 x -fold increase in risk of hospitalisation

associated with treatment non adherence1

* Nonadherence defined as medication possession ratio (MPR) < 80%.

1. Lau D, et al. Diabetes Care. 2004;27:2149–2153; 2. Schectman J, et al. Diabetes Care. 2002;25:1015–1021.
 Hypoglycaemia - Why is this important?

• Hypoglycaemia is associated with increased risk of death, especially in

patients with coronary artery disease or acute myocardial infarction1
• Up to 38% of people with type 2 diabetes experience symptomatic
hypoglycaemia2
o It is believed that many incidences of hypoglycemia go unreported to
healthcare professionals3
• Hypoglycaemia results in reduced quality of life, treatment satisfaction
and therapy adherence2,4

• Hypoglycaemia is associated with cognitive dysfunction and delayed

recovery in the elderly5

• Hypoglycaemia is associated with increased anxiety6

1. Nordin C. Diabetologia.2010; 53: 1552–61; 2. Alvarez Guisasola F, et al. Diab Obes Metab. 2008; 10 Suppl 1: 25−32
3. Leiter LA, et al. Can J Diab. 2005; 29: 186−92; 4. Jermendy G, et al. Health Qual Life Outcomes. 2008; 6: 88
5. Zammitt N, et al. Diabetes. 2008; 57: 732−6 ; 6. Labad J, et al. Diabetologia. 2010; 53: 467−71
 Risk of hypoglycaemia increases as
therapy intensifies

Wright et al. J Diabetes Complicat 2006;20:395–401 (UKPDS 73)

 Burden of weight gain

• Weight gain can be a barrier to intensifying treatment1, 2

• Approximately 50% of patients are very anxious about
their weight3
• Weight gain results in increased cardiovascular risk factors
• weight gain/obesity is associated with hyperlipidaemia,
hypertension, heart disease and stroke4
• Increased body mass index (BMI) has been associated with an
increased risk of morbidity and mortality from coronary heart
disease (CHD)5

1. Davis. Int J Obesity 2004;28(Suppl. 2):S14–S22. 2. Korytkowski. Int J Obesity 2002;26(Suppl. 3):18–24. 3. Alberti. Pract Diab Int 2002;19:22–24. 4. WHO obesity fact sheet.
www.who.int. 5.Fava SL, et al. Arteriosclerosis, Thrombosis and Vascular Biology. 1996
 Most therapies also result in weight gain over time

UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355:2427–43
 Relationship between BMI and cardiovascular
disease mortality

3,0

2,6 Men
Relative Risk of Death

2,2 Women
1,8

1,4

1,0
Lean Overweight Obese
0,6
<18.5 18.5 20.5 22.0 23.5 25.0 26.5 28.0 30.0 32.0 35.0 >40.0
– – – – – – – – – –
20.4 21.9 23.4 24.9 26.4 27.9 29.9 31.9 34.9 39.9

Body Mass index

Calle et al. N Engl J Med 1999;341:1097.
 Barriers to achieve glycemic goals

Disease Factors Patient

• Chronic condition • Non-adherence
• Progressive condition • Hypoglycemia
• Weight gain

Provider
• Clinical inertia
– Recognition of the problem but
failure to act or
– Failure to initiate or intensify
therapy appropriately
1. Liebl A, et al. Diabetologia. 2002
2. Harris SB, et al. Diabetes Res Clin Pract. 2005
3. Alvarez Guisasola F, et al. Diab Obes Metab. 2008
Clinical Inertia Result in Inadequate in HbA1c
Control
 Expectations for new agents
and/or new strategies

 Consistent efficacy across broad range of Type 2 Diabetes

Mellitus
 Lowering HbA1c to targets as close to normal as possible
without unacceptable hypoglycaemia in selected
populations
 Not increasing cardiovascular event

 Lowering HbA1c without weight gain

 Not increasing risk of target organ damage (eg. kidney)

DPP-4 Inhibitors and Incretin Mimetics Address a
Core Defect in A Unique Way

Inadequate Acute Chronic

Glucose Insulin glucagon
absorption β-cell β-cell
resistance suppression dysfunction insufficiency

α-glucosidase TZDs2 sulphonylurea1

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–S18; 4. Garber AJ. Diabetes Care. 2011;34(Suppl 2):S258–S263.
 DPP-4 Inhibitors and incretin mimetics address a
core defect in a unique way
Inadequate Acute Chronic
Glucose Insulin glucagon
absorption β-cell β-cell
resistance suppression dysfunction insufficiency

DPP-4 DPP-4
inhibitors and inhibitors and
incretin incretin
α-glucosidase TZDs2 mimetics 3 sulphonylurea1 mimetics4
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–S18; 4. Garber AJ. Diabetes Care. 2011;34(Suppl 2):S258–S263.
 Benefits and limitations of T2DM treatment options

DPP-4 Sulfonil- GLP-1

  Biguanide Glinide TZD AGI Insulin
inhibitor urea agonist

FPG + ++ ++ + ++ Neutral + +++

PPG ++ ++ + ++ + ++ +++ +++

Level of Risk

Moderate to
Hypoglycemia Neutral Moderate Neutral Mild Neutral Neutral Neutral
severe

Mild to
Weight gain Neutral Mild Benefit Mild Moderate Neutral Benefit
Moderate

Contraindicated Contraindicated
CV event Neutral Neutral Neutral Neutral Neutral Neutral
in CHF in CHF

Drug-drug Modera-
Neutral Moderate Neutral Neutral Neutral Neutral Neutral
interaction te

Adapted from: Rodbard HW, et al. Endocr Pract. 2009;15:540-559.

 Algoritme pengelolaan DM Tipe 2 di Indonesia
KONSENSUS PERKENI 2015

Modifikasi pola hidup sehat

HbA1c ≥ 7.5% HbA1c ≥ 9.0%

HbA1c < 7.5%
Gejala (-) Gejala (+)
Monoterapi* dengan salah Kombinasi 2 obat* dengan Kombinasi 2 obat
satu obat di bawah ini mekanisme kerja yang Kombinasi 3 obat
berbeda Kombinasi 3 obat Insulin ± obat jenis lain

Metformin atau obat lini pertama yang lain +

• Metformin • Agonis GLP-1 • Agonis GLP-1
Metformin atau obat lini pertama yang lain +

• Agonis GLP-1 • Penghambat DPP-IV • Penghambat DPP-IV

Obat lini kedua +

• Penghambat DPP-IV • Tiazolidindion • Tiazolidindion
• • Mulai atau intensifikasi Insulin
Penghambat • Penghambat SGLT-2 Penghambat SGLT-2
Glukosidase Alfa • Insulin Basal • Insulin Basal
• •
Keterangan
Penghambat SGLT-2** • SU/Glinid Kolsevelam**
• Tiazolidindion • Kolsevelam** • Bromokriptin-QR *Obat yang terdaftar, pemilihan dan
• Sulfonilurea • Bromokriptin-QR • Penghambat penggunaannya disarankan
• Glinid • Penghambat Glukosidase Alfa mempertimbangkan faktor keuntungan,
Glukosidase Alfa kerugian biaya, dan ketersediaan sesuai
Jika HbAc1 > 6.4% tabel 11
Jika belum memenuhi sasaran
dalam 3 bulan tambahan Jika belum memenuhi
dalam 3 bulan, mulai terapi insulin ** Kolsevelam belum tersedia di Indonesia
sasaran dalam 3 bulan, masuk
obat ke 2 (kombinasi 2
ke kombinasi 3 obat
atau intensifikasi terapi insulin Bromokriptin QR umumnya digunakan pada
obat)
terapi tumor hipofisis

Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia. 2015.

abcd
 ADA/EASD 2015 – guidelines for managing hyperglycaemia
Monotherapy Metformin
Efficacy (↓HbA1c) High
Hypo risk Low risk
Weight Neutral/loss
Side effects GI/lactic acidosis
Cost Low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any
specific preference – choice dependent on variety of patients- and disease-specific factors

Metformin + Metformin + Metformin + Metformin + Metformin + Metformin +

Dual Therapy SU TZD DPP-4i SGLT2i GLP-1 RA Insulin(basal)
Efficacy (↓HbA1c) High High Intermediate Intermediate High Highest
Moderate risk Low risk Low risk Low risk Low risk High risk
Hypo risk
Gain Gain Neutral Loss Loss Gain
Weight
Hypoglycaemia Edema.HF,FXs Rare GU, dehydration GI Hypoglycaemia
Side effects
Low High High High High Variable
Cost
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference – choice
dependent on variety of patients- and disease-specific factors
Metformin + Metformin + Metformin + Metformin + Metformin + Metformin +
SU + TZD + DPP-4i+ +
DPP-4i SGLT2i + GLP-1 RA + + Insulin +
TZD SU SU SU SU TZD

OR DPP-4i OR DPP-4i OR TZD OR TZD OR TZD OR DPP-4i

OR SGLT2-i OR SGLT2i OR SGLT2i OR DPP4i OR Insulin OR SGLT2i

Triple Therapy OR GLP-1 RA OR GLP-1 RA OR
OR Insulin Insulin OR GLP-1 RA
OR Insulin OR Insulin

If HbA1c target not achieved after ~3 months of triple therap and patients (1) on oral combination, move to injectable; (2) on GLP-1 RA, add basal insulin; or (3)
on optimally treated basal insulin, add GLP-1 RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2i
Combination
injectable
therapy Basal insulin + mealtime insulin or GLP-1 RA

Adapted from Inzucchi S, et al. Diabetes Care 2015

 Dipeptidyl Peptidase-IV inhibitor
• The concept is to allow the endogenous GLP-1 to remain in
circulation for a longer period. (raise GLP-1 levels 2- to 3-fold ).
• DPP-IV inhibitors are oral, rather than injectable.
• associated with a low incidence of hypoglycemia or gastrointestinal
side effects and have a remarkable low incidence of adverse
reactions.
• Preliminary long-term studies suggest a durable effect on glycemia
and improvement in some parameters of beta-cell function.
• They are indicated as monotherapy and in combination with metformin,
thiazolidinediones and insulin.
• They appear to be weight neutral
 Why DPP-4 Inhibitors?
• Excellent in patients with mild hyperglycemia requiring insulin secretagogue
• Efficacy: Lower HbA1C by 0.8% . Primarily lowers postprandial glucose levels but has
also been shown to reduce fasting plasma glucose
• No contraindication in heart failure and no risk of edema or lactic acidosis
• Can be used in renal insufficiency without risk of hypoglycemia or lactic acidosis
• Very minimal side effects, No weight gain
• Immediate activity without causing hypoglycemia
• Most effective when used with metformin
• Adverse effects: well tolerated, no hypoglycemia when used as monotherapy. More
recently reported to be associated with pancreatitis, ?causative?
 DPP-4 Inhibitors:
Selectivity for DPP-4 compared to QPP*/DPP-2, DPP-8 &DPP-9
Selectivity for DPP-4 compared to the DPP gene family (QPP/DPP-2, DPP-8 and DPP-9)

QPP*/DPP-2 DPP-8 DPP-9

Linagliptin > 100,000 40,000 > 10,000

Sitagliptin > 5,500 > 2,660 > 5,500

Vildagliptin > 100,000 270 32

Saxagliptin > 50,000 390 77

Alogliptin > 14,000 > 14,000 > 14,000

* Quiescent cell proline dipeptidase

Deacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.
 Linagliptin - Trajenta
• May 2, 2011 The FDA approved linagliptin –
Trajenta the newest of the DPP-4 inhibitors by
Boehringer Ingelheim and Lilly for the treatment
of Type 2 diabetes
– FDA approved either as monotherapy or in
combination with metformin, glimepiride or
pioglitazone
– Linagliptin is primary eliminated by non-renal
excretion and does not accumulate with mild to
moderate renal dysfunction
 Linagliptin – Mechanism of action

Linagliptin

http://cdn.intechweb.org/pdfs/21462.pdf access on 05.03.2015

 DPP IV inhibitors Excretion Route*

Share of renal excretion No dose adjustment

Linagliptin 1 5% and/or no additional drug
monitoring required1
All other DPP-4 inhibitors
Sitagliptin2,3 87%
are primarily excreted via
the kidneys
Vildagliptin4,5 85%
They all require dose-
adjustment, or are not
75% recommended in patients
Saxagliptin6
with renal impairment.
Drug-related kidney
monitoring may also be
required
* of currently globally approved DPP-4 inhibitors
Data from multiple trials, includes metabolites and unchanged drug; excretion after single dose administration of [14C] labeled drug

1. Trajenta Local Product Information 2014.

2. Vincent SH, et al. Drug Metab Dispos. 2007;35(4): 533–538
3. Sitagliptin Prescribing Information 2015
4. He H, et al. Drug Metab. Dispos.2009 37(3):545–554
5. Vildagliptin Prescribing Information 2014
6. Saxagliptin Prescribing Information 2015
 No dose adjustment: Linagliptin is the only DPP-4 inhibitor
that can be given in full dose even in patients with renal
impairment
exposure

in exposure
Fold increase in exposure
renal

normal renal
relative to normal renal

to normal
function
function

function
Fold increase in
relative to
relative
Fold
Fold

(n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6)
Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 on HD
(mL/min) Renal impairment status (mL/min) Renal impairment status
exposure
Fold increase in exposure
renal
relative to normal renal

Fold increase in exposure

relative to normal renal
function

function
Fold

(n=8) (n=8) (n=8) (n=7) (n=8)

Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD
Renal impairment status
(mL/min) Renal impairment status

ESRD = end-stage renal disease; HD = Haemodialysis; * Estimated creatinine clearance values were calculated using the Cockcroft-Gault formula

Source: Graefe-Mody U, et al. Diabetes, Obes Metab. 2011; 13(10): 939 - 946
2
Geometric mean ratios fet al.or saxagliptin were calculated from the geometric mean data reported by Boulton et al; 90% confidence intervals are not available from that publications.
3
Numbers of patients, 90% confidence intervals and definitions of renal impairment status according to creatinine clearance are not available for the vildagliptin study.
 Prescribing characteristics of DPP-4 inhibitors

Renal Impairment* Hepatic Impairment

Inhibitor

Linagliptin     
Not recommended (EU) Not recommended (EU)
Sitagliptin  ½ dose (US)1 ¼ dose (US)1  Not recommended1

Vildagliptin2  Not recommended1 Not recommended1 Not recommended Not recommended

½ dose (EU) ½ dose (use with caution) 

Saxagliptin3  ½ dose (US)1
not recommended in ESRD (EU)
(Moderate: use with Not recommended1
½ dose (US) 1
caution)

Alogliptin **  ½ dose ¼ dose  Not recommended1

CrCl = Creatinine clearance; ESRD = end-stage renal disease

•Assessment of renal function recommended prior to initiation of treatment and periodically thereafter
** Alogliptin is not available in Indonesia
1. Not studied/no clinical experience
2. Assessment of hepatic function recommended prior to initiation of vildagliptin and periodically thereafter
3. Dose reduction (2.5 mg) when saxagliptin co-administered with strong CYP450 3A4/5 inhibitors (e.g. ketoconazole)
Adapted from Deacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.
 Linagliptin clinical profile

Efficacy Safety & Tolerability

Overall safety profile similar to placebo:
Meaningful and reliable efficacy • No clinically relevant weight gain
across complete range of oral • Very low risk of hypoglycaemia
diabetes therapies
Most common adverse
reaction: nasopharyngitis
Durable efficacy in
longer term treatment Not associated with
up to 2 years an increase in CV risk

Primarily excreted
One dose fits all
via bile & gut

Once-daily Renal excretion = 5%

With or without food

No dose adjustment in
Convenience renal or hepatic impairment
 Linagliptin is well tolerated

(2)
Linagliptin Placebo
Organ-specific adverse
n 2,523 1,049
event (AE) rate for AE Headache 2.9% 3.1%
previously associated
with the DPP-4 inhibitor
class1 Upper respiratory tract 3.3% 4.9%
infection
Pancreatitis: Nasopharyngitis 5.9% 5.1%
1 per 538 person years
versus zero in 433
person years for Hepatic enzyme increase 0.1% 0.1%
comparator1
Serum creatinine increase 0.0% 0.1%

Urinary tract infection 2.2% 2.7%

Blood and lymphatic

1.0% 1.2%
system disorders
Hypersensitivity 0.1% 0.1%

Schernthaner G, et al. Diab, Obes, Metab. 2012; 14(5): 470- 478

Natural Progression of Type 2 Diabetes May Result in
the Need for Combination Therapy

– Maintaining glycemic control in patients with type 2

diabetes can be challenging due to the natural progression
of the disease1
– The natural progression of type 2 diabetes may require
multiple agents with comprehensive mechanisms of
actions1
– An agent of one therapeutic category may be added to an
agent of a different therapeutic category, with the
following exception2:
• Agents with similar mechanisms of action may not be effective in
combination
1. Campbell IW. Diabetes. 2000;7(10):625-
631.
2. Kuritzky L et al. Diabetes Ther. 2011;
2(3):162-177.
 Treating early and effectively with
combination therapies
Conservative vs proactive management in glucose management
OAD +
multiple daily
Diet & OAD OAD OAD OAD + insulin
exercise monotherapy up-titration combination basal insulin injections

10

A1C, 9
%
8
Mean A1C
of patients
7

6 Early use of combination of submaximal doses of

Duration of diabetes agents can improve glycemic control without
significantly increasing side-effects
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
 Improves adherence in T2DM
with single pill combination
Texas Medicaid Database
Patients with Type 2 Diabetes switched from dual therapy
to SPC therapy versus remaining on dual therapy

Therapies studied were branded or generic SPCs of metformin/glyburide, metformin/rosiglitazone and

metformin/glipizide (or analogous dual therapies)
FC,
FC, free
free combination;
combination; MPR,
MPR, medication
medication possession
possession ratio
ratio (proportion
(proportion ofof days
days that
that patients
patients were
were in
in possession
possession of
of their
their medication);
medication);
SPC,
SPC, single-pill
single-pill combination.
combination.
SPC
SPC users:
users: 7570;
7570; dual-therapy
dual-therapy users:
users: 14,762.
14,762.
Cheong
Cheong C,
C, et
et al.
al. Clin
Clin Ther.
Ther. 2008;30:1893–1907.
2008;30:1893–1907.
 COMBINATION THERAPY WITH OHO
• Early combination is mandatory
• Combine OHO with different site action
• Benefit for control side effect : Low dose and Optimum action
Class Added Agent Available as
Linagliptin Trajenta Duo
Metformin + DPP-4 inhibitor Saxagliptin Kombiglyze XR
Sitagliptin Janumet
Metformin + glinide Repaglinide Prandimet
Glipizide Metaglip and generic
Metformin + sulfonylurea
Glyburide Glucovance and generic
Pioglitazone ACTOplus Met
Metformin + thiazolidinedione
Rosiglitazone* Avandamet
Pioglitazone Duetact
Thiazolidinedione + sulfonylurea
Rosiglitazone* Avandaryl

Remember that any two *Use

medications together is
restricted due to increased risk of
better than anymyocardial
one alone!!!!
infarction (MI)
 Synergistic effects of Metformin and Linagliptin

Metformin Linagliptin

AMPK  GLP-1  GLP-1 DPP4

activation production Gut Inactivation inhibition

 GIP

Pancreas
Liver
 GLP-1

 Insulin  Glucagon
 Gluconeogensis
(Glucose dependent)
 Hyperglycaemia
(fasting and post-prandial
AMPK: AMP activated protein kinase; DPP4: Dipeptidyl peptidase; GIP: Glucose-dependent insulinotropic polypeptide; GLP-1:
Glucagon-like peptide 1
Source: Scheen AJ. Expert Opin Drug Metab Toxicol. 2013;9:363–377.
 Metformin + Linagliptin: Combinations of oral glucose lowering
agents with complementary mechanisms of action

Target site Action Metformin Linagliptin

Pancreatic β-cell
Enhances glucose-dependent insulin
secretion 
Pancreatic α-cell Suppresses glucagon secretion 
Lowers hepatic glucose production
 
Improves insulin resistance

Safety and
Low risk of hypoglycaemia
 
tolerability
No additional weight gain
 
Drucker DJ, Nauck MA. Lancet. 2006;368:1696–1705.
Del Prato S, et al. Int J Clin Pract. 2005; 59:1345–1355.
Inzucchi SE. JAMA. 2002;287:360–372.
 Comparable efficacy vs. Glimepiride and sustain for
104 weeks of treatment

Mean (± SE) of HbA1c in Percent Linagliptin Glimepiride

7.5

7.0
-0.6
6.5
-0.6

6.0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100105
Treatment duration Weeks
Completers cohort: Linagliptin n = 233, glimepiride n = 271
Mean baseline HbA1c: 7.2% (linagliptin), 7.3% (glimepiride)

Completers cohort (CC) post-hoc analysis: All patients who completed the full 104 weeks on treatment in the FAS without important
protocol violation that did not receive rescue medication and did achieve defined HbA1c goals as described previously 2. All observed
cases were included.
1 Model includes treatment, baseline HbA1c and number of prior OADs
2 As described previously by Seck et al. Int J Clin Pract 2010; 64: 562-576
Source: Gallwitz B, et al. Lancet. 2012; 380 (9840): 475-83
 Lower incidence of hypoglycaemia and significant relative
weight loss with linagliptin compared to glimepiride

Incidence of hypoglycaemia Weight change (kg)

Linagliptin
Glimepiride

2.0
1.5
+1.3
1.0
79% 0.5
0
12 28 52 78 104
-0.5 weeks

-1.0
-1.5 -1.4
-2.0 p<0.0001
-2.7

Double blind, glimepirirde-controlled study. Superiority of Trajenta vs glimepirirde in incidence of hypoglycaemic events and body weight change
from baseline (Full analysis set)

Gallwitz B, et al. Lancet. 2012

 Early combination of Linagliptin-Metformin reduce
HbA1c up to 3.7% in poorly controlled patients
Randomized arm1 (placebo-corrected), Week 24 Open-labelarm2

Lin 2.5 BID + Lin 2.5 BID + Lin 2.5 BID +

Met 500 mg Met 1,000 mg Met 500 mg Met 1,000 mg Met 1,000 mg
BID BID BID BID BID

Baseline HbA1c, % 8.7 8.5 8.7 8.7 11.8

Patients, n 141 138 137 140 66
0

-0.5 -0.8
-1.2 -1.3
Change in HbA1c from

-1.0
-1.7
-1.0
baseline, %

-1.5
***
-3.7 -2.0

-2.0 ***
-3.0
-3.0

-3.5 Reduction HbA1c up to 3.7% in poorly -4.0

controlled patients
LIN, linagliptin; MET, metformin.
*** p < 0.0001, combination therapy versus respective monotherapy.
1. Randomized arm: mean (SE); full analysis set, last observation carried forward. 2. Open-label arm in
patients with poor glycemic control: mean (SE); full analysis set, observed cases (n = 48).
Adapted from Haak T, et al. Diab Obes Metab. 2012;14:565–574.
 Similar efficacy of Linagliptin
2,5 mg BID vs 5 mg QD in combination with Metformin

Ross SA et al. Curr Med Res Opin 2012; 28(9): 1-10

 Incidence of hypoglycaemia
Low with both Linagliptin 2.5 mg BID and 5 mg QD
(in combination with metformin) and similar to placebo

Investigator-defined hypoglycemia†
Patients with ≥ 1 event (% treated set)

Linagliptin 2.5 mg BID Linagliptin 5 mg QD Placebo

+ metformin + metformin + metformin
≥ 1 event (%)
Patients with

2.3*

3.1* 0.9*

*There were no reported cases of severe hypoglycaemia (event requiring assistance of another person to actively administer carbohydrate, glucagon, or resuscitative actions).
†Confirmed plasma glucose concentration ≤ 70 mg/dL (3.9 mmol/L).
 Summary

• Diabetes is difficult to control due to its barrier in disease condition,

patients, and provider.
• As patient with type 2 diabetes develop complication (including renal
impairment), renal function should be considered when choosing an
antidiabetic therapy.
• Linagliptin has an unique pharmacological profile that shows good
tolerability in renal and hepatic impaired type 2 DM patient, similar efficacy
to Sulfonilurea with low risk of hypoglycemia and weight neutral.
• Early combination of Linagliptin + Metformin result in significant HbA1c
reduction up to 3.7% in poorly controlled patients.