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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 5  |  Issue : 1  |  Page : 16-22

Sodium-glucose cotransporter-2 inhibitors and cardiovascular outcomes in type 2 diabetes mellitus: A systematic review


Clinical Pharmacy and Practice, College of Pharmacy, University, Doha, Qatar

Date of Web Publication20-Jan-2017

Correspondence Address:
Ziad G Nasr
College of Pharmacy, Qatar University, P. O. Box: 2713, Doha
Qatar
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DOI: 10.4103/2468-6360.198800

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  Abstract 

Sodium-glucose cotransporter - 2 (SGLT2) inhibitors are a novel class of anti-diabetics proven to reduce blood pressure, blood glucose and body weight. However, the long-term cardiovascular (CV) safety implications of these agents remain unclear. This systematic review aimed to evaluate the available clinical trial evidence pertaining to long-term cardiovascular safety of SGLT2 inhibitors. The databases EMBASE and MEDLINE were searched. Randomized controlled trials assessing CV safety of SGLT2 inhibitors compared with placebo or anti-diabetic medications were included. Two investigators independently extracted study data and completed risk of bias assessments (sequence generation, allocation concealment, blinding, incomplete outcome data, or selective outcome reporting and other biases). Outcomes included CV death, myocardial infarction, and stroke. A total of 464 studies were identified in the electronic search and 14 from other sources. Sixteen randomized clinical trials were included after full-text review. All studies reported at least one of the pre-defined outcomes (CV death, myocardial infarction, and stroke). Nineteen CV deaths were reported in SGLT2 inhibitors groups versus 10 CV deaths in placebo or other comparator arms; numerically higher in the dapagliflozin arms. The number of CV events was numerically higher in SGLT2 inhibitor groups than in other arms. Risk of bias assessment showed mixed results, with overall quality assessments deemed unclear for 6 of 16 studies (37.5%). Findings showed CV outcomes do occur in patients taking SGLT2 inhibitors yet the clinical significance remains unclear. These results can be considered hypothesis generating, as studies were limited by inadequate power and/or follow-up time. Future longitudinal studies are needed to further assess the efficacy and safety profiles of these new agents before they become widely adopted in clinical practice.

Keywords: Cardiovascular, quality, safety, sodium-glucose cotransporter-2 inhibitor, type 2 diabetes mellitus


How to cite this article:
Nasr ZG, Jalali FB, Ahmed DD, Wilby KJ. Sodium-glucose cotransporter-2 inhibitors and cardiovascular outcomes in type 2 diabetes mellitus: A systematic review. J Health Spec 2017;5:16-22

How to cite this URL:
Nasr ZG, Jalali FB, Ahmed DD, Wilby KJ. Sodium-glucose cotransporter-2 inhibitors and cardiovascular outcomes in type 2 diabetes mellitus: A systematic review. J Health Spec [serial online] 2017 [cited 2017 Sep 24];5:16-22. Available from: http://www.thejhs.org/text.asp?2017/5/1/16/198800


  Introduction Top


Diabetes mellitus is one of the most prevalent and fastest growing diseases worldwide, with a global prevalence of 387 million patients. It is estimated to increase up to 592 million by 2035 and a direct association with an excess of 4.9 million deaths in 2014.[1] Type 2 diabetes mellitus (T2DM) is characterised by impaired cell responsiveness to the effect of insulin. At early stages of the disease, the body compensates for this defect by increasing the release of insulin from β-cells in the pancreas. However, as the disease progresses, β-cells' ability to produce insulin becomes insufficient to overcome insulin resistance resulting in uncontrolled plasma glucose levels. This gives rise to several complications which are mainly cardiovascular (CV) related.[1]

Diabetes mellitus and its complications cause a substantial burden of disease on societies worldwide and its prevalence is increasing significantly in every country, which is mainly due to lifestyle changes.[2] T2DM accounts for 90% of diabetes cases, with others being labelled as type 1 or gestational.[3] Patients with T2DM have approximately 2-4-fold higher risk of CV complications than healthy individuals, and it is estimated that around 65% of people with T2DM will die as result of CV complications.[1] Managing plasma glucose levels has shown to reduce the onset and severity of T2DM complications including CV risks.[4]

There are several medications available for the treatment of T2DM. However, it was found that only 52.5% of patients were able to achieve adequate glycaemic control with their current therapies.[5] Hence, different treatments and/or drug combinations may be needed to achieve adequate glycaemic control. According to the American Diabetes Association guidelines on the management of T2DM, if lifestyle changes were not effective in achieving adequate glycaemic control, various pharmacological options are available and can be considered. Metformin is recommended as a first-line agent, followed by sulfonylureas, meglitinides, pioglitazone, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists before add-on insulin therapy. However, several adverse effects are seen with those agents including weight gain with insulin, sulfonylureas and glitazones, hypoglycaemia with insulin and sulfonylureas and oedema, fractures and exacerbation of heart failure with glitazones.[6]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are relatively a new class of anti-diabetic agents.[7] They work by decreasing the reabsorption of glucose in renal proximal tubules, independent of insulin.[8] Canagliflozin, dapagliflozin and empagliflozin are the currently Food and Drug Administration (FDA)-approved medications from the SGLT2 inhibitors class.[9],[10],[11] In March 2013, canagliflozin was the first SGLT2 inhibitor to receive the FDA approval.[9] It is an orally active inhibitor, indicated as an adjunct therapy to diet and exercise.[12] In randomised controlled trials (RCTs), canagliflozin significantly reduced body weight and blood glucose.[13] The results from a pooled analysis of clinical studies showed a significant reduction in mean HbA1C (up to 0.92% absolute reduction) and fasting plasma glucose with the use of canagliflozin.[14] Furthermore, when compared to sitagliptin and glimepiride, canagliflozin demonstrated more effective glycaemic control.[15],[16] In general, canagliflozin was well tolerated by patients in RCTs and the risk of hypoglycaemia was very low.[15]

Dapagliflozin received the FDA approval in January 2014.[10] Management of T2DM with dapagliflozin as a monotherapy or add-on therapy with other anti-diabetic medications has shown significant reduction in fasting blood glucose as well as HbA1C reductions (up to 2.7% reduction with the 10 mg dose).[17],[18] In 2012, the FDA rejected the approval of dapagliflozin because of concerns related to bladder cancer.[19] However, further trials refuted this concern and dapagliflozin was granted approval in 2014.[10] Finally, in August 2014, FDA approved empagliflozin as a safe and effective SGLT2 inhibitor.[11] Similar to dapagliflozin and canagliflozin, several clinical trials have proven the efficacy and safety of empagliflozin as a single anti-diabetic medication or when added to other anti-diabetic medications from different classes.[20]

The CV safety of anti-diabetic medications has become an acute area of concern. Rosiglitazone, sulfonylureas and insulin are three traditional anti-diabetic medications that have been associated with increased risk of CV events in patients with T2DM.[21] In 2008, the FDA mandated all new anti-diabetic medications to provide evidence that they do not increase risk of CV diseases.[22],[23] However, the CV safety profile of SGLT2 inhibitors and information related to CV outcomes (e.g. myocardial infarction [MI], stroke, cardiac death, heart failure and arrhythmia) is currently under investigation. In addition, study quality and risks of bias were rarely considered in previous papers that have assessed the CV risks associated with SGLT2 inhibitors. Therefore, the objective of this review was to provide a comprehensive summary and critical analysis of the available literature pertaining to CV safety (MI, stroke, angina and CV-related death) of SGLT2 inhibitors in patients with T2DM.


  Methods Top


A literature search was completed using the databases EMBASE (1980 to May 2016) and MEDLINE (1948 to May 2016). The search terms employed for electronic database searching were 'canagliflozin' OR 'dapagliflozin' OR 'empagliflozin' OR 'Invokana' OR 'Forxiga' OR 'Jardiance' OR 'TA-7284' OR 'BMS512148' OR 'BI10773' OR 'sodium-glucose cotransport 2 inhibitor' OR 'SGLT2 inhibitor' combined with 'cardiovascular death' OR 'stroke' OR 'myocardial infarction' OR 'cardiovascular event' OR 'secondary outcome' OR 'side effect' OR 'adverse drug event' combined with 'type 2 diabetes mellitus' OR 'T2DM' OR 'diabetes', using AND to combine search term categories. Keywords were linked to MeSH terms and subject headings in search engines, where applicable. The search was limited to studies in humans and those published in English. Online study registries were reviewed to capture the potential availability of unpublished data. Manual searching of the reference lists of identified articles and review articles was also used to capture any record not accounted in the electronic search. The search was completed by two investigators independently in a parallel manner.

Studies were included in the systematic review based on predefined inclusion criteria: RCTs that evaluated any of the SGLT2 inhibitors compared with either placebo or other anti-diabetic medication and had reported CV outcomes. Outcomes of interest were stroke, MI or cardiac death. Studies were excluded if they were not published as full manuscripts, written in non-English language, non-human trials and did not report any incidence of CV events or CV death. Two investigators assessed each identified study for inclusion and a third investigator resolved any discrepancy that could not be solved through discussion.

Data extracted included study design and duration, sample size, interventions and CV outcomes. Data were extracted by two investigators and verified by a third investigator. Data were also extracted for risk of bias assessments according to the Cochrane Collaboration's risk of bias assessment tool for RCTs.[24] This tool included information on six domains including random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other biases based on study design or possible identified confounders. Any study perceived to have at least 1 'high' or 2 'unclear' risk of bias in any category was deemed to have an overall 'unclear' quality.


  Results Top


Literature search

The literature search produced 464 hits from electronic sources and 14 hits from manual searching as shown in [Figure 1]. After title and abstract review, the full-text versions of 40 articles were downloaded for review. After assessment against inclusion criteria, a total of 16 articles were included in the systematic review.[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40] Eight studies evaluated dapagliflozin, six trials evaluated empagliflozin while two others evaluated canagliflozin. Reasons for article exclusions are given in [Figure 1].
Figure 1: Flow diagram for study selection and inclusion.

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Study characteristics

All studies were RCTs out of which 11 were placebo-controlled while the remaining five compared SGLT2 inhibitors to other anti-diabetic medications (2 - sulfonylurea-controlled [31],[39] and 3 - DPP-4 inhibitors-controlled studies),[26],[27],[37] with background of standard anti-diabetic therapy. All studies reported CV events or CV-related deaths.[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40] Characteristics and results of each included study are given in [Table 1]. Most studies included patients ≥18 years of age with one study focused having a lower age limit of 55 years of age and four studies with an upper age limit of 80 years. SGLT2 inhibitors and their comparators were administered orally once daily. Doses of canagliflozin ranged from 100 to 300 mg. Doses of dapagliflozin ranged from 2.5 to 20 mg while doses of empagliflozin ranged from 5 to 25 mg. In the active-controlled studies, glipizide dose ranged from 5 to 20 mg.[31],[39] A single sitagliptin dose of 100 mg was used in one study [37] while a 5 mg dose of linagliptin was used in two other studies.[26],[27] In six studies out of all included studies, interventions were used as add-on therapy in which background therapy included metformin, sulfonylureas or pioglitazone.[27],[29],[30],[35],[39],[40] Follow-up periods ranged from 12 to 208 weeks.
Table 1: Study characteristics and results

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Risk of bias assessment

Risk of bias assessments and the overall quality of the studies are given in [Table 2]. Fourteen studies had adequate sequence generation,[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[37],[39],[40] with only two studies having unclear information.[36],[38] Ten out of 16 trials had adequate allocation concealment [25],[26],[27],[29],[31],[33],[34],[37],[39],[40] while six others did not.[28],[30],[32],[35],[36],[38] Notably, almost all trials have reported adequate information related to blinding, except for two studies.[28],[31] One of these was rated 'unclear' with regard to blinding as there was a significant difference in some of the adverse events, which may have resulted in the unblinding of participants or investigators.[31] Two out of 16 studies reported incomplete outcome data.[35],[39] One study was deemed to have 'unclear' risk of bias for incomplete data reporting since not all patients were accounted for final analysis of the study (four cases missed).[35] Some studies scored 'unclear' on selective outcome reporting as safety outcomes were lacking, especially relating to CV safety.[36],[38],[40] Other sources of bias included confounding factors such as variation in baseline characteristics among the study groups. However, it was not clear whether these variations are substantial to the point that they could be considered as a high risk of bias, so only four studies were rated as unclear regarding these criteria.[32],[34],[35],[37] Overall, the quality of six studies was deemed 'unclear'.[17],[32],[35],[36],[38],[39]
Table 2: Risk of bias assessment

Click here to view


Cardiovascular events

Evaluating all studies identified, except for Zinman et al.,[25] that the number of CV events was numerically higher in SGLT2 inhibitor groups than in other arms (4 cases of non-fatal MI, 1 case of stroke and 3 other CV events).[28],[33],[35] By looking at the incidence of CV events in our studies, it is notable that more CV incidence was seen in trials that evaluated dapagliflozin when compared to trials assessing empagliflozin and canagliflozin (6 events vs. 1 event vs. no event, respectively).[28],[33],[35] Noteworthy, investigators of those studies found that those events to be doubtfully related to the study drug.[28],[33] Only one case of angina in one study was observed in other comparator groups, specifically in the metformin-allocated arm that was also not related to the study drug.[28]

Those events had likely appeared due to pre-existing comorbidities in the studied population.

Cardiovascular death

CV deaths were seen numerically higher in dapagliflozin arms,[30],[31],[32],[34],[35],[38],[39] than in empagliflozin arms,[26],[27],[29],[40] or canagliflozin arms [36],[37] (12 deaths, versus 4 deaths, versus 3 deaths, respectively). However, in four of these studies, death did not seem to be related to the study drug as reported by the investigator.[29],[36],[37],[40] Three studies reported five CV deaths in the placebo group while assessing safety in empagliflozin and dapagliflozin trials.[29],[34],[38] Moreover, five significant deaths were observed in one dapagliflozin study in the glipizide/metformin arm.[39] In total, 19 CV deaths were reported in SGLT2 inhibitors groups versus 10 CV deaths in placebo or other comparator arms. However, none of the studies reported any P value or confidence interval (CI) indicating that there was no statistical evaluation for CV safety.

We identified one large trial assessing empagliflozin's CV safety as a primary end-point, in terms of time to the first occurrence of any of the following adjudicated components of the primary composite end-point: CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) and non-fatal stroke. The study compared empagliflozin (10 mg and 25 mg once daily) with placebo. The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95% CI, 0.74 - 0.99; P = 0.04 for superiority). The study showed no significant between-group differences in the rates of MI or stroke, but lower CV-related death rates in the empagliflozin group (3.7% vs. 5.9% in the placebo group; 38% relative risk reduction [RRR]; P < 0.001) and death from any cause (5.7% and 8.3%, respectively; 32% RRR; P < 0.001).[25]


  Discussion Top


This systematic review identified 15 studies that reported CV events and CV-related deaths in patients receiving SGLT2 inhibitors with T2DM. CV events and deaths were numerically higher in the SGLT2 inhibitor groups, specifically in dapagliflozin treatment groups; however, these findings are only hypothesis generating given that none of these outcomes were part of the primary or secondary end-points in the included studies and that none of them were statistically evaluated (There were no P values or CIs reported).[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40] Only one study assessed CV safety of empagliflozin as a primary end-point when compared to placebo and showed lower CV-related deaths in the empagliflozin group with no significant between-group differences in the rates of other CV events such as stroke or MI.[25]

Our findings were in-line with previously published studies but offer greater insight into the quality of identified studies. A previous meta-analysis was conducted that assessed the CV outcomes of SGLT2 inhibitors.[41] The study concluded that there is no evidence for increase in CV risks with use of SGLT2 inhibitors. Moreover, the study estimated that the CV outcomes for dapagliflozin had yielded an odd ratio of 0.73 (CI, 0.46 - 1.16) compared with the control arm. This estimate was consistent with the European Medicines Agency (EMA) report on dapagliflozin as well, with reported hazard ratio of 0.82 (CI, 0.58 - 1.15). In addition, EMA stated that dapagliflozin did not show an increased in CV events.[42] Furthermore, the same meta-analysis concluded that canagliflozin was not associated with an increased risk for the CV outcomes compared with placebo or active comparator with an odd ratio of 0.95 (CI, 71 - 1.26). Similarly, in the FDA report of canagliflozin, another meta-analysis assessed the CV safety of canagliflozin.[12] This study included all major adverse CV events. The estimated hazard ratio was 0.91 (95% CI 0.68, 1.22), deeming canagliflozin not to be associated with a significant increase in the risk of CV disease.

Most studies we identified were found to be well designed and at a low risk of bias. Overall, the major limitation of quality is the lack of CV outcomes being reported as a study outcome. Therefore, the majority (aside from Zimman et al.,) did not have power to detect differences between groups in terms of CV outcomes or events. However, it appears that these studies were not prone to reporting biases directly related to the CV outcomes. Furthermore, these studies were conducted for limited durations and potential bias from shorter treatment durations may have not allowed for detection of these outcomes. Future surveillance studies and adverse effect reporting must be relied upon to determine if CV safety signals emerge when these agents are used over the long-term.

While this review provides a comprehensive and updated analysis of the CV safety of SGLT2 inhibitors, some limitations should be noted. We did not pool results and meta-analyse, but this would have been inappropriate based on the numbers obtained. If attempted, the results would be weighted highly for Zimman et al., as this study included CV outcomes as a primary end-point. Therefore, we believe a qualitative systematic review that discussed findings with respect to quality markers were better suited at this time. Further, as previously mentioned, treatment durations were relatively short (up to 4 years) and conclusions regarding long-term safety cannot be made.

Our review has many implications for both clinical practice and research. First, clinicians should be aware of CV outcomes in patients with diabetes and be sure to report these outcomes to appropriate bodies if they do occur. It is likely that many CV events are overlooked or assumed to be due to the disease itself, whereas clinicians must be vigilant about reporting when patients are taking medications with potential CV consequences. Second, clinicians and researchers should begin designing longitudinal studies to assess the safety of these agents as the longest follow-up period identified was 208 weeks (4 years). Finally, we urge researchers in this area to adequately power studies to detect CV outcomes during trial development especially as regulatory bodies are now requiring these data for approval. Three studies are currently being conducted that aim to achieve these points.[43],[44],[45]


  Conclusion Top


After summarising and evaluating the available literature regarding SGLT2 inhibitors and CV safety, it was occasionally noted that CV events occurred and sometimes numerically increased when compared to placebo or other comparator anti-diabetic medications. However, these findings are only speculative as identified studies did not have enough power to detect outcomes. Overall, study quality was deemed acceptable; hence, findings are unlikely to be biased from other external factors. The major point identified by this review is the lack of long-term studies to assess CV safety with these agents. Therefore, additional future longitudinal studies should be designed to capture event rates over several years as more experience is gained. At present, SGLT2 inhibitors appear to be safe for use in patients with type 2 diabetes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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