Curriculum vitae 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 ofmedicine, 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
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 metformin more 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 No 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 Not described
Studies that identifies (6) Excluded because combination, not randomized, can not be obtained full test Further evaluation with modified Jadad Score (2)
Critical appraisal 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
The quality of the study Name of study Score JADAD Score modified JADAD Gallwitz 4 6 Forst 3 5
Study description Study Subjects Intervention Comparison Follow up Galwitz Type 2 DM Linagliptin (776 subjects) Glimepiride 1-4 104 weeks mg (775 subjects) 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 7,7 Forst 8,5 8,2 Fasting blood glucose 9,1 VS 9,2 (mmol/l) 0,51Fasting blood glucose 10,5 VS 10,0 (mmol/l)
Diabetes Mellitus Patients (n = 1249) DATA COLLECTION Met + Linagliptin N = 627 Retrieved N = 377 Not retrieved N = 250 Met + Sulfonylurea N = 632 Retrieved N = 357 Not retrieved N = 275
RESULTS
Demographic characteristics Characteristic Linagliptin + Metformin Treatment group 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 Characteristics Linagliptin + Metformin Treatment group 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 Characteristics Treatment 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 Proportion of patients with a decrease in HbA1c Treatment group 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 event Lina + SU + Met 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 59.1% 61.7% still had hypertension or had a new onset of hypertension - 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 patients receiving 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 Linagliptin Treatment group Average cost (IDR) SD (IDR) - 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 Treatment group Component of cost 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 52,356 0.3% 876,779 5.0% catheterization/transfusion 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 ratio Treatment 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 0.427-0.067 change) ICER per patient who experience a 72,973,675 decrease in HbA1c in a year 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 for linagliptin 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 on clinical effectiveness Systematic review showed that there was no difference in the achievement of HbA1c level between groups who receive linagliptin and sulfonylurea, while the adverse event of hypoglycemia in linagliptin occurred in lower proportion compared to sulfonylurea. Economical evaluation 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 (%).
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 and IDR 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.
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