A. RINGKASAN KASUS

Seorang laki-laki berusia 56 tahun mengalami kesemutan, ngilu, dan mata

kabur hingga sejak 1,5 tahun yg lalu. Keluhan disertai penurunan berat badan

sebanyak 5 kg. Pasien juga mengeluhkan sering buang air kecil. GDS pasien saat

pertama kali di periksa 1,5 tahun yang lalu 483 mg/dl. GDS seminggu yang lalu 180

mg/dl. Pasien merasakan keluhan kesemutan dan ngilu memperberat saat

melakukan aktivitas, dan mata kabur memperberat saat gula darah meningkat. Saat

dilakukan istirahat keluhan agak berkurang. Pasien sudah kedokter dan sudah diberi

obat metformin dan vitamin dari puskesmas. Dengan pemberian obat-obat tersebut

keluhan pasien berkurang dan kadar gula darah terkontrol.

B. ANALISIS PICO

PERTANYAAN JAWABAN

Patient Seorang laki-laki 56 th penderita DM tipe 2 dengan GDS 180 mg/dl

Intervention Metformin

Comparison Liraglutide di kombinasi dengan metformin

Outcome Kombinasi Liraglutide dengan Metformin dapat menurunkan KGD

The well-built clinical question : Apakah Kombinasi Liraglutide dengan Metformin

lebih efektif dalam menurunkan KGD?

C. ANALISIS CONSORT

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PAPER SECTIONAnd topic

Item

Descriptor Reported onPage #

Content

TITLE & ABSTRACT

1 How participants were allocated to interventions (e.g., "random allocation", "randomized", or "randomly assigned").

2046 Liraglutide vs insulin glargine and placebo in combinationwith metformin and sulfonylurea therapy in type 2 diabetesmellitus (LEAD-5 met+SU): a randomised controlled trial & Methods This randomised (using a telephone or web-basedrandomisation system), parallel-group, controlled 26 weektrial of 581 patients with type 2 diabetes mellitus on priormonotherapy (HbA1c 7.5–10%) and combination therapy(7.0–10%) was conducted in 107 centres in 17 countries.

Liraglutide vs insulin glargine dan placebo dalam kombinasi dengan metformin dan terapi sulfonilurea pada Diabetes mellitus tipe 2. Metode secara acak (menggunakan telepon atau web), kelompok paralel, 26 minggu pengendalian percobaan dari 581 pasien dengan diabetes mellitus tipe 2 yang terlebih dahulu menerima monoterapi (HbA1C 7.5-10%) dan terapi kombinasi (7.0-10%) dilakukan di 107 pusat di 17 negara.

INTRODUCTION

Background

2 Scientific background and explanation of rationale.

2047 Type 2 diabetes mellitus is a progressive multi-systemdisease in which individuals exhibit varying degrees ofdeclining beta cell function, insulin resistance and afailure to suppress postprandial glucagon secretion.

Currently available therapiesdo not adequately control glycaemia in the long term as

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they do not address the issue of declining beta cellfunction and do not impact positively on weight orcardiovascular concerns associated with the disease.

Diabetes melitus tipe 2 adalah penyakit multi-sistem progresive dimana individu menunjukkan berbagai tingkat penurunan fungsi sel beta, resistensi insulin, dan kegagalan untuk menekan sekresi glukagon postprandial.Saat ini tersedia terapi yang tidak cukup kuat mengontrol glikemi jangka panjang, masalah penurunan fungsi sel beta, dan masalah kardiovaskuler terkait penyakit.

METHODSParticipant

s

3 Eligibility criteria for participants and the settings and locations where the data were collected.

2048 The 581 randomised patients in this multicentre (107 sites),multinational (17 countries) trial were 18–80 years old,with type 2 diabetes treated with oral glucose-loweringdrugs (OGLAs) (94–95% combination therapy) (Table 1)for at least 3 months before screening. General inclusioncriteria included: HbA1c level of 7.5–10% if on OGLAmonotherapy or 7–10% if on OGLA combination therapy,and BMI≤45kg/m2.

Pengacakan pada sel pasien di 107 pusat di 17 negara , usia 18-80 tahun dengan diabetes melitus tipe 2 dengan oral glucose-lowering drugs (OGLAs) (94-95% terapi kombinasi) (tabel 1) selama 3 bulan sebelum pemeriksaan lapangan. Inklusi umum kriteria seperti tingkat Hb A1C 7,5-10% jika OGLA monoterapi 7-10% atau kombinasi dan BMI ≤ 45kg/m2.

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Interventions

4 Precise details of the interventions intended for each group and how and when they were actually administered.

2048 Patients were randomly allocated to three interventions(2:1:2) to receive: once-daily liraglutide (blinded); oncedailyliraglutide placebo (blinded) or once-daily insulinglargine (open-labelled; sanofi-aventis, Paris, France), all incombination with metformin and glimepiride (open-labelled).Liraglutide and liraglutide placebo were suppliedby Novo Nordisk A/S (Bagsvaerd, Denmark)

Pasien secara acak dialokasikan untuk 3 intervensi, sekali sehari liraglutide (blinded) sekali sehari liratlugide placebo, sekali sehari insulin glargin, dalam kombinasi dengan terapi metformin dan glimepiride. Liraglutide dan liraglutide placebo disuplai oleh Novo Nordisk A/S (Bagsverd, Denmark)

Objectives 5 Specific objectives and hypotheses.

2047 The objective of the present study was to compare theefficacy and safety of liraglutide with that of self-titratedbasal insulin glargine (A21Gly,B31Arg,B32Arg humaninsulin) in patients with type 2 diabetes not adequatelycontrolled with metformin and glimepiride.

Tujuan pelantikan adalah untuk membandingkan efikasi dan keamanan liraglutide dengan titrasi basal insulin glargin pada pasien dengan DM 2 yang tidak cukup dengan terapi metformin dan glimeprid

Outcomes 6 Clearly defined primary and secondary outcome measures and, when applicable, any methods

2049 The primary efficacy outcome measure was change inwhole blood HbA1c after 26 weeks of treatment. The

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used to enhance the quality of measurements (e.g., multiple observations, training of assessors).

secondary outcome measures included changes in bodyweight,waist circumference, FPG, eight point plasmaglucose (PG) profiles, beta cell function (proinsulin toC-peptide ratio) and BP.

Ukuran hasil efikasi primer adalah perubahan HbA1 stelah 26 minggu. Perubahan sekunder berdasarkan perubahan BB, lingkar pinggang, FPG, plasma glukosa, fungsi sel beta (pro insulin terhadap C-peptida rasio), BP

Sample size

7 How sample size was determined and, when applicable, explanation of any interim analyses and stopping rules.

2048 The 581 randomised patients in this multicentre (107 sites), multinational (17 countries) trial were 18–80 years old, with type 2 diabetes treated with oral glucose-lowering drugs (OGLAs) (94–95% combination therapy) (Table 1) for at least 3 months before screening

Pengacakan pada sel pasien di 107 pusat di 17 negara , usia 18-80 tahun dengan diabetes melitus tipe 2 dengan oral glucose-lowering drugs (OGLAs) (94-95% terapi kombinasi) (tabel 1) selama 3 bulan sebelum pemeriksaan lapangan. Inklusi umum kriteria seperti tingkat Hb A1C 7,5-10% jika OGLA monoterapi 7-10% atau kombinasi dan BMI ≤ 45kg/m2.

Randomization --

Sequence generatio

n

8 Method used to generate the random allocation sequence, including details of any restrictions (e.g., blocking, stratification)

2048 Randomisation (using a telephone or web-based randomisation system)

Pengacaknb menggunakan telepon atau pengacakan web)

Randomization --

Allocation concealme

nt

9 Method used to implement the random allocation sequence (e.g., numbered containers or central

2049 At screening, all participantswere given a 6 digit participant number. Atrandomisation, eligible participants were allocated to

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telephone), clarifying whether the sequence was concealed until interventions were assigned.

one of the three treatment groups using a telephone- orweb-based randomisation system. Participants were stratifiedby whether they were treated with monotherapy orcombination therapy for their diabetes at screening. Ablock size of five was defined for both groups. Theblinded electronic-sealed codes were accessible to theinvestigators, affiliate and international product safetypersonnel or any other relevant party who might havehad a need for breaking the treatment code; for example,for safety or regulatory purposes.

Pada skrining peserta di beri nomer 6 digit, peserta yang memenuhi syarat dialokasikan untuk 1 dari grup, pengacakan dengan telepon atau web di kelompokkan menerima kombinasai. Sebuah kartu ukurean 5 kotak di b erikan untuk kedua grup yang berisi kode-kode yang dapat di akses oleh penyidik untuk keamanan, keselamatan, dan keperluan resmi

Randomization --

Implementation

10 Who generated the allocation sequence, who enrolled participants, and who assigned participants to their groups.

Not mentioned

Blinding (masking)

11 Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment. If done, how the success of blinding was evaluated.

2048 Patients were randomly allocated to three interventions (2:1:2) to receive: once-daily liraglutide (blinded); once-daily liraglutide placebo (blinded) or once-daily insulin glargine (open-labelled; sanofi-aventis, Paris, France), all in combination with metformin and glimepiride (open-labelled)

Statistical 12 Statistical methods used 2050 Each endpoint was analysed using

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methods to compare groups for primary outcome(s); Methods for additional analyses, such as subgroup analyses and adjusted analyses.

an analysis of covariance (ANCOVA) model with treatment, pre-treatment and country as fixed effects and baseline as the covariate

Pasien secara acak di alokasikan untuk menerima liraglutide sehari sekali dan plasebo, sehari sekali liraglutide plasebo, sehari sekali glargin insulin, semua dikombinasi dengan metformin dan glimeprid

RESULTS

Participant flow

13 Flow of participants through each stage (a diagram is strongly recommended). Specifically, for each group report the numbers of participants randomly assigned, receiving intended treatment, completing the study protocol, and analyzed for the primary outcome. Describe protocol deviations from study as planned, together with reasons.

2051 Fig.1 Flow of patients through the study

Recruitment

14 Dates defining the periods of recruitment and follow-up.

Not mentioned

Baseline data

15 Baseline demographic and clinical characteristics of each group.

Not mentioned

Numbers analyzed

16 Number of participants (denominator) in each group included in each analysis and whether the analysis was by "intention-to-treat". State the results in absolute numbers when feasible (e.g., 10/20, not 50%).

2050 A total of 973 patients were screened, 581 were randomisedand 522 completed the study (Fig. 1). The highestwithdrawal rate was seen in the placebo group, which wasmainly driven by withdrawal because of ineffective therapyat a level of 11.3%. AE withdrawals occurred for 4.7%(liraglutide), 0.9% (placebo) and

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2.1% (insulin glargine) ofparticipants. Treatment groups were well matched (Table 1)

The data were analysed for the intent-to-treat population,defined as patients who were exposed to at least one doseof trial product(s) after randomisation. For the primaryendpoint, HbA1c, the statistical analysis was also performedwithout the last observation carried forward on the perprotocolpopulation (participants completing the studywithout significant protocol violations) (ESM Table 1).Each endpoint was analysed using an analysis of covariance(ANCOVA) model with treatment, pre-treatment andcountry as fixed effects and baseline as the covariate

Sebanyak 973 pasien diskrining, 581 diacak522 dan menyelesaikan studi (Gambar 1). Tingkat penarikan tertinggi terlihat pada kelompok plasebo, yangterutama didorong oleh penarikan karena terapi tidak efektifpada tingkat 11,3%. Penarikan AE terjadi pada 4,7%(liraglutide), 0,9% (plasebo) dan 2,1% (glargine insulin) daripeserta. Kelompok perlakuan relatif sama (Tabel 1)

Data dianalisis untuk populasi intent-to-treat,didefinisikan sebagai pasien yang terkena setidaknya satu dosisproduk percobaan (s) setelah randomisasi. Untuk primertitik akhir, HbA1c, analisis statistik

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juga dilakukantanpa pengamatan terakhir dilakukan ke depan pada perprotocolpopulasi (peserta menyelesaikan studitanpa pelanggaran protokol signifikan) (ESM Tabel 1).Setiap titik akhir dianalisis menggunakan analisis kovarians(ANCOVA) dengan model pengobatan, perawatan pra dannegara sebagai efek tetap dan baseline sebagai kovariat

Outcomes and

estimation

17 For each primary and secondary outcome, a summary of results for each group, and the estimated effect size and its precision (e.g., 95% confidence interval).

Liraglutide reduced HbA1c significantly vs glargine (1.33% vs 1.09%; −0.24% difference, 95% CI 0.08, 0.39; p=0.0015) and placebo (−1.09% difference, 95% CI 0.90, 1.28; p<0.0001)

Liraglutide mengurangi HbA1c secara signifikan glargine vs (1,33% vs 1,09%; perbedaan -0,24%, 95% CI 0,08, 0,39, p = 0,0015) dan plasebo (-1,09% perbedaan, 95% CI 0,90, 1,28, p <0,0001)

Ancillary analyses

18 Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those pre-specified and those exploratory.

Not mentioned

Adverse events

19 All important adverse events or side effects in each intervention group.

Hypoglycaemic episodes The proportion of patients experiencing minor hypoglycaemia (FPG <3.1 mmol/l) during the treatment period in the liraglutide group (27.4% patients) was not different from the insulin glargine group (28.9%) but higher compared with the placebo group (16.7%)

The most common AEs in the liraglutide group were

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gastrointestinal and of mild or moderate severity (mainly nausea)

Table 2 Individual adverseevents with frequency >5%

Hipoglikemik episode Proporsi pasien yang mengalami hipoglikemia ringan (FPG <3,1 mmol / l) selama masa pengobatan pada kelompok liraglutide (pasien 27,4%) tidak berbeda dari kelompok glargine insulin (28,9%) tetapi lebih tinggi dibandingkan dengan kelompok plasebo (16,7%)

Yang AE yang paling umum pada kelompok liraglutide adalah gastrointestinal dan keparahan ringan atau sedang (terutama mual)

Tabel 2 individu yang merugikanacara dengan frekuensi> 5%

DISCUSSION

Interpretation

20 Interpretation of the results, taking into account study hypotheses, sources of potential bias or imprecision and the dangers associated with multiplicity of analyses and outcomes.

Not mentioned

Generalizability

21 Generalizability (external validity) of the trial findings.

Not mentioned

Overall evidence

22 General interpretation of the results in the context of current evidence.

2047 Liraglutide added to metformin and sulfonylurea produced significant improvement in glycaemic control and bodyweight compared with placebo and insulin glargine. The difference vs insulin glargine in HbA1c was within the predefined non-inferiority margin

Liraglutide ditambahkan ke metformin dan sulfonilurea

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menghasilkan peningkatan yang signifikan dalam kontrol glukosa darah dan berat badan dibandingkan dengan plasebo dan glargine insulin. Vs perbedaan insulin glargine dalam HbA1c dalam marjin non-inferioritas yang telah ditetapkan

D. UJI VALIDITAS

Terapi

Is the reserch valid?

1a. Was the assigment of patient

to tretments randomised?

1b. Was the randomisation list

concealed?

1c. Were subject and clinicians

‘blind’ to which treatment was

being received?

iya

iya

iya

"Pasien diacak (2:01:02) untuk liraglutide 1,8 mg

sekali sehari (n = 232), liraglutide plasebo (n =

115) dan open-label glargine insulin (n = 234),

semua dalam kombinasi dengan metformin (1 g

dua kali sehari) dan glimepiride (4 mg sekali

sehari) "

Randomisasi (menggunakan sistem pengacakan

telepon atau berbasis web) yang diikuti selama

6 minggu pada periode di mana peserta

ditempatkan pada terapi kombinasi standar

dengan metformin dan glimepiride

Penyidik, peserta dan monitor studi buta dengan status pengobatan liraglutide dan kelompok plasebo setiap saat.

2a. Were all subject who entered

the trial accounted for at its

conclusion?

2b. Were they analysed in the

group to which they were

randomised?

Tidak

iya

Sebanyak 973 pasien diskrining, 581 secara acak

dan 522 menyelesaikan studi

Data dianalisis setelah randomisasi

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3a. Aside from the experimentl

treatment, were the groups

treated equally?

3b. Were the groups similiar at

the start of the trial?

tidak

Tidak di jelaskan di dalam jurnal

Pasien diacak (2:01:02) untuk liraglutide 1,8 mg

sekali sehari (n = 232), liraglutide plasebo (n =

115) dan open-label glargine insulin (n = 234)

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