Background
|
Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are licensed for the treatment of type 2 diabetes (T2D) and more recently for heart failure in those with and without diabetes. |
In T2D, both canagliflozin and empagliflozin reduce major adverse cardiovascular events (MACE) but dapagliflozin does not. All three agents reduce heart failure in established diabetes and dapagliflozin reduces heart failure in those without diabetes. Furthermore, safety concerns have emerged, either during trials or through post-marketing surveillance, such as SGLT2i exposure possibly being associated with LLA, DKA, bone fracture and GMI. |
For effectiveness, population-based pharmacoepidemiology studies can confirm and extend the findings of randomised controlled trials (RCTs) to broader populations not eligible for trial participation and explore safety, for which RCTs are not usually powered, in more detail. |
Why carry out this study?
|
We did a pre-planned and registered, impartial systematic review asking: do the benefits of SGLT2is in T2D extend to those ineligible for RCT participation, and are safety concerns which arose during the trials (or in post-marketing) detected, in population-based observational pharmacoepidemiology studies? We considered and reported all clinical event-based outcomes for effectiveness and safety in studies which met our inclusion/exclusion criteria. |
What was learned from the study?
|
A total of 37 population-based studies including adults (n = 1,300,184) with T2D were identified. These appear to confirm that SGLT2is in T2D appear safe from the CVD perspective, and may have associated benefit in primary as well as secondary CVD prevention, particularly in HF-associated events. However, SGLT2i exposure may be associated with an increased risk of GMI, LLA and DKA, although longer follow-up studies are needed. |
Digital Features
Introduction
Methods
Results
Exposure/study number | Study summary |
---|---|
SGLT2i class | |
1.1 | The large 2017 main CVD-REAL cohort study explored the association of SGLT2i class exposure vs. OADs on HHF (primary outcome and composite component) [58]. SGLT2i exposure was associated with a reduction in the CVD composite of ACM and HHF (Table S6.3) and with ACM (Table S14.3) and HHF (Table S10.7) composite components alone with narrow CIs and authors suggest benefit may extend to primary prevention of HHF (although subgroup analysis on the basis of pre-existing CVD was not presented) |
1.2 | A large 2018 CVD-REAL sub-analysis explored the association of SGLT2i class vs. OAD on stroke and MI events [57]. SGLT2i exposure was associated with a reduction in the risk of stroke in all analyses (Table S9.6) and a neutral association with the risk of MI (reduced in the on-treatment cohort but not in the ITT cohort, Table S8.6) and suggests that the benefit may extend to primary prevention of these outcomes (although this subgroup analysis is not presented). The CIs were narrow |
1.3 | A further large 2017 CVD-REAL sub-analysis investigated the effect of SGLT2i class vs. OADs on CVD [54]. SGLT2i exposure was associated with a reduction in MACE (primary prevention-only, Table S7.2) and HF (primary and secondary prevention, Table S10.10), and a neutral association in non-fatal stroke and non-fatal MI (Tables S9.5 and S8.5) with no effect on the negative control, atrial fibrillation. The MACE benefit appeared greatest in those aged ≥ 65 years (DNS) and CIs were narrow for all outcomes |
1.4 | CVD-REAL 2 was a large 2018 cohort study exploring the association of SGLT2i class exposure vs. OADs on HHF, MI and stroke [56]. SGLT2i exposure was associated with a reduction in HHF (Table S10.9), MI (Table S8.4), stroke (Table S9.4) and the composite of HHF and death (Table S6.4) in all analyses. The CIs were narrow. The effect remained consistent in pre-planned subgroup analysis of those without pre-existing CVD (DNS) |
1.5 | A small 2017 American cohort study explored the association of SGLT2i class vs. DPP4i exposure on HHF [55]. SGLT2i exposure was associated with a reduction in HHF in the PS-matched, IPTW and MSM methods with narrow CIs (Table S10.4). This association was driven mainly by findings among people aged ≥ 65 years and/or with pre-existing diabetes complications (DNS) |
1.6 | A large 2018 American cohort study explored the association between SGLT2i class vs. non-SGLT2i AHDs on MACE, HHF, non-fatal stroke and non-fatal MI [66]. SGLT2i exposure in the ITT analysis was associated with a reduction the primary composite outcome of ACM and HHF (Table S6.5), the HHF component alone (Table S10.6) and the secondary outcome of MACE overall (Table S7.3) but a neutral association with the non-fatal MI (Table S8.7) and non-fatal stroke (Table S9.7) components when analysed individually. The associated effects reported in the ITT analysis were amplified in the on-treatment analysis (DNS). All CIs were narrow. The results remained consistent in all the pre-planned subgroup analyses, including with and without pre-existing CVD, suggesting an associated benefit in both primary and secondary prevention (DNS) |
1.7 | A large 2018 South Korean cohort study investigated the association of SGLT2i class exposure vs. DPP4i on HHF [40]. SGLT2i exposure was associated with a reduction in HHF in all time periods analysed up to 3 years post-initiation in the whole population and in the secondary prevention population with varying CI width (a duration–response effect) but not in the primary prevention population with the associated reduction in HHF only apparent in time periods > 1-year post-exposure (lagged duration–response effect) (Table S10.5) |
1.8 | A medium-sized 2018 American cohort study explored the association of SGLT2i class vs. DPP4i on HHF, stroke, IHD and hospitalised PVD (negative control, schizophrenia) [62]. SGLT2i exposure was associated with a neutral effect for all outcomes including negative control (Tables S6.2, S10.3, S9.2, S8.1). The CIs were wide. These findings remained stable irrespective of baseline HbA1c and prior metformin use and also in the maximally adjusted and time-varying model (DNS) |
1.9 | A large 2019 American cohort study explored the association of SGLT2i class vs. SUs and DPP4is [37]. Versus SUs, SGLT2i exposure was associated with a lower risk of MI, HHF and stroke with a reduction also observed in the composite of MI and stroke. Versus DPP4is, SGLT2i exposure was associated with a reduction in HHF, MI, stroke with a reduction also observed in the composite of MI and stroke, all CIs were narrow (all comparisons in Tables S6.1, S10.1, S9.1, S8.3). The associated effect persisted in sensitivity analyses in those aged < 65 years but not those aged ≥ 65 years, but the associated reduction in CVD and HHF remained when the primary/secondary CVD prevention groups and individual agents were analysed separately (DNS) |
1.10 | A medium-sized 2019 Scandinavian cohort study explored the association of SGLT2i class vs. DPP4i on primary/secondary prevention of MACE, HHF, incident MI and stroke [44]. SGLT2i use in the ITT analysis was associated with a reduction in the risk of HHF (in those with and without a history of HF but only in those with pre-existing CVD, when analysed separately) and also an associated neutral effect on MACE and its components (in both primary/secondary CVD prevention) (Tables S10.2, S9.3, S8.2, S7.1). CIs were narrow. The on-treatment analysis was associated with a reduction in MACE, but not in AMI and stroke (driven by a reduction in CVD mortality) while the reduction in HF was amplified (DNS). Individuals aged ≥ 65 years saw an associated reduction in both MACE and HHF versus those aged < 65 years (DNS), who did not |
1.11 | A small 2019 American cohort study explored the association of SGLT2i class vs. OAD in those with a diagnosis of HF, using loop-diuretic prescriptions as a proxy for HF symptomatic severity [51]. SGLT2i exposure was associated with a reduction in new loop-diuretic use but no change in diuretic use in those already exposed (Table S10.8) |
Empagliflozin | |
1.12 | A medium-sized 2019 American cohort study explored the association of empagliflozin vs. sitagliptin on HHF [63]. In the population overall there was a reduction in HHF associated with empagliflozin exposure, greater in the broad definition of HHF (HHF mentioned anywhere on discharge, DNS) compared to the specific one (HHF in primary position of discharge, Table S10.15). In subgroup analyses (pre-existing CVD, HF, sex and empagliflozin dose), the associated reduction for the broad HHF definition remained stable and demonstrated a dose–response effect but not for the specific definition (CVD subgroups in Table S10.15, other DNS). The CIs were wide. There was no association with negative control outcome, seasonal flu vaccination |
Canagliflozin | |
1.13 | A large 2018 American study investigated the association of canagliflozin exposure vs. all non-SGLT2i users and also vs. select non-SGLT2i (DPP4i, GLP‐1RA, TZD, SU and insulin) and head-to-head with other SGLT2is (followed by other all SGLT2is vs. non-SGLT2i) on the association with HHF [65]. See Table S13 for baseline characteristics in each of the datasets. In the on-treatment analysis, a reduced association with HHF was observed in canagliflozin vs. all non-SGLT2i comparison (primary outcome) with narrow CIs, canagliflozin vs. select non-SGLT2is comparison and SGLT2is vs. non-SGLT2is but not for canagliflozin head-to-head with other SGLT2is (Table S10.16). This attenuated in the ITT analysis (DNS). In those with established CVD (75% of the post-index events), there was also an associated reduction with canagliflozin vs. AHDs but not head-to-head with other SGLT2is, suggesting a class effect (DNS) |
1.14 | A medium-sized 2018 American cohort study explored the association of canagliflozin vs. DPP4i, GLP-1RA and SUs (analysed separately) on HHF (primary event-based outcome and diuretic use as a proxy) and a CVD composite of MI and stroke (secondary outcome) (Tables S11 and S12) [45]. Canagliflozin was associated with a risk reduction for HHF (Table S10.12) and diuretic use in all comparisons and a neutral effect for the composite CVD endpoint (Table S6.6) and the individual components of the composite (MI Table S8.10; stroke Table S9.10, other DNS) in both primary and secondary CVD prevention. The CIs were narrow. The on-treatment and baseline HbA1c-adjusted analyses yielded the same results (DNS) |
Dapagliflozin | |
1.15 | An unmatched medium-sized 2019 Taiwanese cohort study explored the association of dapagliflozin head-to-head with empagliflozin on the composite of CV mortality, MI, stroke and HHF (negative control, incident AF) [47]. Dapagliflozin exposure was associated with a neutral effect on the composite (Table S6.10), MI and stroke, but was associated with a reduction in HHF compared with empagliflozin (MI Table S8.11; stroke Table S9.11; HHF Table S10.14). This associated reduction remained stable in standardised mortality analysis, the low dose group and also when adjusting for CVD risk, regardless other CVD drug exposure (DNS). Both drugs showed a neutral effect on the negative control. The composite CI was narrow, but the other outcomes CIs were of varying width |
1.16 | A medium-sized 2018 CVD-REAL sub-analysis investigated the association of dapagliflozin vs. DPP4i on MACE [64]. The on-treatment analysis showed dapagliflozin was associated with a reduced risk of MACE (Table S7.4), MACE, unstable angina and HHF expanded composite (DNS) and HHF alone (Table S10.11). For the MACE components there was a neutral effect on non-fatal MI (Table S8.9) and non-fatal stroke (Table S9.9). The CIs were narrow throughout. There was also a reduced association with incident AF. The results remained stable in the ITT analysis but primary/secondary CVD prevention groups were not analysed separately (DNS) |
1.17 | A medium-sized 2017 Swedish cohort study explored the effect of dapagliflozin vs. insulin’s association with non-fatal CVD [61]. Dapagliflozin exposure was associated with a reduction of non-fatal CVD in the PS-matched and the adjusted model (DNS), for both the on-treatment (PSM Table S6.7) and ITT analyses (DNS). The CIs were narrow. Primary/secondary CVD prevention was not analysed |
1.18 | A small 2017 UK cohort study explored the association between dapagliflozin and unexposed controls on incident CVD (secondary outcome) [49]. A neutral association (Table S6.8) on incident CVD in the low-risk (of CVD) population was observed (incident CVD in the overall population not assessed). The CIs were narrow |
1.19 | A medium-sized 2019 Swedish cohort study examined the association of dapagliflozin vs. OADs on MACE, HHF, MI, stroke and AF [60]. Dapagliflozin was associated, in the ITT analysis, with a lower risk of HHF (Table S10.13) but a neutral association on MACE (Table S7.5), MI (Table S8.8), stroke (Table S9.8) and AF. The CIs were narrow. The associated on-treatment effect was amplified such that MACE reduction became significant (DNS) |
1.20 | A medium-sized 2019 Scottish cohort study explored the association of dapagliflozin exposure vs. non-exposure on CVD (coronary/cerebrovascular disease) [59]. This was a secondary analysis. Dapagliflozin was associated with a neutral effect with narrow CIs on incident CVD in the dose–response analysis (Table S6.9) |
Exposure/study number | Study summary |
---|---|
SGLT2i class | |
2.1 | The main large 2017 CVD-REAL cohort study explored the association of SGLT2i class exposure vs. OADs on ACM [58]. SGLT2i exposure was associated with a reduction in ACM alone with narrow CIs (Table S14.3) and also in the composite with HHF (Table S6.3), stable geographically |
2.2 | A large 2017 Scandinavian study (CVD-REAL sub-analysis) explored the association of CVD mortality and ACM in SGLT2i class-exposed vs. OADs [54]. Authors report an association of lower CVD mortality in those exposed to SGLT2i (Table S14.4) in those with and without established CVD, with a greater reduction in those aged > 65 years (DNS). There was also a reduced association with ACM (Table S14.4). The CIs were narrow |
2.3 | A large 2018 American cohort study explored the association between SGLT2i class vs. non-SGLT2i AHAs on ACM [66]. SGLT2i exposure was associated with a reduction in ACM (and also in the composite of ACM and HHF, Table S6.5) in the ITT cohort (Table S14.5), stable in the pre-planned subgroup analysis (DNS). The CIs were narrow |
2.4 | The large 2018 CVD-REAL 2 cohort study exploring the association of SGLT2i class exposure vs. OADs on ACM [56]. SGLT2is were associated with a reduction in the ITT (Table S14.6) and on-treatment analyses, in those with and without established CVD groups (DNS) for ACM alone (Table S6.4). The CIs were narrow |
2.5 | A medium-sized 2019 Scandinavian cohort study explored the association of SGLT2i class vs. DPP4i on CVD mortality [44]. SGLT2is showed a neutral association with CVD mortality in the population overall in the ITT analysis (Table S14.1) but a reduced association in the on-treatment analysis (DNS). For ACM, SGLT2i use was associated with a reduction in the risk of ACM in the ITT (Table S14.1) and on-treatment groups (DNS). The CIs were narrow |
2.6 | A medium-sized 2019 Israeli case–control explored the association of SGLT2i class exposure vs. DPP4i on ACM [34]. This study showed an associated reduction in the odds of ACM in both the crude (DNS) and the adjusted model for SGLT2is (secondary analysis, Table S14.2). The CIs were wide |
Canagliflozin | |
2.7 | A medium-sized 2018 American cohort study comparing canagliflozin exposure pairwise with DPP4i, GLP-1RAs and SUs showed a neutral effect of CVD mortality in all comparisons (Table S14.9). These associations remained stable when adjusted for baseline HbA1c level (DNS) [45]. For ACM, there was a neutral association with canagliflozin (part of CVD composite) overall (Table S14.9) and in primary/secondary CVD prevention. These associations remained stable when adjusted for baseline HbA1c level (DNS). The CIs were wide for all comparisons |
Dapagliflozin | |
2.8 | A medium-sized 2017 Swedish study explored the effect of dapagliflozin vs. insulin’s association with ACM [61]. Dapagliflozin exposure was associated with a reduced risk of ACM in both those with, with narrow CIs, and without pre-existing CVD, with wider CIs than those with CVD (Table S14.10) |
2.9 | A small 2017 UK cohort study explored the association between dapagliflozin and unexposed controls on ACM [49]. There was an associated reduction in ACM in the both the low-risk (of CVD) population and the population overall for dapagliflozin with narrow CIs (including those with prevalent CVD) (Table S14.11) |
2.10 | A medium-sized 2019 Swedish cohort study examined the association between dapagliflozin vs. non-SGLT2i OADs on CVD mortality and ACM [60]. Dapagliflozin exposure was associated with a lower risk of CVD mortality (MACE component) in both the ITT (Table S14.7) and on-treatment groups (DNS). For ACM, dapagliflozin was associated with a lower risk of ACM in both analyses (ITT, Table S14.7). The CIs were narrow |
2.11 | A medium-sized 2018 CVD-REAL sub-analysis investigated the effect of dapagliflozin vs. DPP4i on CVD mortality (MACE component) and ACM (single outcome) [64]. This study showed a neutral association on CVD mortality in the on-treatment analysis (Table S14.8). For ACM there was a reduced association (Table S14.8). The results for both outcomes remained stable in subgroup/sensitivity analysis (DNS). The CIs were narrow |
Dapagliflozin head-to-head with empagliflozin | |
2.12 | A medium-sized 2019 Taiwanese cohort study explored the association of dapagliflozin head-to-head with empagliflozin for CVD mortality [47]. Dapagliflozin showed a neutral association with CVD mortality ((Table S14.12) as part of a composite outcome), with wide confidence intervals, (stable in sensitivity analyses, DNS). The CIs were wide |
Exposure/study number | Study summary |
---|---|
SGLT2i class | |
3.1 | A medium-sized 2018 Scandinavian study using Sweden and Denmark’s population registers, analysed separately, explored SGLT2i class vs. GLP-1RAs’ (only Sweden for the maximally adjusted model) association with AKI [50]. Both the unadjusted and maximally adjusted HR showed a neutral association for AKI in those exposed to SGLT2i but both CIs were wide (Table S15.1, Fig. 2). The CIs were moderately wide. In subgroups analysis, the effects remained stable except in those with pre-existing CVD, which was associated with a reduction in AKI (DNS) |
3.2 | A medium-sized 2019 Israeli study explored the deterioration of CKD status and hospitalisation for AKI in those exposed to SGLT2i class vs. DPP4i [34]. SGLT2i exposure was associated with a reduced odds of the composite of hospitalisation with AKI, initiation of dialysis and sustained eGFR < 15 but with no effect on deterioration of CKD category (Table S15.2, Fig. 2). The CIs were narrow |
3.3 | A small 2017 American cohort study compared the use of SGLT2i class vs. OAD, in two separate datasets, analysed separately, on the association with AKI [43]. Two definitions of AKI (KDIGO and ICD) were used and SGLT2i exposure was associated a reduction AKI in the MS dataset (adjusted and unadjusted) but not the smaller GHS dataset, where the associated effect attenuated in the adjusted model (Table S15.3, Fig. 2). The CIs were narrow. These results remained stable when SGLT2i drugs were analysed individually |
Exposure/study number | Study summary |
---|---|
SGLT2i class | |
4.1 | |
4.2 | A medium-sized 2018 American cohort study compared the hazard of LLA associated with SGLT2i class exposure vs. DPP4is and SUs [52]. The study reports an elevated association of LLA compared to DPP4i and a neutral association compared to SUs in all analyses with wide CIs for both comparisons. Overall, 83% of the amputations were of the toe and metatarsal (Table S16.2, Fig. 3). In subgroup analysis, characteristics associated with an increased LLA risk were history of amputation, baseline insulin use and history of CKD in both analyses (but metformin use and history of CVD-only in the SU comparison, DNS). Results remained stable in sensitivity analysis, expect for canagliflozin alone, which had a higher HR (DNS) |
4.3 | A medium-sized 2018 American cohort study investigated the association of SGLT2i class vs. DPP4i with LLA [33]. The maximally adjusted HR suggests SGLT2i exposure was associated a neutral effect on risk of LLA (Table S16.3, Fig. 3). The CIs were wide. Three-quarters of detected amputations occurred at the level of partial foot. In subgroup analysis, there was a neutral association for increased risk in those aged ≥ 65 years, with pre-existing PVD or with at ≥ 1 vascular complication of diabetes (‘high-risk group’, DNS). The risk of amputation was higher in the dapagliflozin or empagliflozin group than the canagliflozin group and the results remained stable in sensitivity analysis (DNS) |
4.4 | |
4.5 | A medium-sized 2018 American study investigated the association of SGLT2i class vs. GLP-1RAs and DPP4i with LLA with a neutral association in both comparisons (Table S16.5, Fig. 3) [35]. The CIs were wide. Compared to users of older T2D drugs (metformin, TZDs and SUs), SGLT2i exposure was associated with an increased risk of vascular ulcers, osteomyelitis and PVD but not compared to DPP4is/GLP-1RA (DNS). Results remained stable in sensitivity analysis, except that when those with prior amputation were included SGLT2i exposure was associated with increased risk (DNS) |
4.6 | A medium-sized 2018 Scandinavian study explored the association of SGLT2i class vs. GLP-1RA for LLA [50]. There was an increased associated risk of amputation overall (but not toe and metatarsal amputation) in both the whole population (Sweden and Denmark) and the maximally adjusted model (Sweden only) (Table S16.6, Fig. 3). The CIs were wide. In subgroup analysis, the associations remained stable geographically and for sex, although there was an associated increased risk in those ages < 65 years and in those with pre-existing CVD (but not previous amputation, DNS) |
4.7 | A large 2018 American cohort study investigated the association of SGLT2i class vs. non-SGLT2i with incident BKA [66]. There was an associated increased risk of BKA in the ITT group (DNS) and a neutral association risk of BKA in the on-treatment group, although the CIs were wide (Table S16.7, Fig. 3). Subgroup analyses suggest an associated elevated risk of BKA in men, those on insulin, those not exposed to GLP-1RA, those with ≥ 2 CV risk factors and in those with pre-existing renal disease (CIs wider still, DNS) |
Canagliflozin | |
4.8 | |
Dapagliflozin | |
4.9 |
Exposure/study number | Study summary |
---|---|
SGLT2i class | |
5.1 | A medium-sized 2018 Scandinavian study explored the association of SGLT2i class vs. GLP-1RA on DKA [50]. SGLT2i exposure was associated with a neutral risk of DKA in both unadjusted (Sweden and Denmark) and the maximally adjusted population (Sweden only) but with very wide CIs (Table 11.1, Fig. 4). In subgroup analysis, those aged < 65 years appeared to be at increased risk of DKA vs. older users (DNS) |
5.2 | A large 2019 South Korean study comparing SGLT2i class exposure vs. DPP4i on DKA risk [41]. Authors report neutral association for DKA (with no evidence of a duration–response effect, Table S17.2, Fig. 4) and narrow CIs. Subgroup analysis in those with microvascular disease and those exposed to diuretics had a higher associated HR but remained non-significant (DNS) |
5.3 | |
5.4 | A medium-sized 2017 US study compared SGLT2i class vs. OADs (excluding metformin) on DKA [67]. There was a neutral association for DKA but with extremely wide CIs (broad definition, DNS), which attenuated with a more specific definition of T2D (Table S17.4, Fig. 4). The specific definition attempted to exclude possible T1D; this reduced the analysis population by 10% but DKA events by > 50%. In the per-protocol sensitivity analysis, SGLT2i exposure was associated with a significant risk of DKA under the broad definition but not in the specific definition (DNS) |
Dapagliflozin | |
5.5 |
Exposure/study number | Study summary |
---|---|
SGLT2i class | |
6.1 | A medium-sized 2018, Scandinavian study investigated the association of SGLT2i class vs. GLP-1RAs on fracture risk [50]. Both the unadjusted (Sweden and Denmark) and the maximally adjusted population (Sweden-only) data showed an associated increased fracture risk, with narrow CIs (Table S18.1, Fig. 5). This association remained stable when hospitalised fractures and osteoporotic fractures were analysed separately (DNS) |
6.2 | A medium-sized 2019 German nested, 1:40 matched, case–control study explored the association of metformin + SGLT2i class vs. metformin + any OAD on upper- and lower-limb fracture [46]. There was a neutral association in both the crude (DNS) and adjusted analysis (Table S18.2, Fig. 5), with narrow CIs. Subgroup analysis by fracture site, SGLT2i dose, falls and CVD remained stable (DNS) |
Canagliflozin | |
6.3 | A large 2019 American cohort study assessed the association between canagliflozin vs. GLP-1RAs on the risk of fractures in two data sources combined [38]. Canagliflozin was associated with a neutral risk of fracture, both when the data sources were analysed separately (DNS) and combined (Table S18.3, Fig. 5) with narrow CIs. There was a neutral association with an elevated risk of fracture in subgroup/sensitivity analysis (DNS) |
Dapagliflozin | |
6.4 | A small 2018, UK study cohort study investigated the association of dapagliflozin exposure vs. dapagliflozin-unexposed persons on any fracture risk [48]. The study reported a neutral association of dapagliflozin on fragility fractures (defined by site: vertebral, humerus, proximal femoral, distal radius; DNS) and all fractures (Table S18.4, Fig. 5). The CIs were narrow. The results remained stable in sensitivity analysis in those at higher risk of fracture (DNS) |
Outcome/exposure/study number | Study summary |
---|---|
Urinary tract infection | |
7.1 | A medium-sized 2018 Scandinavian study explored the association of SGLT2i class vs. GLP-1RA on UTI [50]. There was a neutral association for UTI in whole population and also in the maximally adjusted (Sweden only) population with narrow CIs (Table S19.1, Fig. 6), stable in all subgroup analyses (DNS) |
7.2 | |
7.3 | |
7.4 | A medium-sized 2019 Canadian cohort study explored the association for UTI in older people comparing SGLT2i class exposure vs. DPP4i, seeking a duration–response effect [42]. There was a reduced association with UTI at 30, 90 and 120 days post-initiation overall, with narrow CIs (Table S19.4, Fig. 6; 120 days, other DNS) and in both men and women when analysed separately (DNS) |
Canagliflozin | |
7.5 | |
Genital mycotic infection | |
SGLT2i class | |
7.6 | |
7.7 | A medium-sized 2019 Canadian study explored the association of SGLT2i class vs. DPP4i on GMI, seeking a duration–response effect [42]. There was an elevated associated risk of GMI, sustained over time, in the overall population with narrow CIs (Table S19.4, Fig. 7; 120 days, other DNS) and in both men and women when analysed separately, stable in sensitivity analysis (DNS) |
7.8 | A medium-sized 2018 American study explored the (within-person) association of SGLT2i class with GMI using a prescription symmetry analysis (antifungal prescription rates as proxy for GMI) before and after SGLT2i initiation [32]. There was an associated increased risk of antifungal prescription at 30, 60, 90, 180 and 365 days post-initiation, suggesting sustained risk (Table S19.5 for 365 days, other DNS). The association remained in subgroup analysis for both men and women (but women at higher risk, DNS). Canagliflozin was associated with a higher risk of an antifungal prescription compared to dapagliflozin and empagliflozin exposure (individual drug analysis, DNS) |
Canagliflozin | |
7.9 | A medium-sized 2017 American cohort study explored the association of canagliflozin vs. non-canagliflozin controls with GMI [53]. There was an increased association overall for GMI (Table S19.6, Fig. 7); but when analysed separately, the association remained for women but not for men (DNS). The CIs were narrow |
Exposure/study number | Study summary |
---|---|
SGLT2i class | |
8.1 | |
Dapagliflozin | |
8.2 | |
8.3 | |
8.4 |
Outcome/exposure/study number | Study summary |
---|---|
Pancreatitis | |
9.1 | One medium-sized 2018 Scandinavian study explored the association of SGLT2i class vs. GLP-1RA exposure on the pancreatitis [50]. There was a neutral association with pancreatitis in the whole population (Sweden and Denmark, DNS), the maximally adjusted population (Sweden only) with wide CIs (Table S21) and in subgroup analysis (DNS) |
Outcome/exposure/study number | Study summary |
---|---|
Venous thromboembolism | |
10.1 | One medium-sized 2018 Scandinavian study explored the effect of SGLT2i class vs. GLP-1RA for VTE [50]. This study showed a neutral association for VTE in the whole population (Sweden and Denmark, DNS), the maximally adjusted population with narrow CIs (Sweden-only, Table S22) and subgroup analysis (DNS) |
Cardiovascular Disease
Non 3-Point MACE Cardiovascular Composites
All-Cause Mortality (ACM) and Hospitalised Heart Failure (HHF) Composite
Myocardial Infarction (MI) and Stroke Composite
Other Composites
MACE
Myocardial Infarction
Stroke
Heart Failure
Mortality
Renal Outcomes (Acute Kidney Injury)
Amputation
Diabetic Ketoacidosis
Fracture
Genitourinary Infections
Urinary Tract Infections
Genital Mycotic Infections
Hypoglycaemia
Pancreatitis
Venous Thromboembolism
Discussion
Outcome | RCT evidence summary |
---|---|
Major adverse cardiovascular events | Both empagliflozin and canagliflozin reduce cardiovascular morbidity and mortality in patients with T2D at high CVD risk, on the basis of CVOT data For MACE Empagliflozin, HR 0.86 (95% CI 0.74, 0.99) Canagliflozin, HR 0.86 (96% CI 0.75, 0.97) |
Myocardial infarction | For non-fatal MI, none of the CVOTs showed a significant reduction in this component of the MACE composite Empagliflozin, HR 0.87 (95% CI 0.70, 1.09) Canagliflozin, HR 0.85 (95% CI 0.69, 1.05) Dapagliflozin, HR 0.77 (95% CI 0.77, 1.01) |
Stroke | For non-fatal stroke, all of the CVOTs showed a neutral effect on this component of the MACE composite Empagliflozin, HR 1.24 (95% CI 0.92, 1.67) Canagliflozin, HR 0.90 (95% CI 0.71, 1.15) Dapagliflozin, HR 1.01 (95% CI 0.84, 1.21) |
Heart failure | For hospitalised HF all three CVOTs suggest that SGLT2i exposure leads to a reduction in this outcome Empagliflozin, HR 0.65 (95% CI 0.50, 0.85) Dapagliflozin, HR 0.73 (95% CI 0.61, 0.88) The DAPA-HF trial, in patients with and without T2D with baseline HF, showed a reduction for first worsening of HF, CVD mortality and ACM [4] |
Mortality | The CVOT trials returned the following results for mortality outcomes Empagliflozin: CVD mortality, HR 0.62 (95% CI 0.49, 0.77); ACM, HR 0.68 (95% CI 0.57, 0.82) Canagliflozin: CVD mortality, HR 0.87 (95% CI 0.72, 1.06); ACM, HR 0.87 (95% CI 0.74, 1.01) |
Renal outcomes | Post-marketing reports to the FDA have suggested that both canagliflozin and dapagliflozin are associated with AKI, particularly after immediate treatment initiation. This is multifactorial because of volume depletion, hypotension or on concomitant nephrotoxic drugs [69]. However, both CVOTs and RCTs designed to test the effect on SGLT2is in diabetic nephropathy suggest that empagliflozin, canagliflozin and dapagliflozin are associated with a reduced incidence of worsening nephropathy (although the benefit may be reduced in those with more severe renal disease at baseline, possibly via a direct renovascular effect) [70] Empagliflozin showed a reduction in the composite of progression of microalbuminuria, doubling of serum creatinine, initiation of RRT or death from renal causes, HR 0.61 (95% CI 0.53, 0.70) [71] For canagliflozin, there was a reduction of the composite of ESRD, doubling of serum creatinine or death from cardiovascular and renal causes, HR 0.70 (95% CI 0.59, 0.82) [6] In the case of dapagliflozin, exposure was associated with a reduction of the composite of ≥ 40% in eGFR, new ESRD or death from cardiovascular or renal causes, HR 0.76 (95% CI 0.67, 0.87) [3] |
Amputation | SGLT2is, and particularly canagliflozin, have been associated with increased risk of amputation. Two RCTs investigating canagliflozin demonstrated a two-fold increase in the risk of (mainly toe and foot) amputation with those with PVD, neuropathy and prior amputation at the most elevated risk (IRR per 1000 patient-years, 5.9 vs. 2.8 (CANVAS) and 7.5 vs. 4.2 (CANVAS-R) [5]). Pharmacovigilance studies have also demonstrated an increased risk of amputation. Absolute numbers were low and the proportionality reporting ratio of adverse event descriptions may have been biased by knowledge of concern around SGLT2i exposure and amputation risk, making such events more likely to be reported in those taking SGLT2i [15] |
Diabetic ketoacidosis | DKA, often euglycaemic, has been reported in people taking SGLT2i agents, particularly canagliflozin. In all three CVOTs the numbers of DKA events were numerically higher in those exposed to SGLT2is but the absolute numbers were low Empagliflozin: n = 4 vs. 1 Canagliflozin: IRR 0.6 per 1000 patient-years vs. 0.3 Case series have also described associating SGLT2i exposure with an increased risk of DKA [23] |
Bone fracture | SGLT2i exposure, especially canagliflozin, has been associated with an increased fracture risk. Putative mechanisms include trauma following postural hypotension brought about by the volume-depleting effect of SGLT2is (increased risk soon after therapy initiation) or a reduction of BMD (which would lead to a slower increase in risk of fracture as bone mineral depletion necessarily takes time) In RCTs involving canagliflozin some, but not all, demonstrated a higher risk of fracture in those exposed to canagliflozin [6, 25]. For instance, a dose–response effect was demonstrated in patients taking 100 mg and 300 mg of canagliflozin (IRR 1.4 and 1.5 fracture per 100 patient-years) and was elevated compared to placebo (IRR 1.1 per 100 patient-years) [25]. In a BMD trial, canagliflozin, when compared to placebo, was associated with a progressive decline in BMD at the hip, with larger daily doses associated with a greater decline in BMD [7, 10] Trials of dapagliflozin on BMD did not show an effect [18] and neither did pooled trial analysis of fracture risk for empagliflozin [16] Meta-analysis of safety outcomes did not find an increased fracture risk for empagliflozin and dapagliflozin, and the elevated OR for canagliflozin was not statistically significant, OR 1.15 (95% CI 0.71, 1.88), although the source studies were not powered to detect fracture as an outcome [24] |
Genitourinary infection | RCTs of SGLT2is show a two- to four-fold increase in the incidence of genitourinary candidiasis, with vulvovaginal candida infection occurring in 10–15% of women exposed, compared to placebo [8, 22]. Meta-analyses have also found that exposure to SGLT2is is associated with an increased risk of female genital candida infection [12, 19, 72] |
Hypoglycaemia | SGLT2i are insulin-independent agents and are not associated with an elevated risk of hypoglycaemia when not co-prescribed with treatment that cause hypoglycaemia. They reduce the risk of hypoglycaemia compared to SUs and insulin, and hence may be indicated in people at high risk of hypoglycaemia (and weight gain); however, they may increase the risk of hypoglycaemia when co-prescribed with these other drugs [11, 20, 26] |
Pancreatitis | |
Venous thromboembolism | SGLT2is have been putatively suggested to increase the risk of VTE, due to the haemoconcentration occurring through the osmotic diuresis which they bring about. There is no literature identified from RCTs to suggest an elevated risk of VTE |