Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study
BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4365 (Published 14 November 2018) Cite this as: BMJ 2018;363:k4365Linked news
SGLT2 inhibitors for diabetes are linked to increased risk of lower limb amputation
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“In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis” [1]. This is impressive also for patients if they read the abstract [1]. The message has been repeated in the open access part of the News [2]. In table 2 of the article [1] we read that the number of the above-named complications per 1000 patient-years was, correspondingly, 2.7 vs. 1.1 and 1.3 vs. 0.6 [1] which are quite low incidence rates. For amputations, these figures are within the range of lower extremity amputation for patients with diabetes reported to be 1.5-5.0 per 1000 patient-years [3]. Ketoacidosis is a separate topic beyond the scope of this response; discussed in [4].
The reason for the enhanced amputation rate remains speculative and whether it concerns all SGLT2 inhibitors is controversial [5]. Existing records may not be sufficient to prove a causal relationship [6,7]. The retrospective cohort study and meta-analysis of 4 observational databases found no evidence of increased risk of below-knee lower extremity amputations for patients with type 2 diabetes mellitus treated with SGLT2 inhibitors, in particular, with canagliflozin [3,8]. The EMPA-REG OUTCOME trial did not report of an increased risk of amputation with empagliflozin [8].
Dr. Ueda et al. [1] discuss the putative mechanism of the increased risk of amputation - namely, volume depletion due to the diuretic effect. This is in keeping with other studies suggesting that "standard" diuretics are a risk factor for amputation [9]. It is therefore essential that patients on SGLT2 inhibitors, and diuretics in general, maintain hydration at all times [9]. So, there is a tool against this rare complication arguably associated with the treatment by SGLT2 inhibitors. Obviously, further research is needed.
Reassuringly, the frequency of more general diabetic-foot related adverse events was reported to be significantly lower among reports for SGLT2 inhibitors than among reports for non-SGLT2 inhibitor drugs with the diabetes indication, although this difference was tapered after exclusion of reports listing insulin therapy as a concomitant drug [6]. Importantly, the study [1] found no association between the use of SGLT2 inhibitors and the risk of serious urinary tract infection, venous thromboembolism, acute pancreatitis and bone fracture, which are adverse events of current concern.
The following considerations are often left out of attention comparing the GLP1 receptor agonists and SGLT2 inhibitors. Hypoglycemic effects of the latter are unrelated to the stimulation of the insulin secretion by beta cells. There are experimental data about proliferation of beta cells and reduction of apoptosis under the influence of GLP-1 receptor agonists; however, direct evidence in humans is lacking [10-12]. At the same time, an exhaustion of beta cells as a result of the stimulation by GLP-1 receptor agonists is not excluded [13]. It is known that beta cells can be exhausted by excessive stimulation [14]. On the contrary, keeping insulin secretion at rest prevents the beta-cells exhaustion [15]. The insulin hypersecretion contributes to an increase in body weight [15,16]. This indicates that drugs acting without stimulation of the insulin secretion are preferable, other things being equal.
References
1. Svanström H, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ 2018;363:k4365.
2. Kmietowicz Z. SGLT2 inhibitors for diabetes are linked to increased risk of lower limb amputation. BMJ. 2018;363:k4828.
3. Yuan Z, et al. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study. Diabetes Obes Metab. 2018;20:582-9.
4. Jargin SV. Re: Effects of a low carbohydrate diet. BMJ Rapid Response 16 November 2018 https://www.bmj.com/content/363/bmj.k4583/rr-2
5. Scheen AJ. Does lower limb amputation concern all SGLT2 inhibitors? Nat Rev Endocrinol. 2018;14:326-8.
6. Fadini GP, Avogaro A. SGLT2 inhibitors and amputations in the US FDA Adverse Event Reporting System. Lancet Diabetes Endocrinol. 2017;5:680-1.
7. Tanaka A, Node K. Increased amputation risk with canagliflozin treatment: behind the large cardiovascular benefit? Cardiovasc Diabetol. 2017;16:129.
8. Ryan PB, et al. Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes Metab. 2018;20:2585-97.
9. Auersperg EV. Re: Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ Rapid Response 15 November 2018 https://www.bmj.com/content/363/bmj.k4365/rr
10. Fleming A, Rosenberg L. Prospects and challenges for islet regeneration as a treatment for diabetes: a review of islet neogenesis associated protein. J Diabetes Sci Technol. 2007;1:231-244.
11. Garber AJ. Incretin effects on β-cell function, replication, and mass: the human perspective. Diabetes Care 2011;34(Suppl. 2):S258-263.
12. Talbot J, et al. β-Arrestin1-mediated recruitment of c-Src underlies the proliferative action of glucagon-like peptide-1 in pancreatic β INS832/13 cells. Mol Cell Endocrinol. 2012;364:65-70.
13. van Raalte DH, Verchere CB. Glucagon-like peptide-1 receptor agonists: beta-cell protection or exhaustion? Trends Endocrinol Metab. 2016;27:442-445.
14. Montane J, et al A. Stress and the inflammatory process: a major cause of pancreatic cell death in type 2 diabetes. Diabetes Metab Syndr Obes. 2014;7:25-34.
15. Salvi R, Abderrahmani A. Decompensation of β-cells in diabetes: when pancreatic β-cells are on ICE(R). J Diabetes Res 2014;2014:768024.
16. Erion KA, Corkey BE. Hyperinsulinemia: a Cause of Obesity? Curr Obes Rep. 2017;6:178-86.
Competing interests: No competing interests
The authors briefly discuss the putative mechanism of the increased risk of amputation--namely, volume depletion due to the diuretic effect of this drug class. This is in keeping with other studies (1,2) suggesting that "standard" diuretics are a risk factor for amputation. For this reason (and in order to prevent acute kidney injury) it is essential that patients on SGLT inhibitors, and diuretics in general, maintain hydration at all times. Failing that, these and several other drugs should be withheld when dehydration is unavoidable.
1. Gary T et al. Graz Critical Limb Ischemia Score: A Risk Score for Critical Limb Ischemia in Peripheral Arterial Occlusive Disease. Medicine (Baltimore) 2015; 94(27)
2. Joëlle A et al. Antihypertensive drug therapy and the risk of lower extremity amputations in pharmacologically treated type 2 diabetes patients. Pharmacoepidemiology and Drug Safety 2004; 13(3)
Competing interests: No competing interests
Re: Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study
Sodium glucose cotransporter 2 (SGLT2) inhibitors have been associated with cardiovascular (CV) benefits in randomized clinical trials (RCTs) [1]. However, specific safety issues remain unclear. Ueda et al. observed an increased risk of lower limb amputation and of diabetic ketoacidosis with the use of SGLT2 inhibitors compared to glucagon-like peptide 1 (GLP1) receptor agonists (incidence rate 2.7 vs. 1.1 events per 1000 person years, HR 2.32 [95% CI 1.37; 3.91], and 1.3 vs. 0.6, HR = 2.14 [1.01; 4.52], respectively) [2].
Ueda et al. reported an original analysis of nationwide registers from Sweden and Denmark, to assess the risk of seven serious adverse events when using SGLT2 inhibitors. They used a propensity score matched cohort of 34 426 new users of SGLT2 inhibitors or GLP1 receptor agonists. Their results suggested potential harmful effects of SGLT2 inhibitors. We examined these results at the light of those of 3 powerful RCTs [3-5] assessing SGLT2 inhibitors in patients with type 2 diabetes, to discuss the agreement between observational and experimental data, taking into account the benefit/risk balance estimations.
First, the three CV outcomes RCTs assessing SGLT2 inhibitors [3-5] showed conflicting results regarding the risk of amputation. In the CANVAS Program [3], patients randomized to canagliflozin displayed higher rates of lower limb amputation (HR 1.97 [95% CI 1.41; 2.75]). In the EMPAREG OUTCOME trial [4, 6] and in the DECLARE TIMI 58 trial [5], the risk of amputation was not increased in the SGLT2 inhibitor group compared to placebo (HR=1.00 [95% CI 0.70; 1.44] and 1.09 [95% CI 0.84; 1.40], respectively); these confidence intervals excluding the HR estimated in CANVAS. As expected, the meta-analysis of the risk increase of amputation in those 3 RCTs displayed a significant heterogeneity (I² = 77%, supplementary figure available on request). The meta-analysis of the risk increase of diabetic ketoacidosis was consistent across the 3 RCTs (RR = 2.14 [95% IC 1.24; 3.71], I² = 0%, supplementary figure available on request).
Second, the treatment effect estimation through those three randomized, double-blinded, placebo controlled trials has a high level of evidence and a lower risk of bias than from pharmaco-epidemiological study. Diabetic ketoacidosis was a pre-specified safety outcome in all 3 RCTs; amputations were adverse events of interest in the CANVAS Program trial [3], collected retro- and prospectively in the DECLARE TIMI 58 trial [5], and searched for in post hoc analysis in the EMPAREG OUTCOME trial [6].
Third, register-based cohort are usually helpful as they allow big sample size and then to overcome the limit of statistical power for safety issue in RCT regarding rare events. However, the study of Ueda et al. included 17 213 patients treated with SGLT2 inhibitors, 61% with dapagliflozin, 38% with empagliflozin and only 1% with canagliflozin. The three CV RCTs pooled results on 19 056 patients treated with SGLT2 inhibitors, i.e. a similar sample size. However, the power of the study of Ueda et al. was considerably lower than the meta-analysis of the 3 RCTs, with only 62 amputations and 30 diabetic ketoacidosis against 552 and 62 in the meta-analysis, respectively (supplementary figure available on request).
Fourth, the meta-analysis of Zelniker et al. showed a decreased risk of major adverse cardiovascular events (MACE) and of CV death or hospitalization for heart failure with SGLT2 inhibitors (HR = 0.89 [95% CI 0.83; 0.96] and HR = 0.77 [95% CI 0.71; 0.84], respectively) [1]. The absolute risk difference for amputation, diabetic ketoacidosis, MACE and hospitalization for heart failure, estimated from the 3 RCTs, suggested a favorable benefit/risk balance for the SGLT2 inhibitors, even when taking into account the risk of amputation and of diabetic ketoacidosis (Table available on request).
To conclude, Ueda et al. suggested a risk of amputations with SGLT2 inhibitors, but the meta-analysis of more powerful RCTS excluded a class effect. The risk of diabetic ketoacidosis seemed to be related to the class, but did not offset the CV benefits. Pharmaco-epidemiology approach could help to identify safety signal, but its potentially biased estimation should be interpreted with caution. When both approaches disagree, as long as they are powerful enough, RCTs results dominate due to their higher level of evidence. Here, they advocate not to drop out drugs with positive benefit-risk balances.
Supplementary figure: Forest plot showing the effect of SGLT2 Inhibitors on risk of amputation and of diabetic ketoacidosis, through meta-analysis of the CANVAS Program, DECLARE TIMI 58 and EMPAREG OUTCOME trials (available on request)
References
1. Zelniker, T.A., et al., SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet, 2018
2. Ueda, P., et al., Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ 2018;363:k4365
3. Neal, B., et al., Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med, 2017. 377(7): p. 644-657
4. Zinman, B., et al., Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med, 2015. 373(22): p. 2117-28
5. Wiviott, S.D., et al., Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 2018
6. Inzucchi, S., et al., Empagliflozin and Assessment of Lower-Limb Amputations in the EMPA-REG OUTCOME Trial. Diabetes Care 2018 Jan; 41(1): e4-e5.
Competing interests: GG has received support for travel to scientific meetings from Novo Nordisk, Lilly and is a member of the association « Association des toxicologues ». MC has received consulting fees from Boehringer Ingelheim, SANOFI, and speaker honoraria from SANOFI. In the last five years, FG received for his institution fees from Portola Pharmaceuticals for central reading of ultrasound records, from Neurochlore for DSMB coordination, from EryTech Pharma for modeling projects, from RCTs and Steve Consultant for exploring French social security database.