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Glucose Lowering Strategies and 563
Cardiovascular Outcomes

risk -as shown by the composite primary and sec- from the introduction of new strategies to improve
ondary outcomes- and a composite outcome of HF the applicability of trial results to daily clinical prac-
hospitalization and CV death [18,20]. tice, as was agreed by the members of the first CVOT
Summit of the Diabetes and CVD (D&CVD) EASD
Regardless of the CV safety of all anti-hyperglyce- Study Group [32].
mic agents tested, one trial on DPP-4 inhibitors, SA-
VOR-TIMI, found a significantly higher risk for HF in Most CVOTs started after the 2008 FDA/EMA guide-
the treatment group and another, EXAMINE a trend line analyze drugs of the SGLT-2 inhibitor, DPP-4-in-
towards such outcome [12, 13]. In contrast, there were hibitor, or GLP-1 receptor agonist class. Even when
no such concerns in the TECOS trial [14]. Differenc- the ORIGIN trial already focused on the evaluation
es to baseline patient characteristics, as well as to of insulin gargline versus standard care [11], since the
trial design make it difficult to compare results from FDA mandate only one CVOT study investigated CV
these trials. Moreover, the molecular structure differs risks of insulin treatment, the DEVOTE trial on insu-
among DPP-4 inhibitors and so does their safety lin glargine versus insulin degludec. To date there is
profile. As a result, the FDA recently issued a safe- not a single CVO trial on metformin or sulphonylurea
ty warning on saxagliptin and alogliptin increasing alone. Considering that metformin is a first line treat-
the risk of heart failure, particularly in patients who ment for T2D [33] and that sulphonylurea and insulin
already have heart or kidney disease [22]. Despite are also very common therapeutic tools in diabetes
recent meta analyses of randomized clinical trials [34], more CVOTs on these drugs are essential.
including results of SAVOR-TIMI and EXAMINE sug-
gested an increased risk of hospitalization due to Conclusion
HF in T2D patients [23–26], others have found no Since the 2008 FDA/EMA regulations demanded an
difference in hospitalization rates for HF between investigation of CV outcomes for newly developed
treatment with saxagliptin compared with sitagliptin glucose-lowering agents, a number of CVOTs have
or with DPP-4 inhibitors compared with other classes been completed and their results published. These
of anti-diabetes agents [27, 28].
trials, in general, have shown that glucose-lowering
The analyses of results of the aforementioned drugs do not increase CV risks over placebo levels,
CVOTs have been very useful for treatment deci- and even that some drugs, as empagliflozin, cana-
sion-making and patient safety in diabetes [29]. Not gliflozin, semaglutide or liraglutide, can actually lead
only were these trials capable of proving CV safety, to cardiovascular protection. However, despite satis-
but four of them, EMPA-REG OUTCOME, LEADER, fying the requirements of regulatory agencies when
SUSTAIN-6 and CANVAS showed cardiovascular it comes to demonstrating not incrementing CV risk
benefits even when they were primarily designed for beyond a certain safety level, current CVOTs suffer
non-inferiority. However, it is important to note that still from certain design flaws that hinder their po-
these results are so far only valid for the particular tential. Head to head comparisons, broader patient
patient groups enrolled in the studies, and that it is population groups, long-term analysis and an expan-
not clear how translatable they are to the general pa- sion of safety end-points, etc. would serve to improve
tient population. Furthermore, a comparison among CVOT design and expand its applicability spectrum.
results from CVOT is overall difficult, among other Several future CVOT trials are being conducted with
reasons because the definition of CVD risk and/or linagliptin (CARMELINA, CAROLINA), dapagliflozin
CVD is different for each trial, and with it the degree (DECLARE-TIMI), ertugliflozin (VERTIS-CV), exenati-
of severity of prior disease of enrolled patients highly de once weekly (EXCEL), dulaglutide (REWIND) and
variable. Other reasons limiting comparability among albiglutide (HARMONY) which will further enlighten
CVOTs, especially in terms of event rates, apart from us in future.
the aforementioned differences in baseline patient
characteristics, are the variable trial duration and the References
diverse definitions of the primary end-point. In ad- 1. Federal Drug Administration (FDA). Guidance for industry diabetes melli-
dition, another obstacle for compared evaluation of tus—evaluating cardiovascular risk in new antidiabetic therapies to treat
trials evaluating cardiovascular outcomes before and type 2 diabetes. 2008. Compliance Regulatory Information Guidances/
after FDA 2008 regulation is that the routine care ucm071627.pdf.
background from those trials is somehow dissimilar. 2. European Medicines Agency (EMA). Guideline on clinical investigation of
In general, despite the great advance for the clinical medicinal products in the treatment or prevention of diabetes mellitus.
Verfügbar unter. http://www.ema.europa.eu/docs/en_GB/document_library/
practice meant by new CVOTs, there is still room for Scientific_guideline/2012/06/WC500129256.pdf (2012).
improvement [30, 31]. Trial design could still benefit
3. The Diabetes Control and Complications Trial Research Group. The effect

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