Table 3.
Study Design Comparison of Published Literature Assessing the Association between SGLT2i Use and Amputation Risk
| Author/Year (Database) |
Exclusions: Prior insulin, prior amputation, baseline CKD/ESRD, baseline CVD |
Mean Age (years) | Index Drug | Comparator Drug | Exposure Definition | Amputation Site (includes above-knee?) | Confounding Control | Analytic Approach | HR (95% CI) |
|---|---|---|---|---|---|---|---|---|---|
|
Neal 2017 (CANVAS) |
None | 63.3 | CANA | Placebo | --- | Yes | Randomization | ITT | 1.97 (1.41–2.75) |
| None | 63.3 | CANA | Placebo | --- | No | Randomization | ITT | 1.94 (1.31–2.88) | |
| Amputation | 63.3 | CANA | Placebo | --- | Yes | Randomization | ITT | 1.88 (1.27–2.78) | |
| CVD | 63.3 | CANA | Placebo | --- | Yes | Randomization | ITT | 2.34 (1.53–3.58) | |
|
Yuan 2017 (MarketScan CCAE) |
Amputation | 53.3 | SGLT2i | All non-SGLT2i AHAb | 1+ Rx | No | PS matching | ITT | 0.98 (0.68–1.41) |
|
Ryan 2018 (MarketScan CCAE)a |
None | 55 | CANA | All non-SGLT2i AHA | 1+ Rx | No | PS matching | AT | 0.56 (0.32–0.92) |
| None | 55 | CANA | All non-SGLT2i AHA | 1+ Rx | No | PS matching | ITT | 1.01 (0.80–1.28) | |
| Amputation | 55 | CANA | All non-SGLT2i AHA | 1+ Rx | No | PS matching | AT | 0.47 (0.25–0.83) | |
| Amputation | 55 | CANA | All non-SGLT2i AHA | 1+ Rx | No | PS matching | ITT | 0.99 (0.77–1.27) | |
| Insulin | 55 | CANA | All non-SGLT2i AHA | 1+ Rx | No | PS matching | AT | 1.10 (0.38–2.51) | |
| Insulin | 55 | CANA | All non-SGLT2i AHA | 1+ Rx | No | PS matching | ITT | 1.00 (0.59–1.60) | |
| Insulin, Amputation | 55 | CANA | All non-SGLT2i AHA | 1+ Rx | No | PS matching | AT | 0.87 (0.26–2.15) | |
| Insulin, Amputation | 55 | CANA | All non-SGLT2i AHA | 1+ Rx | No | PS matching | ITT | 1.00 (0.58–1.63) | |
| None | 55 | CANA | Select non-SGLT2i AHAc | 1+ Rx | No | PS matching | AT | 1.08 (0.65–1.75) | |
| None | 55 | CANA | Select non-SGLT2i AHA | 1+ Rx | No | PS matching | ITT | 0.96 (0.77–1.21) | |
| Amputation | 55 | CANA | Select non-SGLT2i AHA | 1+ Rx | No | PS matching | AT | 0.85 (0.47–1.46) | |
| Amputation | 55 | CANA | Select non-SGLT2i AHA | 1+ Rx | No | PS matching | ITT | 0.93 (0.72–1.18) | |
| Insulin | 55 | CANA | Select non-SGLT2i AHA | 1+ Rx | No | PS matching | AT | 1.12 (0.57–2.04) | |
| Insulin | 55 | CANA | Select non-SGLT2i AHA | 1+ Rx | No | PS matching | ITT | 1.20 (0.91–1.57) | |
| Insulin, Amputation | 55 | CANA | Select non-SGLT2i AHA | 1+ Rx | No | PS matching | AT | 0.82 (0.36–1.68) | |
| Insulin, Amputation | 55 | CANA | Select non-SGLT2i AHA | 1+ Rx | No | PS matching | ITT | 1.07 (0.79–1.42) | |
|
Chang 2018 (MarketScan CCAE) |
Insulin, Amputation | 54.2 | SGLT2i | DPP4i | 1+ Rx | Yes | SMR weighting | AT | 1.50 (0.85–2.67) |
| Insulin | 54.2 | SGLT2i | DPP4i | 1+ Rx | Yes | SMR weighting | AT | 1.73 (1.01–2.98) | |
| Insulin, Amputation | 52.7 | SGLT2i | GLP-1 receptor agonist | 1+ Rx | Yes | SMR weighting | AT | 1.47 (0.64–3.36) | |
| Insulin | 52.7 | SGLT2i | GLP-1 receptor agonist | 1+ Rx | Yes | SMR weighting | AT | 1.53 (0.70–3.34) | |
| Insulin, Amputation | 51.5 | SGLT2i | SU/metformin/TZD | 1+ Rx | Yes | SMR weighting | AT | 2.12 (1.19–3.77) | |
| Insulin | 51.5 | SGLT2i | SU/metformin/TZD | 1+ Rx | Yes | SMR weighting | AT | 2.19 (1.27–3.77) | |
|
Adimadhyam 2018 (MarketScan CCAE) |
Insulin, CKD | 54.7 | SGLT2i | DPP4i | 1+ Rx | Yes | PS matching | AT | 1.38 (0.83–2.31) |
| Insulin, CKD, Amputation | 54.7 | SGLT2i | DPP4i | 1+ Rx | Yes | PS matching | AT | 1.04 (0.63–1.73) | |
| Insulin, CKD, CVD | 54.7 | SGLT2i | DPP4i | 1+ Rx | Yes | PS matching | AT | 1.50 (0.76–2.97) | |
| Insulin, CKD | 54.7 | CANA | DPP4i | 1+ Rx | Yes | PS matching | AT | 1.15 (0.64–2.07) | |
| Insulin, CKD | 54.7 | SGLT2i | DPP4i | 1+ Rx | No | PS matching | AT | 1.38 (0.79–2.42) | |
|
Dawwas 2018 (MarketScan CCAE) |
Amputation, ESRD | 54.5 | SGLT2i | DPP4i | 1+ Rx | No | PS matching | AT | 0.88 (0.65–1.15) |
| Amputation, ESRD | 54 | SGLT2i | SU | 1+ Rx | No | PS matching | AT | 0.74 (0.57–0.96) | |
|
Our Study (MarketScan CCAE) |
None | 52.5 | SGLT2i | DPP4i | 2+ Rx | No | SMR weighting | AT | 1.69 (1.20–2.38) |
| None | 52.5 | SGLT2i | DPP4i | 2+ Rx | No | SMR weighting | ITT | 1.43 (1.01–2.03) | |
| None | 52.5 | SGLT2i | SU | 2+ Rx | No | SMR weighting | AT | 1.02 (0.67–1.55) | |
| None | 52.5 | SGLT2i | SU | 2+ Rx | No | SMR weighting | ITT | 1.02 (0.69–1.50) | |
| None | 52.5 | SGLT2i | All non-SGLT2i AHA | 2+ Rx | No | SMR weighting | AT | 1.02 (0.54–1.93) | |
| None | 52.5 | SGLT2i | All non-SGLT2i AHA | 2+ Rx | No | SMR weighting | ITT | 1.06 (0.60–1.86) | |
| None | 52.5 | CANA | DPP4i | 2+ Rx | No | SMR weighting | AT | 1.77 (1.22–2.57) | |
| None | 52.5 | CANA | SU | 2+ Rx | No | SMR weighting | AT | 1.18 (0.77–1.83) | |
| None | 52.5 | CANA | All non-SGLT2i AHA | 2+ Rx | No | SMR weighting | AT | 0.85 (0.38–1.91) | |
| None | 52.5 | SGLT2i | DPP4i | 1+ Rx | No | SMR weighting | AT | 1.29 (0.95–1.77) | |
| None | 52.5 | SGLT2i | SU | 1+ Rx | No | SMR weighting | AT | 0.84 (0.59–1.20) | |
| None | 52.5 | SGLT2i | All non-SGLT2i AHA | 1+ Rx | No | SMR weighting | AT | 0.86 (0.49–1.50) | |
| Insulin | 52.5 | SGLT2i | DPP4i | 2+ Rx | No | SMR weighting | AT | 1.54 (1.06–2.23) | |
| Insulin | 52.5 | SGLT2i | SU | 2+ Rx | No | SMR weighting | AT | 0.85 (0.55–1.32) | |
| Amputation | 52.5 | SGLT2i | DPP4i | 2+ Rx | No | SMR weighting | AT | 1.54 (1.06–2.23) | |
| Amputation | 52.5 | SGLT2i | SU | 2+ Rx | No | SMR weighting | AT | 0.84 (0.54–1.31) | |
| CKD | 52.5 | SGLT2i | DPP4i | 2+ Rx | No | SMR weighting | AT | 1.37 (0.92–2.05) | |
| CKD | 52.5 | SGLT2i | SU | 2+ Rx | No | SMR weighting | AT | 0.69 (0.43–1.11) | |
| CVD | 52.5 | SGLT2i | DPP4i | 2+ Rx | No | SMR weighting | AT | 1.96 (1.23–3.12) | |
| CVD | 52.5 | SGLT2i | SU | 2+ Rx | No | SMR weighting | AT | 0.81 (0.46–1.43) | |
|
Udell 2018 (US DoD Health System) |
Amputation | 65.8 | SGLT2i | All non-SGLT2i AHA | 1+ Rx | No | PS matching | AT | 2.01 (0.89–4.53) |
| Amputation | 65.8 | SGLT2i | All non-SGLT2i AHA | 1+ Rx | No | PS matching | ITT | 1.99 (1.12–3.51) | |
|
Ueda 2018 (Swedish/Danish National Register) |
ESRD | 61 | SGLT2i | GLP-1 receptor agonist | 1+ Rx | No | PS matching | AT | 2.32 (1.37–3.91) |
| ESRD | 61 | SGLT2i | GLP-1 receptor agonist | 1+ Rx | No | PS matching | ITT | 1.90 (1.25–2.87) | |
| ESRD, CVD | 61 | SGLT2i | GLP-1 receptor agonist | 1+ Rx | No | PS matching | AT | 2.12 (0.96–4.69) | |
| ESRD, Amputation, | 61 | SGLT2i | GLP-1 receptor agonist | 1+ Rx | No | PS matching | AT | 2.48 (1.14–5.40) |
Abbreviations: CCAE, Commercial Claims and Encounters; DoD, Department of Defense; CKD, chronic kidney disease; ESRD, end-stage renal disease; CVD, cardiovascular disease; SGLT2i, sodium-glucose cotransporter-2 inhibitor; CANA, canagliflozin; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP, glucagon-like peptide; SU, sulfonylurea; TZD, thiazolidinedione; AHA, anti-hyperglycemic agents; Rx, prescription; PS, propensity score; SMR, standardized mortality ratio; ITT, intention-to-treat; AT, as-treated; CI, confidence interval
a.
Only MarketScan CCAE results shown for Ryan et al. Other results, not shown, were reported for MarketScan Medicare Supplement, MarketScan Medicaid Supplement, and Optum, and are made available by authors at http://data.ohdsi.org/AhasHfBkleAmputation/
b.
All non-SGLT2i AHA: DPP4i, GLP-1 RA, TZD, SU, insulin, other AHA (acarbose, bromocriptine, miglitol, nateglinide, repaglinide)
c.
Select non-SGLT2i AHA: DPP4i, GLP-1 RA, other AHA