Table 2.
Cost-effectiveness and uncertainty results
| Study, year | Comparison | Cost, year | Effect measure | Which is cost effective | ICER (currency) | Threshold | Quadrant (location in source) | Key driver | Sensitivity analysis | First sensitive factor | Second sensitive factor | Third sensitive factor |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Barnett, 2018 [37] | Liraglutide vs. sitagliptin | Direct, 2016 | QALY, LY, incidence of DRC, onset of DRC | Liraglutide | 15,423/QALY, (GBP) | GBP20,000/QALY | QNE (Fig. 2) | Lower rates and delayed onset of DRCs offset the higher treatment cost | DSA generally confirmed findings. Except lipid or hypoglycaemia difference only led to the same effect but more cost, and BMI or SBP difference only led to 150k+ and 279k+ ICER; PSA likewise | Lipid difference only | Hypoglycaemia difference only | BMI difference only |
| Basson, 2018 [36] | Dulaglutide vs. exenatide QW | Direct, 2014 | QALY, LY, incidence of DRC, onset of DRC | Dulaglutide | Dominant (EUR) | EUR30,000/QALY | QSE (Fig. 2) | Lower rates and delayed onset of DRCs offset the higher treatment cost | DSA generally confirmed findings; PSA likewise | Variation in treatment efficacy | Time on treatment | Shorter time horizon (10 years) |
| Ericsson, 2018 [35] | Liraglutide + basal INS vs. lixisenatide + basal INS, IDegLira | Direct, 2016; indirect, 2015 | QALY, LY, incidence of DRC | Liraglutide and IDegLira |
Vs. lixisenatide: 30.802/QALY Scenarios: IDegLira vs. lixisenatide: 34.800/QALY | 23.984/QALY | dominant (SEK) |
SEK100,000–1,000,000/QALY | QNE for liraglutide vs. lixisenatide (Fig. 1, Table 4); QNE for IDegLira vs. lixisenatide = QNE or QSE dependent on dosage (Table 5) | More complications avoided | DSA generally confirmed findings. Except liraglutide was not CE when HbA1c changes were assumed equal; PSA likewise | Hba1c reduction of liraglutide critical in achieving CE | Liraglutide 1.8 mg replaced with 1.2 mg led to liraglutide being dominant | Shorter time horizon (10 years) |
| Tzanetakos, 2018 [34] | Exenatide QW vs. INS glargine, liraglutide | Direct, 2016 | QALY, LY, incidence of DRC | Exenatide QW | Vs. INS glargine: 4499/QALY vs. liraglutide: 2827/QALY (EUR) | EUR36,000/QALY | QNE for exenatide once-weekly vs. IG, QNE for exenatide once-weekly vs. liraglutide (Table 3) | Vs. INS glargine: lower cumulative incidence of DRCs (IHD, MI, hypoglycaemia) offset higher acquisition cost vs. liraglutide: lower cumulative incidence of DRCs (CHF, stroke) and fatality offset higher acquisition cost | DSA generally confirmed findings; PSA likewise | Lower utility to BMI weights | Switching HbA1c threshold | Hba1c effect of exenatide QW 1w set to upper limit |
| Ericsson, 2019 [44] | Semaglutide-I vs. dulaglutide, lixisenatide | Direct, 2018; indirect, 2016 | QALY, LY, incidence of DRC | Semaglutide-I | Vs. dulaglutide: dominant, vs. lixisenatide: dominant (SEK) | SEK500,000/QALY | QSE for semaglutide-I vs. dulaglutide, QSE for semaglutide-I vs. lixisenatide (Fig. 1) | For both comparisons: longer time to onset of DRCs, reduction of DRC incidence (particularly retinopathy) led to reduced costs and higher quality of life with semaglutide-I | DSA confirmed findings. Except with intensification at lower HbA1c threshold for semaglutide-I vs. dulaglutide; PSA confirmed base case | No drift in last intensification | Intensification at HbA1c 7.5% | Shorter time horizon (20 years) |
| Gæde, 2019 [52] | Semaglutide-I vs. dulaglutide, exenatide QW, liraglutide, lixisenatide | Direct, 2017 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I | Primary analysis: dominant Secondary analysis: semaglutide-I 0.5 mg dominant, semaglutide-I 1 mg dominant (DKK) | DKK250,000/QALY (based on UK threshold) | QSE for semaglutide-I 0.5 mg vs. dulaglutide, QSE for semaglutide-I 1 mg vs. dulaglutide (Table 2) | Delay to treatment intensification, lower rates, and delayed onset of DRCs | DSA generally confirmed findings. Including only statistically significant differences made semaglutide-I 0.5 mg non-CE. With different treatment intensification, semaglutide-I was non-dominant but still CE; PSA confirmed base case | Only statistically significant differences | Treatment switch at 3 or 5 years made semaglutide-I 1 and 0.5 mg not dominant | Shorter time horizon (10 years) |
| Hunt, 2019 [43] | Semaglutide-I vs. INS glargine, dulaglutide | Direct + indirect, 2017 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I |
Semaglutide-I 0.5 mg vs. dulaglutide – direct: 4671/QALY direct + indirect: dominant Semaglutide-I 1 mg vs. dulaglutide – direct: 2861/QALY direct + indirect: dominant Semaglutide-I 0.5 mg vs. INS glargine – direct: 11,310/QALY direct + indirect: 4988/QALY Semaglutide-I 1 mg vs. INS glargine – direct: 7515/QALY direct + indirect: 495/QALY (EUR) |
EUR12,900/QALY | Direct costs: QNE for semaglutide-I 0.5 mg vs. glargine, QNE for semaglutide-I 1 mg vs. glargine, QNE for semaglutide-I 0.5 mg vs. dulaglutide, QNE for semaglutide-I 1 mg vs. dulaglutide with indirect costs: QNE, QNE, QSE, and QSE respectively (Table 4) | Semaglutide-I vs. INS glargine: reduction in cumulative incidence of DRCs and increased time to their onset. Largest cost saving from avoided CVD complications. This offset higher pharmacy costs of semaglutide-I. Combining direct + indirect reduced ICER further. Semaglutide-I vs. dulaglutide: same, but avoided ophthalmological complications most notable. Combining direct + indirect led to semaglutide-I dominating | DSA confirmed findings; PSA likewise | Hypoglycaemia difference only | SBP difference only | Lipid difference only |
| Johansen, 2019 [68] | Semaglutide-I vs. dulaglutide | Direct + indirect, 2017 | QALY, LY, incidence of DRC | Semaglutide-I | Semaglutide-I 0.5 mg vs. dulaglutide 0.75 mg: dominant, semaglutide-I 1 mg vs. dulaglutide 1.5 mg: dominant (CAD) | CAD50,000/QALY | QSE for semaglutide-I 0.5 mg vs. dulaglutide 0.5 mg, QSE for semaglutide-I 1 mg vs. dulaglutide 1.5 mg (Fig. 3, Table 3) | Higher cost of semaglutide-I due to longer treatment period (than dulaglutide) before switch to INS, offset by reduced complications, and longer onset until them. Same concept led to higher QALY for semaglutide-I | DSA confirmed findings; PSA: low dose, 66% probability of being CE at 50k/QALY; high dose 73% for PSA scenario analyses: 98% CE for both dose comparisons | Scenario: HbA1c drift at 0.14%, discontinuing GLP1 at 8% HbA1c threshold, and replacing it with INS | Scenario: No INS effect, HbA1c remain at 8% when reached | Shorter time horizon (10 years) |
| Malkin, 2019 [41] | Semaglutide-I vs. liraglutide | Direct, drug, unknown year, DRC 2017 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I | 523/QALY (EUR) | EUR52,390/QALY (3 times Estonian GDP/capita) | QNE (Table 4) | Reduced incidence and delayed time to onset of DRC and avoidance of ulcer, amputation, neuropathy, hypoglycaemia, CVD | DSA confirmed findings. In some cases, semaglutide-I dominated; PSA likewise | Shorter time horizon (10 years) | Use of UKPDS 82 | 0% discount rate |
| Malkin, 2019 [42] | Semaglutide-I vs. dulaglutide | Direct, year unknown | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I | Semaglutide-I 0.5 vs. dulaglutide 1.5: dominant, semaglutide-I 1 vs. dulaglutide 1.5: dominant (EUR) | EUR25,536/QALY (28 times average monthly wage in Slovakia) | QSE for semaglutide-I 0.5 mg vs. dulaglutide 1.5 mg, QSE for semaglutide-I 1 mg vs. dulaglutide 1.5 mg (Table 5) | Reduced incidence and delayed time to onset of DRC and avoidance of ulcer, amputation, neuropathy, hypoglycaemia, CVD | DSA confirmed findings. In DSA it is dominant all the time; PSA is 57–72% likely to be CE | Treatment switch at 7.5% HbA1c | Statistically significant differences only | 0% discount rate |
| Raya, 2019 [39] | IDegLira vs. GLP1, INS mix + GLP1, basal INS, MDI | Direct, 2016 | QALY, LY, incidence of DRC, onset of DRC | IDegLira | Vs. MDI: 3013/QALY, vs. basal: 6890/QALY, vs. GLP1: dominant, vs. GLP1 + INS: dominant (EUR) | EUR30,000/QALY | QNE for IDegLira vs. MDI, QNE for IDegLira vs. basal, QSE for IDegLira vs. INS+GLP1, QSE for IDegLira vs. GLP1 (Table 4, Fig. 2) | Vs. MDI: improved glycemic control led to fewer DRCs, higher cost offset by reduced cost of DRC vs. GLP1 + INS: cost saving because of fewer DRCs vs. basal: higher cost offset by reduced DRCs and delayed onset vs. GLP1: cost saving in general, fewer DRCs | DSA generally confirmed findings. Highly sensitive to (leads to non-CE) abolishment of HbA1c difference though (vs. MDI); PSA likewise | HbA1c difference abolishment vs. MDI OR basal INS | NPH INS cost applied | Statistically significant differences only |
| Viljoen, 2019 [38] | Semaglutide-I vs. dulaglutide | Direct, 2016 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I | Semaglutide-I 0.5 vs. dulaglutide 1.5: dominant, semaglutide-I 1 vs. Dulaglutide 1.5: dominant (GBP) | GBP20,000/QALY | QSE for semaglutide-I 0.5 mg vs. dulaglutide 1.5 mg, QSE for semaglutide-I 1 mg vs. dulaglutide 1.5 mg (Tables 2 and 4, ESM Fig. 2) | Reduced incidence and delayed time to onset of DRC, higher cost due to increased survival offset by fewer DRCs | DSA generally confirmed findings; PSA likewise | Only including statistically significant differences between semaglutide-I 0.5 mg and dulaglutide 1.5 mg | Treatment switch at 7.5% | Dominant in all other scenarios |
| Bain 2020, [51] | Semaglutide-O vs. empagliflozin, sitagliptin, liraglutide | Direct (2019 drug; 2018 DRC) | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-O 14 mg | Vs. empagliflozin: 11,006/QALY vs. sitagliptin: 4930/QALY vs. liraglutide: dominant (GBP) | GBP20,000–30,000/QALY | QNE for semaglutide-O 14 mg vs. empagliflozin 25 mg, QNE for semaglutide-O 14 mg vs. sitaglipin100 mg, QSE for semaglutide-O 14 mg vs. liraglutide 1.8 mg (Table 3, Fig. 2) | Benefit from reduced incidence of DRC and longer mean time to onset of any DRC with semaglutide-O in all comparisons. Increased cost of semaglutide-O from higher acquisition price and longer time to treatment intensification | DSA confirmed findings. Dominance over liraglutide and CE against others unchanged; PSA confirmed base case | Shorter time horizon (10 years) | Treatment switch at 8.0% HbA1c | 26-week treatment effects applied |
| Capel, 2020 [50] | Exenatide QW vs. dulaglutide, liraglutide, lixisenatide | Direct, 2018 | QALY | Exenatide QW 2 mg 1w | Vs. dulaglutide: dominant, vs. liraglutide 1.2 mg: dominant, vs. liraglutide 1.8 mg: dominant, vs. lixisenatide: dominant (EUR) | EUR20,000/QALY gained | QSE for exenatide vs. dulaglutide, QSE for exenatide vs. liraglutide 1.2 mg, QSE for exenatide vs. liraglutide 1.8 mg, QSE for exenatide vs. lixisenatide, (Table 3, Fig. 1) | None stated | DSA completely confirmed findings in base case; PSA likewise | Dominant conclusion not changed | Dominant conclusion not changed | Dominant conclusion not changed |
| Gorgojo-MartíNez, 2020 [49] | Semaglutide-I vs. empagliflozin | Direct, 2018 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I |
Semaglutide-I 1 mg vs. empagliflozin 10 mg: 161/QALY Semaglutide-I 1 mg vs. empagliflozin 25 mg: 625/QALY (EUR) |
EUR30,000/QALY | QNE for semaglutide-I 0.5 mg vs. empagliflozin 10 mg, QNE for semaglutide-I 1 mg vs. empagliflozin 25 mg (Table 3) | Lower rates and delayed onset of DRCs led to higher clinical benefit for semaglutide-I. Higher acquisition cost and longer survival led to higher cost for semaglutide-I. Greater Hba1c reduction biggest contributor to superiority over empagliflozin | DSA generally confirmed findings, except some changes made semaglutide-I CE instead of dominant; PSA likewise | Shorter time horizon (10 years) | Lower 95% CI of HbA1c treatment difference | 5% discount rates |
| Johansen, 2020 [48] | Semaglutide-I vs. liraglutide | Direct, 2018 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I | Semaglutide-I dominant (GBP) | GBP20,000/QALY | QSE (Table 2, Fig. 4) | Longer time to onset of DRCs, time to intensification, higher survival, greater ‘avoidance’ of DRCs | DSA completely confirmed findings, except under a statistically deterministic scenario, where it was still CE; PSA likewise | Shorter time horizon (10 years) | SGLT2 and SU discontinued at treatment intensification | Only statistically significant differences |
| Martín, 2020 [47] | Semaglutide-I vs. dulaglutide, sitagliptin | Direct (2019 drug; 2018 DRC) | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I | 0.5 mg semaglutide-I vs. dulaglutide: dominant, 1 mg semaglutide-I vs. dulaglutide: dominant, 0.5 mg semaglutide-I vs. sitagliptin: dominant, 1 mg semaglutide-I vs. sitagliptin: dominant (EUR) | EUR30,000/QALY | QSE for semaglutide-I 1 mg vs. dulaglutide, QSE for semaglutide-I 1 mg vs. sitagliptin, QSE for semaglutide-I 0.5 mg vs. dulaglutide, QSE for semaglutide-I 0.5 mg vs. sitagliptin (Table 2) | Longer time to onset of DRC, time to intensification, higher survival, greater ‘avoidance’ of DRCs | DSA completely confirmed findings; PSA likewise | Dominant conclusion not changed | Dominant conclusion not changed | Dominant conclusion not changed |
| Capehorn, 2021 [57] | Semaglutide-I vs. empagliflozin | Direct, 2019 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I | 4439/QALY (GBP) | GBP20,000/QALY | QNE (Table 2, Fig. 4) | Reduced incidence of DRCs, delayed onset of DRCs, delayed treatment intensification, driven by greater HbA1c reduction | DSA confirmed findings; PSA likewise | Fixed HbA1c over time and treatment intensification at 3 years | Shorter time horizon (10 years) | Different hypoglycaemia disutilities |
| Guzauskas, 2021 [64] | Semaglutide-O vs. empagliflozin, liraglutide, sitagliptin, MET + SU | Direct, 2020 | QALY, LY, incidence of DRC | Semaglutide-O, except vs. empagliflozin | Vs. empagliflozin: 458.400/QALY vs. liraglutide: 40.100/QALY vs. sitagliptin: 145.200/QALY vs. background (MET+SU): 117.500/QALY (US$) | US$100,000–250,000/QALY | QNE for semaglutide-I vs. liraglutide, QNE for semaglutide-I vs. empagliflozin, QNE for semaglutide-I vs. sitagliptin, QNE for semaglutide-I vs. background medication (Table 2) | Semaglutide-O had fewer MACE and cardiovascular deaths | No mention of robustness to change; but costs/QALYs very sensitive to changes in treatment effect | Change in MACE reduction of semaglutide-O | Changes in Hba1c reduction of semaglutide-O | Change in heart failure and nephropathy HR of semaglutide-O |
| Malkin, 2021 [53] | Semaglutide-O vs. empagliflozin, sitagliptin, liraglutide | Direct + indirect, 2019 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-O | Semaglutide-O vs. empagliflozin: 13,770/QALY, w indirect = 7061/QALY Semaglutide-O vs. sitagliptin: 5938/QALY, w indirect = 516/QALY Semaglutide-O vs. liraglutide: dominate, w indirect cost = dominate (EUR) | EUR20,000/QALY | QNE for semaglutide-O vs. empagliflozin, QNE for semaglutide-O vs. sitagliptin, QSE for semaglutide-O vs. liraglutide. with indirect cost: QNE, QNE, and QSE, respectively (Table 3, Fig. 1) | Greater Hba1c reductions were the key driver of clinical benefits in all comparisons. BMI made smaller contributions. Other RF made small or no contributions | DSA generally confirmed findings; PSA showed 52.7, 70.8%, 68.3% chance of semaglutide-O being CE vs. empagliflozin, sitagliptin, liraglutide, respectively | Treatment switch at 8.0% HbA1c | Use of UKPDS 82 | Shorter time horizon (30 years) |
| Risebrough, 2021 [70] | Semaglutide-O vs. dulaglutide, liraglutide, semaglutide-I | Direct, 2019 | QALY, LY, incidence of DRC, event-free survival | Semaglutide-O | Vs. semaglutide-I: 163,737/QALY, vs. dulaglutide: dominate, vs. liraglutide: dominate (US$) | US$20,000/QALY | QNE for semaglutide-O vs. injectable semaglutide, QSE for semaglutide-O vs. dulaglutide, QSE for semaglutide-O vs. liraglutide (Table 5) | Small differences in AE estimates, HbA1c benefits and event-free survival led to cost savings vs. dulaglutide and liraglutide | DSA confirmed findings; PSA focuses on semaglutide-O vs. semaglutide-I and shows that with increasing WTP, semaglutide-I is more likely to be CE | Daily cost of semaglutide-O | Weight treatment effect of semaglutide-O | Daily cost of semaglutide-O |
| Ehlers, 2022 [58] | Semaglutide-O vs. empagliflozin | Direct, 2020 | QALY, LY, incidence of DRC | Semaglutide-O not cost effective | Semaglutide-O vs. empagliflozin: 1,930,548/QAL (DKK) | DKK357,100/QALY (1 time GDP/capita) | QNE (Fig. 1) | The cost-effectiveness result was driven by a major difference in treatment costs, reflecting the large unit cost difference of Semaglutide-O vs. empagliflozin | DSA confirmed findings; PSA likewise, semaglutide-O was CE in 16% of simulations at set WTP | Discontinuation of semaglutide-O and empagliflozin, and switch to higher-dose, long-acting INS alogliptin in third-line | Shorter time horizon (5 years) | Using trial product estimand |
| Ehlers, 2022 [59] | Semaglutide-I vs. empagliflozin | Direct, 2020 | QALY, LY | Semaglutide-I not cost effective | Semaglutide-I vs. empagliflozin: 745,561/QALY, (DKK and EUR) | DKK357,100/QALY (1 time GDP/capita) | QNE (Fig. 1) | None stated | DSA confirmed findings; PSA likewise | Third-line treatment assumption (comparators replaced with INS) | Third-line treatment assumption (comparators replaced with INS) + third-line occurring at 8% HbA1c instead of 7.5% | Shorter time horizon (5 years) |
| Ekhlasi, 2022 [83] | Dulaglutide vs. liraglutide | Direct, 2018 | QALY | Dulaglutide | Dominant (US$) | US$3598.483/QALY (1 time GDP/capita in Iran 2018) | QSE (Fig. 2) | None stated | DSA confirmed findings; PSA likewise | Cost of liraglutide | Cost of dulaglutide | Hba1c reduction of liraglutide |
| Eliasson, 2022 [60] | Semaglutide-O vs. empagliflozin, sitagliptin | Direct + indirect, 2019 | QALY, incidence of DRC | Semaglutide-O | Direct: vs. empagliflozin = 239,001/QALY, vs. sitagliptin = 120,848/QALY, indirect: vs. empagliflozin = 191,721/QALY, vs. sitagliptin 95,234/QALY (SEK) | SEK500,000/QALY | Direct costs: QNE for semaglutide-O vs. empagliflozin, QNE for semaglutide-O vs. sitagliptin, with indirect costs: QNE and QNE (Fig. 2, Table 1) | Greater reductions in HbA1c led to fewer DRCs, longer time to INS initiation, fewer hypo events, and, lastly, better projected survival | DSA confirmed findings; PSA likewise | 3-year fixed duration until INS initiation | No QOL impact of BMI change | 0% discount rate |
| Franch-Nadal, 2022 [63] | Semaglutide-O vs. empagliflozin, sitagliptin, liraglutide | Direct, 2020 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-O | Vs. empagliflozin: 1339/QALY, vs. sitagliptin: dominant, vs. liraglutide: dominant, 7 mg semaglutide-O vs. sitagliptin: 2011/QALY (EUR) | EUR30,000/QALY | QNE for semaglutide-O vs. empagliflozin, QSE for semaglutide-O vs. sitagliptin, QSE for semaglutide-O vs. liraglutide, QNE for 7 mg semaglutide-O vs. sitagliptin (Table 1) | Extra clinical benefit from using semaglutide-O was due to reduced cumulative incidence and later onset of DRCs. Higher treatment cost of semaglutide-O was offset by the lower DRCs | DSA confirmed findings; PSA likewise | Shorter time horizon (10 years) | UKPDS HbA1c progression with no changes in treatment intensification | Lower 95% CI of HbA1c estimated treatment difference applied |
| Hu, 2022 [76] | Semaglutide-I vs. dulaglutide | Direct, 2021 | QALY, LY, incidence of DRC | Semaglutide-I | 26,957.44/QALY(US$) | US$12,551.5–37,654.50/QALY (1–3 times GDP/capita) | QNE (Fig. 2) | None stated | DSA showed high sensitivity to time-related factors, reversing conclusions of base-case; PSA showed 30.2%, 48.2% and 2.8% chance of being CE at above 3 times GDP/capita, between 1 and 3 times GDP/capita, and below 1 times GDP/capita, respectively | Discounting factor | Shorter time horizon | MI disutility score |
| Malkin, 2022 [61] | Semaglutide-O vs. empagliflozin, dulaglutide | Direct, 2021 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-O | Vs. empagliflozin: 23,571/QALY, vs. dulaglutide: 23,927/QALY, (EUR) | EUR30,000/QALY | QNE for semaglutide-O vs. empagliflozin, QNE for semaglutide-O vs. dulaglutide (Fig. 2) | Reduced incidence and time to onset of DRCs, the higher costs of semaglutide-O were offset by this. Higher HbA1c and weight reduction were the biggest drivers when comparing with empagliflozin and dulaglutide, respectively | DSA confirmed findings; PSA likewise | Shorter time horizon (10 years) | Discount factor of 0% | Only statistically significant differences from NMA |
| Ruan, 2022 [81] | Semaglutide-I vs. dulaglutide | Direct, 2021 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I | Semaglutide-I dominant (CNY) | CNY80,976/QALY (1 times GDP/capita) | QSE (Fig. 2) | Semaglutide-I reduced and delayed the occurrence of DRCs, and reduced mortality. This offset the increase treatment cost | DSA confirmed findings; PSA likewise | Shorter time horizon (5 years) | Shorter time horizon (10 years) | HbA1c threshold at 7.0% |
| Stafford, 2022 [73] | Semaglutide-I vs. canagliflozin | Direct + indirect, 2019 | QALY, LY, incidence of DRC | Semaglutide-I | Using the IHE-DCM model: 14,127/QALY; using the ECHO-T2DM model: 13,188/QALY (CAD) | CAD50,000/QALY | QNE and QNE using both models (Fig. 1) | QALY gains for semaglutide-I were mainly driven by later use of INS caused by higher HbA1c reduction, and greater initial weight loss. Fewer DRCs offset some of the higher treatment costs of semaglutide-I | DSA confirmed findings; PSA likewise | 10% worse HbA1c effect for semaglutide-I | HbA1c threshold set to 7.5% | Discount rate at 3.5% |
| Viljoen, 2022 [62] | Semaglutide-I vs. dulaglutide | Direct, 2020 | QALY, LY, incidence of DRC, onset of DRC | Semaglutide-I | Vs. dulaglutide 3 mg: dominant, vs. dulaglutide 4.5 mg: 228/QALY (GBP) | GBP20,000/QALY | QSE for semaglutide-I vs. dulaglutide 3 mg, QNE for semaglutide-I vs. Dulaglutide 4.5 mg (Fig. 3) | Extra clinical benefit from using semaglutide-I was due to reduced cumulative incidence and later onset of DRCs. Higher treatment cost of semaglutide-I was offset by the lower DRCs | DSA confirmed findings; PSA likewise | HbA1c threshold set to 7.5% | Lower 95% CI of HbA1c treatment difference | Addition of basal INS, then basal bolus |
| Chien, 2020 [75] | No main vs. classes: MET, SU, DPP4, SGLT2, GLP1, unspecified INS | Direct, 2019 | QALY, LY, incidence of DRC | Arm7 (SGLT2) |
Arm 6: – Arm 7 dominates Arm 3 and Arm 8 is cost effective against Arm 1 and Arm 2 Arm 4 and Arm 5 extended dominated Arm 1: MET+SU -> +DPP4 Arm 2: MET +SGLT2 -> +DPP4 Arm 3: MET+DPP4 -> +SU Arm 4: MET+DPP4 -> +SGLT2 Arm 5: MET+GLP1 -> +SU Arm 6: MET+SU -> +DPP4 Arm 7: MET+SU -> +SGLT2 Arm 8: MET+INS -> +SU (NT) |
NT770,770/QALY (forecasted GDP/capita in Taiwan in 2019) |
Arm 7 vs. Arm 3: QSE Arm 7 vs. Arm 8: QSE Arm 7 vs. Arm 1: QNE Arm 7 vs. Arm 2: QNE Arm 4 and Arm 5: extended dominated (Table 3, text) |
None stated | DSA confirmed findings; PSA likewise | Baseline HbA1c | Baseline age | Hba1c threshold |
| Hu, 2021 [76] | No main vs. dapagliflozin + saxagliptin, dapagliflozin, saxagliptin | Direct, 2019 | QALY, LY | Dapagliflozin | Dapagliflozin + saxagliptin vs. saxagliptin: 217,530/QALY dapagliflozin vs. dapagliflozin + saxagliptin: dominate dapagliflozin vs. saxagliptin: 12,191/QALY (US$) | US$10,425.29–31,275.88/QALY (1–3 times GDP/capita in 2019) | QSE for dapagliflozin + MET vs. dapagliflozin + saxagliptin + MET, QNE for dapagliflozin + MET vs. saxagliptin + MET, QNE for dapagliflozin + saxagliptin + MET vs. saxagliptin (Table 4) | None stated | DSA confirmed findings; PSA likewise | Discount rate | Saxagliptin acquisition cost | Dapagliflozin acquisition cost |
| Lin, 2021 [78] | No main vs. linagliptin 5 mg, saxagliptin 5 mg, alogliptin 25 mg, sitagliptin 100 mg, and vildagliptin 50 g | Direct, 2019 | QALY, LY, incidence of DRC | Alogliptin | Alogliptin vs. linagliptin: extended dominate, vs. saxagliptin: dominate, vs. vildagliptin: dominate (US$) | US$10,276/QALY (China capita per GDP in 2019) | QSE for alogliptin vs. linagliptin, QSE for alogliptin vs. saxagliptin: QSE for alogliptin vs. vildagliptin | Reduced cumulative incidence of DRCs | DSA confirmed findings; PSA likewise | Cost of alogliptin and sitagliptin | Reduction of HbA1c for sitagliptin and alogliptin | Discount rate |
| Zupa, 2021 [71] | Empagliflozin vs. semaglutide-I | Direct, 2020 | QALY, LY | Semaglutide-I | 19,964/QALY (US$) | US$50,000–100,000/QALY | QNE (text) | None stated | DSA confirmed findings; PSA likewise | Daily cost of semaglutide-I | Heart failure risk of semaglutide-I | Stroke risk of semaglutide-I |
| Chakravarty, 2018 [65] | Dapagliflozin vs. liraglutide, SU, DPP4, pioglitazone | Direct, 2016 | QALY | Dapagliflozin | Vs. liraglutide: dominant, vs. DPP4: dominant, vs. TZD: 25.835/QALY, vs. SU: 19.005/QALY (US$) | US$50,000/QALY | QSE for dapagliflozin vs. GLP1, QNE for dapagliflozin vs. SU, QSE for dapagliflozin vs. DPP4, QNE for dapagliflozin vs. TZD (Fig. 4, Table 5) | Change in body weight | DSA generally confirmed findings; PSA likewise | Change in weight impact of treatment | Change in Hba1c | Change in SBP |
| Neslusan, 2018 [66] | Canagliflozin vs. dapagliflozin | Direct, 2016 | QALY, LY, incidence of DRC, onset of DRC | Canagliflozin | Dominant (US$) | US$100,000/QALY | QSE (Fig. 2) | Cost offsets from higher acquisition cost, and QALY gains were driven by better HbA1c lowering, which also led to lower event rates from complications, longer time to INS, less INS use | DSA completely confirmed findings; PSA likewise | Shorter time horizon (5 years) | Later treatment intensification | Real-world patient characteristics |
| Hou, 2019 [74] | Canagliflozin vs. dapagliflozin | Direct 2017 | QALY, LY, incidence of DRC | Canagliflozin | Canagliflozin100mg dominant (US$) | US$9117/QALY (GDP/capita of China in 2017) | QSE (Table 3) | Driven by the reduced cumulative incidence of macrovascular and microvascular complications | DSA big impact from cost of drugs, moderate/small impact of disutility/costs of complications; PSA confirmed base case | Cost of canagliflozin and dapagliflozin | Disutility | Cost of complications |
| Ramos, 2019 [40] | Empagliflozin vs. sitagliptin, saxagliptin | Direct, 2018 | QALY, LY, incidence of DRC | Empagliflozin | Vs. sitagliptin: 6464/QALY, vs. saxagliptin: 3878/QALY (GBP) | GBP20,000/QALY | QNE for empagliflozin vs. sitagliptin, QNE for empagliflozin vs. saxagliptin, (Table 5, Fig. 3) | Higher initial cost of SGLT2 offset by higher QALYs and LYs. Higher cost amd more DRCs for empagliflozin because of increased survival. Lower renal complication costs | DSA confirmed findings; PSA likewise | Shorter time horizon (5 years) | Hba1c threshold for treatment switch at 9% | Cardiovascular outcomes up to 3 years |
| Ramos, 2020 [45] | Empagliflozin vs. SoC and liraglutide | Direct, 2018 | QALY, LY, incidence of DRC | Empagliflozin | Empagliflozin + SoC dominant vs. liraglutide + SoC, 6428/QALY vs. SoC alone (GBP) | GBP20,000–30,000/QALY | QSE for empagliflozin vs. liraglutide, QNE for empagliflozin vs. SoC (Table 5, Fig. 3) | Treatment costs, survival, lower CV mortality | DSA confirmed findings; PSA likewise | Shorter time horizon (5 years) | Treatment switch threshold at 9% | CVOT outcome benefits applied for full treatment duration |
| Ramos, 2020 [46] | Empagliflozin vs. Semaglutide-O | Direct, year unknown | QALY, LY, heart failure | Empagliflozin | With hHF: empagliflozin dominant, without hHF: ICER = 186,690/QALY (GBP) | GBP20,000–30,000/QALY | QSE for empagliflozin (with hHF effect) vs. oral semaglutide, QSW for empagliflozin (without hHF effect) vs. oral semaglutide (Table 4, Fig. 1) | Inclusion of hHF effect of empagliflozin. Lower cost of empagliflozin | DSA confirmed findings; but some scenarios very sensitive; PSA likewise | Excluding the treatment effect on hHF | Treatment intensification at different HbA1c thresholds | BMI polynomial utility approach |
| Reifsnider, 2020 [69] | Empagliflozin vs. sitagliptin | Direct, 2018 | QALY, LY, CVD-free LY, incidence of DRC | Empagliflozin | Base case: 6967/QALY in CVD: 3589/QALY in non-CVD: 12,577/QALY (US$) | US$50,000–150,000/QALY | QNE for base case, QNE in CVD population, QNE in non-CVD population (Table 1, ESM Fig. SA3) | Base case: least complications with empagliflozin in the CVD pop: longer CVD-free survival and less cardiovascular death, fewer rates of DRCs in general in the non-CVD pop: lower or similar rates of DRCs | DSA confirmed findings, and showed empagliflozin to be either CE or dominant, depending on parameter. More likely to be dominant in the CVD pop.; PSA confirmed findings | Rebate percentage applied to the wholesale acquisition cost | Shorter time horizon (1 year) | Adherence to empagliflozin (80%*) or commercial perspective |
| Van der Linden, 2020 [54] | Dapagliflozin vs. DPP4 | Direct + indirect, 2018 | QALY, LY, incidence of DRC | Dapagliflozin | Vs. DPP4 class: dominant (EUR) | EUR20,000/QALY | QSE (Table 7, Fig. 2) | Dapagliflozin reduced the incidence of micro- and macrovascular complications, in exchange for more urinary tract infections and gastrointestinal infections, which increased quality of life. Dapagliflozin was cost saving due to lower treatment costs and reduced DRCs | DSA confirmed findings. No change from being dominant; PSA confirmed base case | Dominant conclusion not changed | Dominant conclusion not changed | Dominant conclusion not changed |
| Ehlers, 2021 [56] | Empagliflozin vs. liraglutide | Direct, 2019 | QALY, LY, incidence of DRC | Empagliflozin | Empagliflozin dominant (DKK) | DKK357,100/QALY (1 times the GDP/capita) | QSE (Fig. 2, Table 4) | Longer survival of empagliflozin, higher total cost of liraglutide | DSA confirmed findings. In scenario where liraglutide effects were extended to 13 years (Hba1c 8.5%), liraglutide would have extreme ICER (>3 mill/QALY); PSA likewise | Dominant conclusion not changed | Dominant conclusion not changed | Dominant conclusion not changed |
| Gourzoulidis, 2021 [55] | Empagliflozin vs. dapagliflozin | Direct, 2020 | QALY, LY, incidence of DRC | Empagliflozin | Vs. dapagliflozin: 965/QALY (EUR) | EUR36,000/QALY | QNE (Table 3, ESM Fig. 1) | Empagliflozin had reduced many DRCs, with longer life as a result | DSA confirmed findings, but empagliflozin showed dominance in 3-year model, not shown in tornado diagram; PSA confirmed findings | Discount rate of costs | HR: dapagliflozin vs. empagliflozin | Discount rate health |
| Ramos, 2021 [77] | Empagliflozin vs. liraglutide, sitagliptin | Direct, 2019 | QALY, LY, incidence of DRC | Empagliflozin | Vs. liraglutide: dominant vs. sitagliptin: 75,349/QALY (RMB) | RMB212,676/QALY (3 times GDP/capita) | QSE for empagliflozin vs. liraglutide, QNE for empagliflozin vs. sitagliptin, (Table 4, Fig. 3) | Longer survival of empagliflozin, lower cost from less HF and renal complications, despite higher costs from longer survival | DSA confirmed findings, except when changing treatment switch for liraglutide to 13 years, at HbA1c 8.5%, which puts empagliflozin in QSW; PSA confirmed base case | Effects of liraglutide extended to 13 years /HbA1c threshold of 8.5% | Shorter time horizon (5 years) | CV outcomes only used for 3 years |
| Reifsnider, 2021 [67] | Empagliflozin vs. dapagliflozin, canagliflozin | Direct, 2020 | QALY, LY, incidence of DRC | Empagliflozin | Empagliflozin vs. canagliflozin: dominate empagliflozin vs. dapagliflozin: 3054/QALY Empagliflozin vs. SoC: 32,848/QALY (US$) | US$50,000–150,000/QALY | QSE for empagliflozin vs. canagliflozin, QNE for empagliflozin vs. dapagliflozin, (Table 1, ESM Fig. OS1) | Longer overall survival and reduced rates of clinical events | DSA generally confirmed findings. Using treatment effects that favoured the comparators, made comparators dominant; PSA confirmed base case | Reducing HR for comparator vs. empagliflozin | Shorter time horizon (1, 3, 5, and 10 years) | Commercial perspective |
| Lasalvia, 2022 [82] | Dapagliflozin vs. DPP4 | Direct, 2020 | QALY, LY, incidence of DRC | Dapagliflozin | 1964.80/QALY (US$) | US$5710–17,129.9/QALY (1–3 times GDP/capita) | QNE (Table 4) | None stated | DSA confirmed findings; PSA likewise | Change of time horizon | Hba1c threshold for treatment switch at 9% | Weight reduction effect maintenance |
| Peng, 2022 [80] | SGLT2 vs. DPP4 | Direct, 2020 | QALY, incidence of DRC | SGLT2 | With CVD history: 3244.07/QALY; without CVD history: 4185.64/QALY (US$) | US$30,038–90,114/QALY (1–3 times GDP/capita) | QNE and QNE for comparisons with and without CVD history (Table 1) | None stated | DSA confirmed findings; PSA likewise | Cost of DPP4 | HR of SGLT2 vs. DPP4 on all-cause death | HR of SGLT2 vs. DPP4 on stroke |
| Reifsnider, 2022 [72] | Empagliflozin vs. liraglutide | Direct, 2019 | QALY, LY, incidence of DRC | Empagliflozin | Empagliflozin dominant (US$) | None stated | QSE (Table 1) | Fewer DRCs over time and longer survival due to empagliflozin's effect on patients with CVD | DSA completely confirmed findings; PSA likewise | Disutility of injectable treatment | Drug acquisition cost | Treatment effect for patients with CVD (HR of empagliflozin vs. liraglutide) |
Comparisons list the main comparators and then the alternatives separated by a comma, while ‘and’ is written to show that several different comparisons were made. When one medication is combined with another in the comparison, it is explicitly stated or symbolised with a ‘+’ symbol
1w once per week, AE adverse event, BMI body mass index, CAD Canadian dollars, CE cost-effective, CHF chronic heart failure, CI confidence interval, CNY Chinese Yuan, CV cardiovascular, CVD cardiovascular disease, CVOT Cardiovascular Outcome Trial, DKK Danish kroner, DPP4 dipeptidylpeptidase-4 inhibitors, DRCs diabetes-related complications, DSA deterministic sensitivity analysis, ECHO-T2DM Health Outcomes Model of Type 2 Diabetes Mellitus, ESM electronic supplementary, material, EUR Euro, GBP British pound sterling, GDP gross domestic product, GLP1 glucagon-like peptide-1 recepter agonist, HR hazard ratio, hHF hospitalisation for heart failure, ICER incremental cost-effectiveness ratio, IDegLira combination of liraglutide and INS degludec, IHD ischaemic heart disease, IHE-DCM Institute for Health Economics Cohort Model for T2DM, INS insulin, LY life years, MACE major adverse cardiac events, MET metformin, MDI multiple daily injections, MI myocardial infarction, NMA network meta-analysis, NT Taiwan new dollar, pop population, PSA probabilistic sensitivity analysis, QALY quality-adjusted life-years, QOL quality of life, QSE south-east quadrant, QNE north-east quadrant, QSW south-west quadrant, QW every week, RMB Renminbi, SBP systolic blood pressure, SEK Swedish kroner, SoC standard of care, US$ United States dollar, SGLT2 sodium-glucose cotransporter-2 inhibitors, semaglutide-I/O semaglutide injectable/oral, SU sulfonylurea, TZD thiazolidinedione, UKPDS UK Prospective Diabetes Study, WTP willingness to pay