Comment

SGLT2 inhibitors in clinical practice

On Sept 15, 2015, in Stockholm, the attendees at the intended for pain relief, but high doses caused
Congress of the European Association for the Study weight loss related to increased urinary output due to
of Diabetes were stunned by the presentation of the glycosuria.6 The compound was abandoned due to side-
first randomised investigation of a sodium–glucose effects, mainly diarrhoea, but gained renewed interest
co-transporter-2 (SGLT2) inhibitor, empagliflozin, around 1987 when experimental studies showed that
in the EMPA-REG OUTCOME trial1 in patients with it normalised blood glucose in mice with induced

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type 2 diabetes and atherosclerotic cardiovascular diabetes. As summarised by Abdul-Ghani and DeFronzo,7
disease. The unexpected results (ie, an early-onset it was by that time SGLT1 and SLGT2 receptors were
reduction in morbidity and mortality) caused the identified, and that increased diuresis and lowering of
audience to stand up and applaud the first evidence hyperglycaemia was caused by an inhibition of SGLT2,
that a drug, developed to lower glucose concentration, mainly expressed in the kidneys. Compounds with Lancet Diabetes Endocrinol 2024

was associated with cardiovascular superiority due to better bioavailability and more specific SGLT2 inhibition Published Online
May 17, 2024
a reduction of heart failure. Since then, the mortality than phlorizin were produced, opening the possibility https://doi.org/10.1016/
reduction in the EMPA-REG OUTCOME trial has been for clinical trial test­ing. Following important findings S2213-8587(24)00133-5
See Online/Articles
questioned as this reduction was not seen in similar regarding decreased mortality, reduced heart failure
https://doi.org/10.1016/
studies of other SGLT2 inhibitors.2 This discrepancy hospitalisations, and protracted renal deterioration in S2213-8587(24)00102-5
might, however, relate to patients in the EMPA-REG patients with type 2 diabetes and cardiovascular disease,
OUTCOME being less ill or shorter periods of observation. the spectrum of patients investigated was broadened
The EMPA-REG OUTCOME trial was soon followed to comprise patients with and without type 2 diabetes
by randomised trials of other SGLT2 inhibitors with who had heart failure with reduced or preserved left
similar cardiovascular and renoprotective effects.2 The ventricular ejection fraction, chronic kidney disease,
similarity in these findings suggests that the effect of and acute myocardial infarction. These trials were
SGLT2 inhibitors might represent a class effect, which mostly event driven and powered to study one primary
according to the US Food and Drug Administration outcome, a composite of major cardiovascular events,
is defined as a group of active moieties that share including heart failure. The statistical power was,
scientifically documented properties defined based however, insufficient to confirm the effect of SGLT2
on any combination of three attributes: mechanism inhibition on individual components of the composite
of action, physiologic effect, and chemical structure.3 event and in subgroups of patients, even if results
Furberg and colleagues4 advised caution before accept­ seemed favourable. This shortcoming was especially
ing that drugs within a class are interchangeable, observed for cardiovascular-related mortality and all-
claiming that the only way to support the claims of cause mortality due to short follow-up times and a high
a class effect is via head-to-head comparisons. Such prevalence of heart failure.
comparisons are, however, sparse since the industrial In The Lancet Diabetes & Endocrinology,
incentive to invest in such trials is low due to economical Muhammad Shariq Usman and colleagues8 attempted
reasons. Other demands before accepting a class effect to overcome this problem by performing a systematic
are information on efficacy and safety related to hard search for large primary outcome and secondary outcome
endpoints, such as mortality, myocardial infarction, trials (n>1000) of SGLT2 inhibitors versus placebo,
and heart failure in relevant study populations.4,5 As creating a database of 100 952 patients, including
indicated by meta-analyses, there are reasons to accept also the latest performed trials after acute myocardial
class effects among SGLT2 inhibitors, which is important infarction. They conducted a systematic review and
in the present context with regard to discussion of meta-analysis according to high standards. The effect
a systematic review and meta-analysis.2,5 of SGLT-2 inhibitors was analysed on cardiovascular
The first experiences with SGLT2 inhibition were outcomes in patients with heart failure, type 2 diabetes,
achieved in 1835 by means of phlorizin extracted chronic kidney disease, and atherosclerotic cardiovascular
from root bark of apple trees. Phlorizin was origi­nally disease, including acute myocardial infarction, as well

www.thelancet.com/diabetes-endocrinology Published online May 17, 2024 https://doi.org/10.1016/S2213-8587(24)00133-5 1

 Comment

as in specific subgroups of patients. SGLT2 inhibition more technically oriented limitations which, however,
reduced the risk of first hospitalisation for heart failure seem less important for the clinical application of the
by 29% in patients with heart failure (hazard ratio information provided.
[HR] 0·71 [95% CI 0·67–0·77]), by 28% in patients with In summary, this well performed systematic review
type 2 diabetes (0·72 [0·67–0·77]), by 32% in patients and meta-analysis consolidates the beneficial effects of
with chronic kidney disease (0·68 [0·61–0·77]), and SGLT2 inhibition in a broad group of patients. The study
by 28% in patients with atherosclerotic cardiovascular underlines the importance to use SGLT2 inhibitors as
disease (0·72 [0·66–0·79]). Moreover, SGLT2 inhibition advocated in international management guidelines,
reduced cardiovascular mortality in patients with heart not the least in patients with type 2 diabetes and in
failure by 14% (HR 0·86 [95% CI 0·79–0·93]), by 15% in those with heart failure, as well as in those with chronic
type 2 diabetes (0·85 [0·79–0·91]), by 11% in chronic kidney disease, since need for hospitalisations and
kidney disease (0·89 [0·82–0·96]), and by 13% if the cardiovascular mortality are both reduced. To prescribe
patients with atherosclerotic vascular disease (0·87 SGLT2 inhibitors to a patient with uncomplicated
[0·78–0·97]). The benefits on heart failure-related myocardial infarction is, however, not supported by any
hospitalisation and cardiovascular death were consistent evidence of benefit.
across a majority of 51 demographic patient subgroups as We declare no competing interests.
well as in different combinations of diseases. Exceptions *Lars Rydén, Anna Norhammar
from these favourable outcomes were noted for patients [email protected]
with uncomplicated acute myocardial infarction and in Department for Medicine Solna, Karolinska Institutet, Stockholm SE-171 76,
Sweden
those with heart failure with preserved ejection fraction,
1 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular
in whom there was no notable effect on cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–28.
death. The results of this systematic review and meta- 2 McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 Inhibitors
with cardiovascular and kidney outcomes in patients with type 2 diabetes:
analysis are of obvious importance for physicians a meta-analysis. JAMA Cardiol 2021; 6: 148–58.
managing patients with the diseases covered. 3 US Food and Drug Administration. Pharmacologic class. 2023. https://
www.google.com/url?sa=t&source=web&rct=j&opi=89978449&url=htt
There were some limitations to be considered. ps://www.fda.gov/industry/structured-product-labeling-resources/
pharmacologic-class&ved=2ahUKEwjt4b_osd-FAxUgBxAIHUKYD0IQFnoEC
Some patient groups are not covered by large clinical B0QAQ&usg=AOvVaw3L78kXyLQXMDoBtslbZDqB (accessed May 1, 2024).
trials. Vulnerable groups (ie, those with multiple 4 Furberg CD, Herrington DM, Psaty BM. Are drugs within a class
interchangeable? Lancet 1999; 354: 1202–04.
concomitant diseases and the elderly population) are 5 Shi Q, Nong K, Vandvik PO, et al. Benefits and harms of drug treatment for
usually excluded although common in clinical practice, type 2 diabetes: systematic review and network meta-analysis of
randomised controlled trials. BMJ 2023; 381: e074068.
limiting the generalisability of a systematic review and 6 Chasis H, Jolliffe N, Smith HW. The action of phlorizin on the excretion of
meta-analysis of the present type. Moreover, the time glucose, xylose, sucrose, creatinine and urea by man. J Clin Invest 1933;
12: 1083–90.
of follow-up in most included trials is less than 2 years, 7 Abdul-Ghani MA, DeFronzo RA. Lowering plasma glucose concentration by
leaving the long-term outcome unknown. Further, inhibiting renal sodium–glucose cotransport. J Intern Med 2014;
276: 352–63.
studies that claimed to have recruited patients without 8 Usman MS, Bhatt DL, Hameed I, et al. Effect of SGLT2 inhibitors on heart
failure outcomes and cardiovascular death: a systematic review and
type 2 diabetes used fasting glucose and HbA1c to exclude meta-analysis. Lancet Diabetes Endocrinol 2024; published online May 17.
glucose perturbations. This approach is insufficiently https://doi.org/10.1016/S2213-8587(24)00102-5.
9 Ferrannini G, De Bacquer D, De Backer G, et al. Screening for glucose
sensitive, with the implication that the true proportion perturbations and risk factor management in dysglycemic patients with
of patients with type 2 diabetes is under reported.9 As coronary artery disease—a persistent challenge in need of substantial
improvement: a report from ESC EORP EUROASPIRE V. Diabetes Care 2020;
correctly indicated by the authors, there are also some 43: 726–33.

2 www.thelancet.com/diabetes-endocrinology Published online May 17, 2024 https://doi.org/10.1016/S2213-8587(24)00133-5