Nama : Dr. Dra. Erna Kristin, MSi, Apt

Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia. Apothecaries Degree

Gadjah Mada University, Master degree

Gadjah Mada University, Doctorate degree at Faculty of Medicine, Gadjah Mada University

Appointed as staff of the Department of Clinical Pharmacology, Faculty of Medicine, Gadjah Mada

University, Yogyakarta, 1987-1992.

Appointed as staff of the Department of Pharmacology, Faculty of Medicine, Gadjah Mada

University, Yogyakarta, 1992-present.

Member of International Society of Pharmacoepidemiology (ISPE)

Member of International Society of Pharmacoeconomy and Research Outcome (ISPOR)

Member of The Indonesian Pharmacologist Association (IKAFI)

Member of Indonesian Pharmacist Association (IAI)

Member of Pesticide Working Group, Food and Drug Control

National Committee on Screening and Evaluation of the Safety of Medical Devices, Directorate

General of Drug and Food Control, Ministry of Health of Indonesia

National Committee on Screening and Evaluation of the Safety of Pesticide, Directorate General of

Drug and Food Control, Ministry of Health of Indonesia

National Committee on Screening and Evaluation of the Safety of Cosmeceutical, Directorate

General of Drug and Food Control

National Committee on Evaluation of Drug, Directorate General of Drug and Food Control

Peer Reviewer, Journal of Pharmacoepidemiology and Drug Safety

Peer Reviewer, Journal of Health Service Management

Peer Reviewer, Journal of Public Health

Curriculum vitae

Cost Effectiveness of Linagliptin

versus Sulfonylurea as An Add-on

Therapy to Metformin in Patients

with Type 2 Diabetes Mellitus DEPARTEMEN FARMAKOLOGI DAN TERAPI FK UGM

BOEHRINGER INGELHEIM

2

Backgrounds

Diabetes mellitus (DM) is a chronic disease causing around 1.6 million death in 2015 according to World Health Organization.

It is estimated that DM will be the seventh highest cause of death in 2030

Type 2 DM made up the 90% of all DM worldwide.

The prevalence of type 2 DM increases due to obesity and the lack of activity.

With time, DM may cause complications to the heart, vascular, eye, kidney, and nervous system

Research Question

What is the cost-effectiveness of linagliptin as an add-on therapy to metformin in patients with type 2 DM compared to sulfonylurea?

Objectives

The objective of this study was to evaluate the cost effectiveness of linagliptin compared to sulfonylurea as an add-on therapy to metformin in type 2 DM patients.

LITERATURE REVIEW

Clinical question

Is linagliptin as an add-on therapy to metforminmore effective in decreasing HbA1c compared

to sulfonylurea in type 2 DM patients?

Study type

Randomized controlled clinical trials (RCTs)

Parallel design

Compared the efficacy between Linagliptin and Sulfonylurea as add on Metformin treatment in patients with Diabetes

Subject type

Patients with diabetes tipe 2

Age > 18 years old

Appropriate control group (Sulfonylurea)

Add on Metformin treatment

Searching strategy

Database: Pubmed, EMBASSE

Key words : PICO

#1 “Linagliptin” (All Fields) AND “Sulfonylurea” (All Fields) AND "add on Metformin" (All fieds);

2# “diabetes” (MeSH Terms) OR “diabetes mellitus” (All Fields) OR “type 2diabetes” (All Fields);

3# HbA1C

Searching strategy

Limit search:

•Clinical Trial

•Publish in English

•Above 2000

•The full text can be accessed

Study selection

The studies must :

• Randomized

• Controlled clinical trials

• Comparing Linagliptin and Sulfonylurea as add on Metformin treatment in patients with diabetes

•Outcome: clinical outcome or HbA1C

Study selection

Quality assessment with Modified Jadad Score

Those studies of poor quality (Jadad score < 3) or involving other targeted drugs were excluded

Methodological quality of the trials was evaluated by modiffied Jadad score (range from 0 to 8) which contained randomization, masking, dropouts, and withdrawals.

Modified Jadad

Yes NoNot

described

Reported as randomized 1 0

Randomization is appropriate 1 -1

Double blinding 1 0

Double blinding is appropriate 1 -1

Withdrawal are reported 1 0

Method to report AE 1 0

Statistical analysis are described 1 0

Inclusion and exclusion are reported 1 0

Studies that

identifies (6)

Excluded because

combination, not randomized,

can not be obtained full test

Further evaluation with

modified Jadad Score (2)

Forst Galwitz

Reported as randomized Yes Yes

Randomization is appropriate No No

Double blinding Yes Yes

Double blinding is appropriate No No

Withdrawal are reported Yes Yes

Method to report AE Yes No

Statistical analysis are described Yes Yes

Inclusion and exclusion are reported Yes Yes

Critical appraisal

The quality of the study

Name of study Score JADADScore modified

JADAD

Gallwitz 4 6

Forst 3 5

Study description

Study Subjects Intervention Comparison Follow up

Galwitz Type 2 DM Linagliptin (776 subjects)

Glimepiride 1-4 mg (775 subjects)

104 weeks

Forst Type 2 DM Linagliptin (66 subjects)

Glimepiride 1-3 mg (65 subjects)

12 weeks

Study result

Study

HbA1C in

Linagliptin group

HbA1C in

Sulfonylurea

group

Other outcome

Gallwitz 7,7 7,7Fasting blood glucose

9,1 VS 9,2 (mmol/l)

Forst 8,5 8,2

0,51Fasting blood

glucose 10,5 VS 10,0

(mmol/l)

Dia

bet

es

Me

llitu

s P

atie

nts

(n =

12

49

)

Met + Linagliptin

N = 627

Retrieved

N = 377

Not retrieved

N = 250

Met + Sulfonylurea

N = 632

Retrieved

N = 357

Not retrieved

N = 275

DATA COLLECTION

RESULTS

Demographic characteristics

Characteristic

Treatment group

Linagliptin + Metformin Sulfonylurea + Metformin

% %

Sex

Male 90.9% 77.8%

Female 9.1% 22.2%

Age group (year)

30-39 0.0% 2.5%

40-49 22.7% 11.1%

50-59 40.9% 38.3%

60-69 36.4% 48.1%

Study location

RS A 45.5% 49.4%

RS B 54.5% 50.6%

Most patients in linagliptin and sulfonylurea group were males (> 75%) and most of them were ≥ 50 years old.

Clinical characteristics

CharacteristicsTreatment group

Linagliptin +

Metformin

SU + Metformin

% %

Type of treatment

Inpatient 40.9% 40.7%

Outpatient 95.5% 100.0%

Comorbidities

Yes 54.5% 45.7%

No 45.5% 54.3%

Number of comorbidities

1 36.4% 25.9%

2 18.2% 16.0%

3 0.0% 3.7%

4 0.0% 0.0%

Almost all patients received treatment as outpatients and almost half of the patients also received inpatient treatment. Comorbidities in both treatment groups were

slightly similar.

Clinical characteristics

CharacteristicsTreatment group

Linagliptin + Metformin SU + Metformin

% %

Type of comorbidities

Coronary heart diseases (IHD, ACS, arhytmia) 40.9% 37.0%

Atrial fibrillation 4.5% 2.5%

Peripheral vascular disease 0.0% 0.0%

Acute myocardial infarction 4.5% 7.4%

Stroke 9.1% 4.9%

CHF 13.6% 9.9%

History of amputation 0.0% 0.0%

Blindness 0.0% 3.7%

Renal failure 0.0% 3.7%

Hypertension 40.9% 37.0%

The distribution of type and proportion of each comorbidity were almost similar. Most comorbidities were related to heart diseases.

Comparison of clinical outcomes

Clinical Outcome Treatment group

Proportion of patients with

a decrease in HbA1c

Linagliptin + Metformin SU + Metformin

- % 50.00 46.91

- P value (Chi-square) 0.797

Delta of HbA1c value Linagliptin + Metformin SU + Metformin

- Mean 0.427 -0.067

- SD 2.202 1.761

- P value (T-test) 0.272

More patients in linagliptin group showed a decrease in HbA1c compared to sulfonylurea (50% vs 46.91%) although it was not statistically significant (p =

0.797). The change in HbA1c values between the start and the end of observations (delta) was larger in linagliptin group compared to sulfonylurea

group (0.427±2.202 versus -0.067±1.761), however, it was not statistically significant (p=0.272).

Comparison of adverse event

Adverse eventLina +

Met

SU +

Met

% %

Peripheral edema 0.0% 1.2%

TIA 0.0% 0.0%

Stroke 0.0% 1.2%

Non-fatal MI 9.1% 4.9%

Other MI 4.5% 4.9%

CV death 0.0% 0.0%

Fracture 0.0% 0.0%

Nausea 4.5% 2.5%

Vomiting 0.0% 0.0%

Hypoglycemia 63.6% 64.2%

Hypertension

- Patients with or without baseline hypertension who

still had hypertension or had a new onset of

hypertension

59.1% 61.7%

- Patients without baseline hypertension who had a

new onset of hypertension

36.4% 33.3%

there were no adverse events of TIA, cardiovascular (CV) death, fracture, and vomiting in both groups.

In terms of peripheral edema, stroke, non-fatal MI, and nausea, the linagliptin group showed better outcome compared to sulfonylurea.

The number of patients who experienced hypoglycemia was found slightly higher in sulfonylurea group than in linagliptin group (64.2% vs 63.6%).

The incidence of hypertension in patients receiving sulfonylurea was also slightly higher than in patientsreceiving linagliptin, however, the incidence of newly onset hypertension was more common in the linagliptin group than in the sulfonylurea group (36% vs 33.3%).

Comparison of cost spent

Treatment group Average cost

(IDR)

SD (IDR)

Linagliptin

- linaglitpin+metformin 19,870,463 22,502,611

Sulfonylurea

- sulfonylurea+metformin 17,618,189 32,974,287

The cost spent for patients who received linagliptin was a little higher compared to that spent on patients who received

sulfonylurea (IDR 19,870,463±22,502,611 vs IDR 17,618,189±32,974,287).

Proportion of each component

Component of cost

Treatment group

All Linagliptin All Sulfonylurea

Mean % Mean %

Administrative 452,376 2.3% 285,724 1.6%

Physician 3,121,772 15.7% 2,362,785 13.4%

Hospital stay 1,864,219 9.4% 3,320,285 18.8%

Radiology 183,954 0.9% 539,849 3.1%

Laboratory examination 1,904,235 9.6% 1,720,499 9.8%

Pathology examination - 0.0% 16,176 0.1%

Other additional examinations 578,479 2.9% 693,533 3.9%

DM treatment 628,875 3.2% 371,183 2.1%

Other drugs 5,398,318 27.2% 3,705,724 21.0%

Intravenous

catheterization/transfusion

52,356 0.3% 876,779 5.0%

Medical instrument 2,978,754 15.0% 859,865 4.9%

Surgery 377,778 1.9% 1,461,617 8.3%

Medical treatment 1,859,254 9.4% 950,976 5.4%

Non-physician medical staff 163,866 0.8% 33,573 0.2%

Rehabilitation 210,639 1.1% 419,620 2.4%

Nutrition 95,588 0.5% - 0.0%

Total 19,870,463 100.0% 17,618,189 100.0%

The cost of DM treatment with

linagliptin was slightly higher compared to

sulfonylurea.

However, several other components like hospital stay, radiology examination, intravenous

catheterization/transfusion. surgery, and rehabilitation were higher in the

sulfonylurea group.

Cost-effectiveness Ratio

Cost-effectiveness ratioTreatment group

Linagliptin+met SU+met

Cost (IDR) 19,870,463.21 17,618,189.29

Outcome (proportion of patients

who achieved a decrease in HbA1c)

50% 47%

Outcome (delta in HbA1c value

change)

0.427 -0.067

ICER per patient who experience a

decrease in HbA1c in a year

72,973,675

ICER per 1 unit of HbA1c decrease 4,559,818

Based on cost-effectiveness ratio calculation

linagliptin treatment led to similar clinical outcomes compared to sulfonylurea,

both in proportion of patients and in the difference in HbA1c level,

with additional cost needed in a year forlinagliptin to achieve a decrease in HbA1c (ICERs) were IDR 72.973.675 per patient

and IDR 4.559.818 per 1 unit HbA1c reduction (the difference of HbA1c values of all samples).

Discussion

• Systematic review showed that there was no difference in the achievement of HbA1c level between groups who receive linagliptinand sulfonylurea, while the adverse event of hypoglycemia in linagliptin occurred in lower proportion compared to sulfonylurea.

Systematic review on clinical effectiveness

• Based on main clinical outcome, that is, the proportion of patients who had a decrease in HbA1c and the values of HbA1c, cost and effectiveness diagram showed that linagliptin as add-on therapy to metformin in DM patients compared to sulfonylurea showed a similar clinical outcome/ effectiveness, but it required a slightly higher cost. Additional cost needed for a year to achieve a decrease in HbA1c (ICERs) were IDR 72.973.675 per patient and IDR 4.559.818 per 1 unit HbA1c reduction (%).

Economical evaluation

Summary

Addition of linagliptin as add-on therapy of metformin in DM patients compared to sulfonylurea resulted similar clinical outcomes/ effectiveness but required a slightly higher cost.

Additional cost needed for a year to achieve a decrease in HbA1c (ICERs) were IDR 72,973,675 per patient andIDR 4,559,818 per 1 unit HbA1c reduction (%). This ICER value was less than 1 GDP per Indonesian capita.

These results provide information on economic evidence that can be an input for

the choice of treatment for DM patients.

36