Tio år efter EMPA-REG OUTCOME
– så förändrades diabetesvården
För nästan exakt tio år sedan publicerades EMPA-REG OUTCOME – en studie som visade
att ett glukossänkande läkemedel för patienter med diabetes inte bara visade effekt för
hjärtat, utan även kunde minska risken för kardiovaskulär död, sjukhusinläggning för
hjärtsvikt och senare njurfunktionsnedsättning.
https://www.nejm.org/doi/full/10.1056/NEJMoa1504720
Under det följande decenniet har
diabetesvården genomgått betydande förändringar, där behandlingsfokus successivt har
förskjutits från enbart blodsockerkontroll till att även tidigt ta hänsyn till hjärt- och
njurskydd i behandlingsvalen.
Studien EMPA-REG OUTCOME, som utvärderade SGLT2-hämmaren empagliflozin, visade att
ett glukossänkande läkemedel inte bara visade effekt för hjärtat, utan också kunde minska
risken för kardiovaskulär död och sjukhusinläggning för hjärtsvikt. Resultaten bidrog till ett ökat
intresse för att studera utfall utöver blodsockernivåer för patienter med diabetes och har följts
av ett flertal liknande studier under de senaste tio åren.
Bakgrunden till studien var ett krav från FDA, den amerikanska läkemedelsmyndigheten, 2008
och senare den europeiska läkemedelsmyndigheten som handlade om att samtliga nya
diabetesläkemedel skulle utvärderas i särskilda kardiovaskulära säkerhetsstudier (CVOTs).1,2
Syftet var att säkerställa att läkemedlen inte ökade risken för allvarliga hjärt-kärlhändelser.
Drygt 20 studier initierades under det följande decenniet, vilket gradvis breddade förståelsen
för hur olika behandlingar påverkar risken för samsjuklighet mellan diabetes, hjärt-kärl och
njursjukdom.
– Tidigare fokuserade behandlingen av personer med typ 2 diabetes i första hand på att
sänka blodsockret. Numera ser vi annorlunda på sjukdomen och samsjukligheten med
hjärt- kärl- och njursjukdom blir allt tydligare i takt med framsteg inom forskningen,
säger Lars Rydén, professor emeritus i kardiologi vid institutionen för medicin,
Karolinska Institutet.
Förändringar i riktlinjer och behandlingspraxis
Resultaten från EMPA-REG OUTCOME har därefter också studerats i klinisk vardag. I en
nordisk registerstudie från 2024, med över 43 000 patienter med typ 2-diabetes, visade
behandling med empagliflozin jämfört med DPP-4-hämmare liknande resultat som EMPA-REG
OUTCOME-studien.3
Även GLP-1-receptoragonister, såsom liraglutid och semaglutid, har visat sig kunna minska
risken för allvarliga hjärt-kärlhändelser.4,5
Det innebär att det i dag finns flera
behandlingsalternativ som kan bidra till att både förbättra blodsockerkontrollen och minska
risken för komplikationer i hjärta och njurar.
De senaste årens insikter har lett till uppdaterade behandlingsriktlinjer, både internationellt
och nationellt. Idag utvärderas patienter med typ 2-diabetes och hög risk för hjärt-kärlsjukdom
eller njurpåverkan för behandling som kan minska dessa risker – oavsett genomsnittligt
blodsockervärde (HbA1c).
Det markerar ett skifte mot en mer individanpassad diabetesvård,
där samsjuklighet vägs in tidigare i behandlingsbesluten.
Om EMPA-REG OUTCOME
EMPA-REG OUTCOME var en internationell, randomiserad placebokontrollerad studie med
drygt 7 000 patienter med typ 2-diabetes och etablerad hjärt-kärlsjukdom. Studien
utvärderade effekten av empagliflozin som tillägg till sedvanlig behandling, jämfört med
placebo, under en medianuppföljning på 3,1 år.
Resultaten, som presenterades 2015 vid EASD
i Stockholm och publicerades i New England Journal of Medicine, visade bland annat att
empagliflozin jämfört med placebo minskade risken att drabbas av någon hjärtkärlhändelse,
risken att dö i hjärtkärlhändelse och risken för död oavsett orsak.
Referenser:
1. Guidance for Industry Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2
Diabetes. 2008.
https://www.regulations.gov/document/FDA-2008-D-0118-0029
2. Guideline on the Clinical Investigation of Medicinal Products in the Treatment or Prevention of Diabetes Mellitus
(Revision 1) (European Medicines Agency (EMA) website). 2012. Tillgänglig
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-
products-treatment-or-prevention-diabetes-mellitus-revision-1_en.pdf.
3. Empagliflozin Use Is Associated With Lower Risk of All-Cause Mortality, Hospitalization for Heart Failure, and End-
Stage Renal Disease Compared to DPP-4i in Nordic Type 2 Diabetes Patients: Results From the EMPRISE
(Empagliflozin Comparative Effectiveness and Safety) Study. J Diabetes Res. 2024 Oct 12;2024:6142211. doi:
10.1155/2024/6142211.
https://onlinelibrary.wiley.com/doi/10.1155/2024/6142211
4. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. DOI:
10.1056/NEJMoa1603827.
https://www.nejm.org/doi/full/10.1056/NEJMoa1603827
5. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-1844.
DOI: 10.1056/NEJMoa1607141.
https://www.nejm.org/doi/full/10.1056/NEJMoa1607141
Press release från företaget
_________________________________
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Authors: Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin, Sc.D., David Fitchett, M.D., Erich Bluhmki, Ph.D., Stefan Hantel, Ph.D., Michaela Mattheus, Dipl. Biomath., +5 , for the EMPA-REG OUTCOME InvestigatorsAuthor Info & Affiliations
Published November 26, 2015
N Engl J Med 2015;373:2117-2128
DOI: 10.1056/NEJMoa1504720
https://www.nejm.org/doi/full/10.1056/NEJMoa1504720
BACKGROUND
The effects of empagliflozin, an inhibitor of sodium–glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.
METHODS
We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina.
RESULTS
A total of 7020 patients were treated (median observation time, 3.1 years).
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; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority).
There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were
• significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction),
• hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and
• death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction).
There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events.
CONCLUSIONS
Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.)
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https://www.nejm.org/doi/full/10.1056/NEJMoa1504720
From the article
Discussion
Among patients with type 2 diabetes at high risk for cardiovascular events, those receiving empagliflozin had a lower rate of the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than did patients receiving placebo. The difference between empagliflozin and placebo was driven by a significant reduction in death from cardiovascular causes, with no significant between-group difference in the risk of myocardial infarction or stroke. Since the two groups had similar rates of hospitalization for unstable angina, there was no significant difference in the key secondary outcome, which included the risk of hospitalization for unstable angina. Patients in the empagliflozin group had significantly lower risks of death from any cause and for hospitalization for heart failure than did those in the placebo group.
Although a small dose–response effect for the 10-mg dose of empagliflozin versus placebo and the 25-mg dose versus placebo has been documented for metabolic responses, in our study the two dose groups had similar hazard ratios for cardiovascular outcomes. Thus, in clinical practice, the choice of the empagliflozin dose will probably depend primarily on the achievement of metabolic targets and the occurrence of adverse events.
These benefits were observed in a population with established cardiovascular disease in whom cardiovascular risk factors, including blood pressure and dyslipidemia, were well treated with the use of renin–angiotensin–aldosterone system inhibitors, statins, and acetylsalicylic acid. The reductions in the risk of cardiovascular death in the empagliflozin group were consistent across subgroups according to baseline characteristics.
Notably, reductions in the risks of death from cardiovascular causes and from any cause occurred early in the trial, and these benefits continued throughout the study. The relative reduction of 32% in the risk of death from any cause in the pooled empagliflozin group means that 39 patients (41 in the 10-mg group and 38 in the 25-mg group) would need to be treated during a 3-year period to prevent one death, but these numbers cannot be extrapolated to patient populations with other clinical characteristics.
Even though investigators were encouraged to adjust glucose-lowering therapy according to local guidelines, many patients did not reach their glycemic targets, with an adjusted mean glycated hemoglobin level at week 206 of 7.81% in the pooled empagliflozin group and 8.16% in the placebo group. Our trial was designed to assess the specific effects of empagliflozin on clinical outcomes, and the mechanisms behind the observed benefits are speculative. As such, we infer that the mechanisms behind the cardiovascular benefits of empagliflozin are multidimensional25 and possibly involve changes in arterial stiffness,26,27 cardiac function, and cardiac oxygen demand (in the absence of sympathetic-nerve activation),26 as well as cardiorenal effects,21,26,28,29 reduction in albuminuria,20,30 reduction in uric acid,13–20 and established effects on hyperglycemia, weight, visceral adiposity, and blood pressure.13–20
Our trial provides data to support the long-term use of empagliflozin, as well as strong evidence for a reduction in cardiovascular risk. As observed in previous trials, genital infection was more common in patients treated with empagliflozin. Urosepsis was infrequent but reported in more patients treated with empagliflozin, although there was no increase in the overall rate of urinary tract infection, complicated urinary tract infection, or pyelonephritis. The proportions of patients with diabetic ketoacidosis, volume depletion, thromboembolic events, and bone fracture were low (ranging from <1% for ketoacidosis and thromboembolic events to 5% for volume depletion) and similar in the empagliflozin groups and the placebo group. Concern has been expressed about the renal safety of inhibitors of sodium–glucose cotransporter 2 over time. However, the percentage of patients with acute renal failure (including acute kidney injury) was lower in the empagliflozin groups than in the placebo group, and renal function was maintained with empagliflozin.
In conclusion, patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin had significantly lower rates of the primary composite cardiovascular outcome and of death from any cause than did those in the placebo group when the study drugs were added to standard care.
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