Background
Methods
Model description
Simulated cohorts and treatment effects
1860 | LEAD-6 | Greek*
| |
---|---|---|---|
Patient demographics
| |||
Baseline age (years) | 55.3 (9.2) | 56.7 (10.3) | 64.5 (10.5) |
Duration of diabetes (years) | 6 (5.1) | 8.2 (6) | 10.4 (8.3) |
Percentage male | 52.9% | 51.9% | 51.5% |
Baseline risk factors
| |||
HbA1c (%) | 8.4 (0.8) | 8.2 (1.0) | 8.2 (1.8) |
Systolic blood pressure (mmHg) | 132.2 (14.5) | 133.0 (16.6) | 139.8 (19.3) |
Total cholesterol (mmol/l) | 4.79 (0.38) | 4.7 (0.95) | 5.5 (−) |
HDL (mmol/l) | 1.16 (0.31) | 1.2 (0.3) | 1.2 (0.3) |
LDL (mmol/l) | 2.65 (0.82) | 2.95 (0.8) | 3.7 (1.0) |
Triglycerides (mmol/l) | 2.38 (2.22) | 2.15 (1.35) | 1.9 (1.4) |
Body mass index (kg/m2) | 32.8 (5.2) | 32.9 (5.7) | 30.4 (5.3) |
Proportion smoker¶
| 36.0% | 36.0% | 36.0% |
Cigarettes per day¶
| 18.7 | 18.7 | 18.7 |
Alcohol consumption (Oz/week)¶
| 15.91 | 15.91 | 15.91 |
Racial characteristics
| |||
Proportion White | 90% | 80.6% | 100% |
Proportion Black | 7.5% | 5.5% | 0% |
Proportion Hispanic | 0% | 12.4% | 0% |
Proportion Native American | 0.5% | 1.3% | 0% |
Proportion Asian/Pacific Islander | 2% | 0.2% | 0% |
Baseline CVD complications
| |||
Proportion with myocardial infarction | 2.7% | 2.6% | 12.8% |
Proportion with angina | 1.8% | 1.9% | 5.0% |
Proportion with peripheral vascular disease | 0.9% | 0.6% | 5.6% |
Proportion with stroke | 0.8% | 0.2% | 8.1% |
Proportion with congestive heart failure | 0.4% | 1.5% | 4.2% |
Proportion with atrial fibrillation | 1.5% | 1.5% | 9.1% |
Proportion with left ventricular hypertrophy | 0.2% | 0.2% | 3.1% |
Baseline renal complications
| |||
Proportion with microalbuminuria | 1.1% | 1.1% | 1.1% |
Proportion with gross proteinuria | 0.2% | 0.2% | 0.2% |
Proportion with end-stage renal disease | 0.4% | 0.6% | 0.4% |
Baseline retinopathy complications
| |||
Proportion with BDR | 2.7% | 1.1% | 25% |
Proportion with PDR | 0.2% | 0.2% | 4% |
Proportion with severe vision loss | 0.4% | 0.6% | 4.5% |
Baseline macular edema
| |||
Proportion with macular edema | 1.1% | 0.2% | 1.1% |
Baseline cataract
| |||
Proportion with cataract | 1.7% | 6.9% | 1.7% |
Baseline foot ulcer complications
| |||
Prop. uninfected ulcer | 0.6% | 0.2% | 0.6% |
Prop. infected ulcer | 0.3% | 0.0% | 0.3% |
Prop. healed ulcer | 0.0% | 0.0% | 0.0% |
Prop. history of amputation | 0.0% | 0.2% | 0.0% |
Baseline neuropathy
| |||
Proportion with neuropathy | 11.6% | 7.8% | 14.7% |
Baseline depression
| |||
Proportion with depression†
| 0% | 0% | 9% |
Risk Factor | 1860 clinical trial*
| LEAD-6 clinical trial¶
| Long-term progression | ||||||
---|---|---|---|---|---|---|---|---|---|
Liraglutide (1.2 mg) | Sitagliptin (100 mg) | Liraglutide (1.8 mg) | Exenatide BID (10 μg) | All comparators | |||||
Mean | SD | Mean | SD | Mean | SD | Mean | SD | ||
Change from baseline in HbA1c (%) | −1.24 | 1.04 | −0.90 | 1.04 | −1.12 | 1.22 | −0.79 | 1.22 | No HbA1c creep assumption |
Change from baseline in SBP (mm Hg) | −0.55 | 13.23 | −0.94 | 13.17 | −2.51 | 17.55 | −2.00 | 17.93 | UKPDS progression |
Change from baseline in total cholesterol (mmol/l) | −0.03 | 0.82 | −0.02 | 0.80 | −0.20 | 1.02 | −0.09 | 1.01 | Framingham progression |
Change from baseline in LDL (mmol/l) | 0.08 | 0.69 | 0.13 | 0.68 | −0.44 | 0.84 | −0.40 | 0.84 | Framingham progression |
Change from baseline in HDL (mmol/l) | 0.00 | 0.17 | 0.00 | 0.17 | −0.04 | 0.23 | −0.05 | 0.23 | Framingham progression |
Change from baseline in triglycerides (mmol/l) | −0.19 | 1.42 | −0.40 | 1.38 | −0.41 | 1.50 | −0.23 | 1.48 | Framingham progression |
Change from baseline in BMI (kg/m2) | −1.00 | 0.08 | −0.34 | 0.08 | −1.15 | 1.35 | −1.02 | 1.47 | Constant after returning to baseline |
Major hypoglycaemia (events per 100 patient-years) | 1.00 | 0.00 | 0.00 | 2.00 | 0.00#
| ||||
Minor hypoglycaemia (events per 100 patient-years) | 17.80 | 10.60 | 193.20 | 260.00 | 128.70#
|
Costs and utilities
Cost description | Costs (€) | Reference |
---|---|---|
Management costs
| ||
Annual cost of statins | 147.97 | Experts opinion & Drug price bulletin [15] |
Annual cost of aspirin | 14.41 | Experts opinion & Drug price bulletin [15] |
Annual cost of ACE inhibitors | 78.32 | Experts opinion & Drug price bulletin [15] |
Annual cost of screening for microalbuminuria | 8.66 | Government Gazette* |
Annual cost of screening for gross proteinuria | 8.66 | Government Gazette* |
Annual cost of stopping ACEIs due to side effects | 15.00 | Experts opinion |
Annual cost of eye screening | 10.00 | Experts opinion & Government Gazette¶
|
Annual cost of foot screening program | 10.00 | Experts opinion & Government Gazette¶
|
Annual cost of non-standard ulcer treatment | 0.00 | This is a patient’s expenditure |
Annual cost of anti-depression treatment | 154.50 | Experts opinion & Drug price bulletin [15] |
Annual cost of screening for depression | 10.00 | Experts opinion & Government Gazette¶
|
Direct costs of cardiovascular complications
| ||
Myocardial infarction, 1st year of event | 6000 | G. Kourlaba et al. [19] |
Myocardial infarction, each subsequent year | 1964 | G. Kourlaba et al. [19] |
Angina, 1st year of event | 3613 | National School of Public Health (data on file) |
Angina, each subsequent year | 1197 | National School of Public Health (data on file) |
Congestive heart failure, year of onset | 3910 | National School of Public Health (data on file) |
Congestive heart failure, each subsequent year | 1398 | National School of Public Health (data on file) |
Stroke, 1st year of event | 4406 | G. Kourlaba et al. [19] |
Stroke, each subsequent year | 1976 | G. Kourlaba et al. [19] |
Stroke, death within 30 days | 3675 | Government Gazette† (DRG-code: N30Mα) & G. Kourlaba et al. [19] |
Peripheral vascular disease, year of onset | 5713 | G. Kourlaba et al. [20] |
Peripheral vascular disease, each subsequent year | 1426 | G. Kourlaba et al. [20] |
Direct costs of renal complications
| ||
Hemodialysis, first year | 40352 | |
Hemodialysis, each subsequent year | 40352 | Assumed equal with 1st year hemodialysis cost |
Peritoneal dialysis, first year | 46156 | Experts opinion & Government Gazette† (DRGs-code: Υ28Α and Y02M) |
Peritoneal dialysis, each subsequent year | 43656 | Experts opinion & Government Gazette† (DRG-code: Υ28Α) |
Kidney transplant, first year | 18489 | S. Sidiropoulos [21] |
Kidney transplant, each subsequent year | 5400 | K. Souliotis et al. [17] |
Direct costs of acute events
| ||
Major hypoglycaemic event | 700 | National School of Public Health (data on file) |
Minor hypoglycaemic event | 250 | National School of Public Health (data on file) |
Direct costs of eye disease
| ||
Cost of laser treatment | 731 | Government Gazette† (DRG-code: O03A) |
Cost of cataract operation | 933 | Government Gazette† (DRG-code: O15A) |
Cost following cataract operation | 59 | Experts opinion & Drug price bulletin [15] |
Cost of blindness in year of onset | 11280 | Experts opinion & K. Athanasakis et al. [16] |
Cost of blindness in subsequent years | 6200 | Experts opinion & K. Athanasakis et al. [16] |
Direct costs of neuropathy, foot ulcer and amputation
| ||
Neuropathy, year of onset | 1120 | Experts opinion, Drug price bulletin [15] & Government Gazette¶‡
|
Neuropathy, each subsequent year | 1120 | Experts opinion, Drug price bulletin [15] & Government Gazette¶‡
|
Amputation, year of event | 6629 | Government Gazette† (DRG-code: K11M) |
Amputation, prosthesis | 1150 | Government Gazette‡
|
Gangrene treatment | 5282 | Experts opinion, Drug price bulletin [15] & Government Gazette† (DRGs-code: K11M & K13M) |
Cost of infected ulcer treatment | 2835 | Experts opinion, Drug price bulletin [15] & Government Gazette¶† (DRG-code: Δ20Μ) |
Cost of uninfected ulcer treatment | 387 | Experts opinion, Drug price bulletin [15] & Government Gazette¶
|
Cost after healed ulcer | 120 | Experts opinion & Government Gazette¶
|
Cost of healed ulcer (history of amputation) | 1471 | Government Gazette† (DRG-code: Δ20Χ) |
Costs of interventions
| Drug price bulletin [15] | |
Liraglutide (1.2 mg) | 3.44 per day | |
Liraglutide (1.8 mg) | 5.16 per day | |
Sitagliptin | 1.30 per day | |
Exenatide BID | 2.84 per day | |
Metformin | 0.11 per day | |
Sulphonylurea (Glimepiride) | 0.14 per day | |
Basal insulin (Glargine) | 1.38 per day | |
Consumable costs
| Government Gazette#
| |
Needles for injectable drugs | 0.17 per needle | |
SMBG test strips | 0.43 per strip | |
SMBG lancets | 0.09 per lancet |
Cost-effectiveness analysis
Sensitivity analyses
Results
Base case analyses
Liraglutide vs. sitagliptin
Complication | Liraglutide 1.2 mg | Sitagliptin | Difference | Liraglutide 1.8 mg | Exenatide BID | Difference |
---|---|---|---|---|---|---|
Eye disease, %
| ||||||
Background retinopathy | 17.18 (1.26) | 19.26 (1.29) | −2.08 | 18.64 (1.24) | 20.91 (1.27) | −2.27 |
Proliferative retinopathy | 0.51 (0.22) | 0.67 (0.27) | −0.15 | 0.61 (0.25) | 0.78 (0.27) | −0.17 |
Severe vision loss | 6.78 (0.76) | 7.51 (0.83) | −0.73 | 6.59 (0.78) | 7.46 (0.86) | −0.87 |
Macular edema | 13.59 (1.11) | 15.44 (1.14) | −1.85 | 12.95 (1.04) | 14.88 (1.08) | −1.93 |
Cataract | 10.62 (0.96) | 11.11 (1.02) | −0.49 | 10.27 (1.02) | 10.85 (1.05) | −0.58 |
Renal disease, %
| ||||||
Microalbuminuria | 24.22 (1.35) | 27.02 (1.44) | −2.80 | 28.95 (1.43) | 31.87 (1.55) | −2.92 |
Gross proteinuria | 5.07 (0.71) | 6.38 (0.78) | −1.30 | 6 (0.78) | 7.26 (0.81) | −1.26 |
End-stage renal disease | 0.58 (0.23) | 0.83 (0.29) | −0.26 | 0.65 (0.26) | 0.90 (0.3) | −0.26 |
Diabetic foot & neuropathy, %
| ||||||
Foot ulcer | 30.91 (1.42) | 32.97 (1.48) | −2.07 | 28.36 (1.35) | 30.21 (1.4) | −1.85 |
Amputation | 10.06 (1.05) | 10.54 (1.01) | −0.48 | 8.63 (0.98) | 9.13 (1.01) | −0.51 |
Neuropathy | 47.51 (1.75) | 52.27 (1.69) | −4.76 | 45.74 (1.61) | 50.13 (1.71) | −4.39 |
Cardiovascular disease, %
| ||||||
Congestive heart failure | 13.23 (1.05) | 14.29 (1.08) | −1.06 | 13.54 (1.09) | 14.31 (1.15) | −0.78 |
Peripheral vascular disease | 9.34 (0.90) | 10.82 (1) | −1.49 | 8.69 (0.88) | 10.43 (0.94) | −1.73 |
Angina | 13.01 (1.11) | 13.52 (1.11) | −0.51 | 12.05 (1.02) | 12.87 (1.08) | −0.82 |
Stroke | 8.79 (0.95) | 9.24 (0.91) | −0.46 | 8.69 (0.94) | 9.45 (0.92) | −0.76 |
Myocardial infarction | 17.16 (1.19) | 17.83 (1.22) | −0.68 | 16.31 (1.17) | 17.55 (1.25) | −1.24 |
Hypoglycaemia, %
| ||||||
Major hypoglycaemia | 0.11 (0.01) | 0 (0) | 0.11 | 0 (0) | 0.22 (0.02) | −0.22 |
Minor hypoglycaemia | 23.63 (0.48) | 22.88 (0.45) | 0.75 | 31.66 (0.50) | 34.49 (0.46) | −2.84 |
Liraglutide 1.2 mg | Sitagliptin | Difference | |
---|---|---|---|
Discounted life expectancy (years) | 14.22 (0.18) | 14.09 (0.17) | 0.13 (0.23) |
Discounted quality-adjusted life expectancy (QALYs) | 9.24 (0.12) | 9.05 (0.11) | 0.19 (0.16) |
Discounted total lifetime direct medical costs (€) | 39524 (1100) | 36727 (1113) | 2797 (1468) |
Drug acquisition | 15069 | 11240 | 3829 |
Patient management* | 1939 | 1928 | 11 |
Cardiovascular disease | 5858 | 6170 | −312 |
Renal disease | 1146 | 1253 | −107 |
Diabetic foot and neuropathy | 6665 | 7132 | −467 |
Eye disease | 5325 | 5676 | −351 |
Hypoglycaemia | 3522 | 3329 | 193 |
ICER (€ per QALY gained) | 15101 | ||
Liraglutide 1.8 mg
|
Exenatide BID
|
Difference
| |
Discounted life expectancy (years) | 14.10 (0.17) | 13.96 (0.16) | 0.14 (0.23) |
Discounted quality-adjusted life expectancy (QALYs) | 9.22 (0.12) | 9.03 (0.11) | 0.19 (0.16) |
Discounted total lifetime direct medical costs (€) | 43236 (1049) | 41934 (1065) | 1302 (1492) |
Drug acquisition | 18505 | 14927 | 3578 |
Patient management* | 1931 | 1920 | 11 |
Cardiovascular disease | 5544 | 5980 | −436 |
Renal disease | 1611 | 1692 | −81 |
Diabetic foot and neuropathy | 5859 | 6317 | −458 |
Eye disease | 4461 | 4948 | −487 |
Hypoglycaemia | 5326 | 6149 | −823 |
ICER (€ per QALY gained) | 6818 |
Liraglutide vs. exenatide
Sensitivity analyses
Liraglutide vs. sitagliptin and liraglutide vs. exenatide
Sensitivity analysis | Liraglutide 1.2 mg vs. sitagliptin | Liraglutide 1.8 mg vs. exenatide BID | ||||
---|---|---|---|---|---|---|
Difference in QALYs | Difference in costs [€] | ICER [€ per QALY gained] | Difference in QALYs | Difference in costs [€] | ICER [€ per QALY gained] | |
Base case
|
0.19 (0.16)
|
2797 (1468)
|
15101
|
0.19 (0.16)
|
1302 (1492)
|
6818
|
Model time horizon:
| ||||||
30 years | 0.18 (0.15) | 2857 (1428) | 15767 | 0.18 (0.15) | 1380 (1541) | 7874 |
20 years | 0.12 (0.11) | 2946 (1186) | 23797 | 0.12 (0.12) | 1531 (1218) | 12531 |
10 years | 0.06 (0.06) | 3569 (791) | 61595 | 0.05 (0.06) | 2306 (774) | 43977 |
5 years | 0.04 (0.02) | 3787 (452) | 106618 | 0.03 (0.03) | 2458 (516) | 84503 |
Discount rate:
| ||||||
0% | 0.34 (0.31) | 2319 (2759) | 6776 | 0.36 (0.30) | 552 (2767) | 1529 |
6% | 0.13 (0.11) | 2879 (1057) | 22353 | 0.13 (0.11) | 1529 (1081) | 11754 |
Costs of complications:
| ||||||
Increased by 10% | 0.19 (0.16) | 2694 (1605) | 14541 | 0.19 (0.16) | 1074 (1630) | 5625 |
Decreased by 10% | 0.19 (0.16) | 2902 (1323) | 15666 | 0.19 (0.16) | 1531 (1355) | 8020 |
Physiological parameters:
| ||||||
HbA1c 95% upper limit | 0.23 (0.15) | 2411 (1565) | 10334 | 0.26 (0.16) | 798 (1500) | 3101 |
HbA1c 95% lower limit | 0.14 (0.16) | 3270 (1557) | 23725 | 0.12 (0.16) | 1947 (1500) | 15961 |
UKPDS creep of HbA1c for 5 years | 0.10 (0.15) | 3362 (1597) | 32756 | 0.10 (0.15) | 1922 (1613) | 18940 |
SBP 95% upper limit | 0.20 (0.16) | 2784 (1517) | 14086 | 0.21 (0.15) | 1142 (1500) | 5380 |
SBP 95% lower limit | 0.18 (0.15) | 2897 (1468) | 16246 | 0.19 (0.15) | 1375 (1444) | 7327 |
Lipid 95% upper limit | 0.22 (0.16) | 2744 (1541) | 12693 | 0.22 (0.15) | 1162 (1605) | 5373 |
Lipid 95% lower limit | 0.17 (0.16) | 2781 (1492) | 16577 | 0.16 (0.15) | 1459 (1525) | 9400 |
BMI 95% upper limit | 0.20 (0.15) | 2810 (1500) | 13823 | 0.20 (0.17) | 1274 (1484) | 6231 |
BMI 95% lower limit | 0.18 (0.16) | 2820 (1500) | 16030 | 0.18 (0.16) | 1269 (1460) | 7263 |
BMI benefit maintained | 0.25 (0.15) | 2759 (1476) | 11105 | 0.21 (0.16) | 1312 (1492) | 6408 |
Hypoglycaemia:
| ||||||
No hypo disutility | 0.19 (0.16) | 2797 (1468) | 14867 | 0.18 (0.16) | 1302 (1492) | 7272 |
Disutility of −0.0052 for all hypos | 0.19 (0.16) | 2797 (1468) | 15118 | 0.19 (0.16) | 1302 (1492) | 6699 |
Treatment duration:
| ||||||
7 years | 0.20 (0.15) | 3941 (1428) | 19773 | 0.20 (0.17) | 2114 (1557) | 10458 |
3 years | 0.19 (0.17) | 1329 (1500) | 7123 | 0.19 (0.16) | 275 (1460) | 1480 |
Greek cohort data
| 0.12 (0.14) | 3008 (1775) | 24355 | 0.12 (0.15) | 1586 (1928) | 13424 |
52 week clinical data
| 0.22 (0.17) | 2309 (1508) | 10564 | |||
Liraglutide delayed by 1 year
| 0.12 (0.16) | 2340 (1581) | 19960 | - | - | - |
Liraglutide 1.2 mg cost &:
| ||||||
100% of 1.8 mg efficacy | - | - | - | 0.19 (0.16) | −1473 (1492) | Lira. Dominant |
90% of 1.8 mg efficacy | - | - | - | 0.14 (0.15) | −1016 (1500) | Lira. Dominant |
80% of 1.8 mg efficacy | - | - | - | 0.08 (0.15) | −625 (1613) | Lira. Dominant |
70% of 1.8 mg efficacy | - | - | - | 0.02 (0.15) | −126 (1525) | Lira. Dominant |