Short-term efficacy and safety of SGLT2 inhibitors have been well established, but what happens with long-lasting use of these medications?
As they are the newest medication class on market for treatment of diabetes, SGLT-2 inhibitors’ influence on both cardiovascular and non-cardiovascular health has not been well documented yet.  Most studies that evaluated the SGLT2 inhibitors had a primary goal of establishing their glucose-lowering abilities, hence not many were concerned with evaluating their impact on cardiovascular and other safety outcomes.
One of the studies that is available, published by Bernard Zinman and colleagues, concluded that use of empagliflozin reduced the incidence of cardiovascular events and death when it was added to standard glucose-lowering therapy. Another study, the CANVAS-R trial, argued the benefits of canagliflozin for CV disease to be remarkable with the expense of increased risk of lower leg amputations.
In hopes of validating both CV and non-CV safety of SGLT2-i, researchers in China conducted a meta-analysis of the available randomized controlled trials and observational studies; furthermore, to reduce type I errors from occurring, they completed the trial sequential analysis. Their results were recently published by The American Heart Association.
Investigators completed a literature search of Medline, Cochrane, and Embase to screen for available studies. Two independent reviewers assessed eligibility, and a total of 11 studies that were incorporated in the meta-analysis were head-to-head trials, comparing SGLT2’s to either placebo or other antihyperglycemic medications, and had pre-defined CV outcomes.
Researchers set the primary endpoints as the composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke. Secondary endpoints included each of the primary endpoints as a separate measure, in addition to all-cause mortality, hospitalization for heart failure, and renal microvascular outcomes. Non-CV safety and efficacy of SGLT2’s was examined as well.
The investigators found that across all included studies, patients treated with any SGLT2-i had favorable reduction in composite cardiovascular events and death, hazard ratio of 0.80, p-value of 0.002. After completion of trial sequential analysis (TSA), a firm 20% decrease of primary endpoint was seen with use of SGLT2 inhibitors. Use of SGLT2s was also correlated with a statistically significant decrease in all-cause mortality, HR of 0.67, p-value < 0.001; once again, TSA calculations confirmed the strong 20% reduction. Other secondary endpoints also had more favorable results in patients treated with SGLT2’s.
For instance, HR for nonfatal MI was 0.86 favoring the SGLT2 treatment, while SGLT2 therapy also led to fewer hospitalizations for heart failure when compared to other treatments, HR of 0.62. SGLT2 inhibitors lead to beneficial renal microvascular outcomes by slowing the progression of albuminuria, HR of 0.68. However, study researchers found that patients treated with SGLT2 inhibitors did not have statistically significant reductions in nonfatal stroke rates, HR or 0.96, p-value of 0.67.  When comparing hypoglycemia, AKI, and serious adverse events, patients who were treated with SGLT2 inhibitors had overall better outcomes, with the exception of urinary tract and yeast infections.
Xin-Lin Zhang and colleagues report sustained protective cardiovascular outcomes of the entire class of SGLT2 inhibitors. Considering that patients with diabetes are at a high-risk of cardiovascular disease, choosing an antihyperglycemic agent that exerts beneficial cardiovascular outcomes is of a great importance. There are some limitations to the study as recognized by the investigators; mainly, the publication bias that could have occurred in each of the specific studies included in meta-analysis. Nonetheless, since some of the anti-diabetic medications, particularly rosiglitazone and saxagliptin can lead to heart failure, having documented cardiovascular and non-cardiovascular long-term benefits of SGLT2 inhibitors may lead to future changes in practice.
Practice Pearls:
Use of SGLT2 inhibitors lead to a strong 20% reduction in composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke.Statistically significant reduction in all-cause mortality was seen with use of SGLT2 inhibitors, HR = 0.67.SGLT2 inhibitors offer benefits for non-cardiovascular outcomes as well; AKI, hypoglycemia, and serious adverse events were less likely to occur with SGLT2-i treatment when compared to controls.
Xin-Lin Zhang, Qing-Qing Zhu, Yu-Han Chen, et al. “Cardiovascular Safety, Long-Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis With Trial Sequential Analysis.” Journal of the American Heart Association. 2018.
Accessed Jan 2018.
Bernard Zinman, Christoph Wanner, John Lachin, et al.  “Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes.” New England Journal of Medicine. 2015.
Accessed Jan 2018.
Bruce Neal, Vlado Perkovic, Kenneth Mahaffey, et al. “Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.” New England Journal of Medicine. 2017.  
Accessed Jan 2018.
SGLT2 Inhibitors in Treatment of Type 1
Meta-analysis explores safety and efficacy of sodium-glucose co-transporter 2 inhibitors in patients with type 1 diabetes.
Individuals living with type 1 diabetes most of their lives are exposed to numerous comorbidities that ultimately lead to a significant decrease in estimated life expectancy by approximately 12 years, as we have seen with former studies conducted on the subject. Moreover, considering that patients with type 1 are treated with insulin as their main option for managing blood sugar levels, these individuals have augmented peril to experience serious dose-dependent side-effects such as hypoglycemia or weight gain. Use of oral medications for management of T1D has been investigated before without much success, save for oral pramlintide. When used in combination with insulin for type 2, the new kids in town, SGLT2 inhibitors, have shown to decrease the insulin need, weight gain, and hypoglycemia. But, would the similar effects be produced in patients with type 1 following the combination therapy? To establish a place for SGLT2’s in type 1 diabetes, researchers conducted a systematic review and meta-analysis of randomized controlled trials.
Their findings were recently published in Diabetes Research and Clinical Practice.
El Masri and colleagues conducted a literature review of PubMed, Embase, Scopus, Web of Science and Cochrane library to screen for potential RCTs concerning the use of SGLT2-i in T1D to be included into the meta analysis. Studies that included patients with type 2, or those studies that did not include original data were excluded from the systematic review. Four randomized controlled trials were included with the primary outcome of the analysis being to establish the extent SGLT2-i lead to changes in body weight, insulin need, and HbA1c levels. Rate of adverse events, DKA, and hypoglycemia were the secondary outcomes of the study.
Four RCTs that were included in the study assessed canagliflozin, empagliflozin and sotagliflozin as add-ons to insulin, and dapagliflozin as an add-on to liraglutide and insulin. At conclusion of the analysis, investigators found that individuals treated with SGLT2 inhibitors plus insulin had significant decrease of their A1c levels when compared to placebo; weighted mean difference of 0.39. The highest benefit was observed with dapagliflozin, WMD of 0.66. When assessing body weight changes, all studies showed a statistical significant reduction in weight with SGLT2’s, WMD 2.76.  The greatest weight reduction was noted with canagliflozin, WMD of 4.39.
Lastly, with respect to total daily insulin dose, all treatments led to statistically significant reduction.  Canagliflozin and dapagliflozin led to a significant decrease of insulin dose, as shown by WMD 5.03. Empagliflozin led to a decreased need of insulin dosage between 0.08 and 0.11 units/kg, p-value <0.05; while sotagliflozin reduced insulin by 15.3% from baseline, p-value of 0.002. When looking at secondary outcomes, each of the studies included did not report a significant difference of hypoglycemia risk, incidence of adverse events or increase in the frequency of DKA episodes.
The results of the meta analysis presented by El Marsi et al. provide promising evidence of SGLT2-i use in type 1 diabetes.  Not only was there benefit in lowering insulin dosage need, reducing body weight, and bettering A1c outcomes in individuals with T1D, the addition of SGLT2-i did not result in significant increase in adverse reactions, hypoglycemia, or incidence of DKA. Prior to accepting the results from this systematic review on a large scare, bigger-prospective studies with longer durations will need to be completed to evaluate the usefulness of SGLT2’s in T1D on a population level.   Regardless of the limitation of including only 4 RCTs into this systemic review, compelling results that we have seen with this review should instigate researchers to further investigate the use of SGLT2 inhibitors in the treatment of type 1 diabetes.
Practice Pearls:
• The addition of SGLT2 inhibitors to insulin resulted in reduction of baseline HbA1c levels, decreased insulin dose needed, and lowering of body weight in patients with type 1.
• SGLT2-i did not increase the risk of DKA, hypoglycemic episodes, or adverse events.
• Larger, prospective RCTs are needed to explore a true value of routine SGLT2-i use as an add-on therapy to insulin in individuals with type 1 diabetes.
Dana El Masri, Samiran Ghosh, Linda Jaber.  “Safety and Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Type 1 Diabetes: A Systematic Review and Meta Analysis.” Diabetes Research and Clinical Practice. 2018.
Accessed Jan 2018.
Shona Livingstone, Daniel Levin, Helen Looker, et al. “Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008-2010.” JAMA 2015.  
Accessed on Jan 2018.
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