https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00537-3/fulltext
Post-trial monitoring of a randomised controlled trial of intensive glycaemic control in type 2 diabetes extended from 10 years to 24 years (UKPDS 91)
- Prof Amanda I Adler, MD †
- Ruth L Coleman, MSc †
- Jose Leal, DPhil
- Prof William N Whiteley, PhD
- Prof Philip Clarke, PhD
- Prof Rury R Holman, FMedSci
- Show footnotes
https://doi.org/10.1016/S0140-6736(24)00537-3
Det är en sensationell studie, en ”guldstudie”, 5-stjärnig studie, landmarkstudie.
Det finns knappast något liknande inom medicin totalt sett där man har uppföljning under så lång tid. Det är 42 års uppföljning med 80 000 patientår och det är fantastiskt att det här metabola minnet sitter kvar så många år efteråt
Ursprungsstudien till den aktuella studien publicerades 1998, UKPDS, United Kingdom Prospective Diabetes Study. Då ingick nära 4 200 deltagare som följdes under 20 års tid.
Forskarna undersökte utgången för patienter med nydiagnosticerad typ 2-diabetes som randomiserades till att antingen få så kallad intensiv blodsockersänkande behandling med läkemedel eller enbart rekommenderad livsstilsförändring, främst ändrade kostvanor. De deltagare som lottades till tidig läkemedelsbehandling fick antingen metformin – om de bedömdes som överviktiga – eller sulfonureider eller insulin.
– Usprungsstudien är otroligt citerad och underlag för alla internationella riktlinjer för klinisk behandling av typ 2-diabetes. Den visade att metformin har en egen effekt, förutom att den sänker blodsockret, på minskad hjärtinfarkt och död. Det var också första gången det visades att det finns ett metabolt minne. Ju tidigare man gick in för ett bra långtidsblodsocker, HbA1c, ju bättre blev effekten på komplikationer,
Efter den inledande studien fortsatte cirka 3 300 patienter att följas i 10 år. Den aktuella studien med nära 1 500 patienter har undersökt långtidsresultaten efter ytterligare 14 års tid.
Resultaten för metformin visade en absolut risk för död oavsett orsak på 34,4 dödsfall per 1 000 personår jämfört med 49,3 i kontrollgruppen. Metfori8n hade 20% mindre risk för död vid uppöljning, dubbelt så mycket som gruppen som randomiserades till SU eller insulin.
I Svensk förening för diabetologis ”Mål och målsättning för 2024” rekommenderas ett HbA1c på under 48 mmol per mol för typ 2-diabetespatienter de första två åren efter sjukdomens debut. Se under HbA1c T2DM
– Alla typ 2-diabetespatienter ska ha farmakologisk behandling direkt vid diagnos med metformin och det senaste är att vi nu behandlar även prediabetes, innan patienten fått typ 2-diabetes. Redan vid 6,1 mmol per liter i fasteblodsocker ska man gå in med aktiva åtgärder, i första hand livsstilsåtgärder. Detta diskuteras också i ”Målsättning och mål vid diabetes 2024”. Se under avsnitet Prediabetes.
Nyhetsinfo
www red DiabetologNytt
ABSTRACT
Summary
Background
The 20-year UK Prospective Diabetes Study showed major clinical benefits for people with newly diagnosed type 2 diabetes randomly allocated to intensive glycaemic control with sulfonylurea or insulin therapy or metformin therapy, compared with conventional glycaemic control.
10-year post-trial follow-up identified enduring and emerging glycaemic and metformin legacy treatment effects.
We aimed to determine whether these effects would wane by extending follow-up for another 14 years.
Methods
5102 patients enrolled between 1977 and 1991, of whom 4209 (82·5%) participants were originally randomly allocated to receive either intensive glycaemic control (sulfonylurea or insulin, or if overweight, metformin) or conventional glycaemic control (primarily diet). At the end of the 20-year interventional trial, 3277 surviving participants entered a 10-year post-trial monitoring period, which ran until Sept 30, 2007. Eligible participants for this study were all surviving participants at the end of the 10-year post-trial monitoring period. An extended follow-up of these participants was done by linking them to their routinely collected National Health Service (NHS) data for another 14 years.
Clinical outcomes were derived from records of deaths, hospital admissions, outpatient visits, and accident and emergency unit attendances. We examined seven prespecified aggregate clinical outcomes (ie, any diabetes-related endpoint, diabetes-related death, death from any cause, myocardial infarction, stroke, peripheral vascular disease, and microvascular disease) by the randomised glycaemic control strategy on an intention-to-treat basis using Kaplan–Meier time-to-event and log-rank analyses. This study is registered with the ISRCTN registry, number ISRCTN75451837.
Findings
Between Oct 1, 2007, and Sept 30, 2021, 1489 (97·6%) of 1525 participants could be linked to routinely collected NHS administrative data. Their mean age at baseline was 50·2 years (SD 8·0), and 41·3% were female. The mean age of those still alive as of Sept 30, 2021, was 79·9 years (SD 8·0). Individual follow-up from baseline ranged from 0 to 42 years, median 17·5 years (IQR 12·3–26·8). Overall follow-up increased by 21%, from 66 972 to 80 724 person-years. For up to 24 years after trial end, the glycaemic and metformin legacy effects showed no sign of waning. Early intensive glycaemic control with sulfonylurea or insulin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 10% (95% CI 2–17; p=0·015) for death from any cause, 17% (6–26; p=0·002) for myocardial infarction, and 26% (14–36; p<0·0001) for microvascular disease. Corresponding absolute risk reductions were 2·7%, 3·3%, and 3·5%, respectively.
Early intensive glycaemic control with metformin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 20% (95% CI 5–32; p=0·010) for death from any cause and 31% (12–46; p=0·003) for myocardial infarction.
Corresponding absolute risk reductions were 4·9% and 6·2%, respectively. No significant risk reductions during or after the trial for stroke or peripheral vascular disease were observed for both intensive glycaemic control groups, and no significant risk reduction for microvascular disease was observed for metformin therapy.
Interpretation
Early intensive glycaemic control with sulfonylurea or insulin, or with metformin, compared with conventional glycaemic control, appears to confer a near-lifelong reduced risk of death and myocardial infarction. Achieving near normoglycaemia immediately following diagnosis might be essential to minimise the lifetime risk of diabetes-related complications to the greatest extent possible.
Funding
University of Oxford Nuffield Department of Population Health Pump Priming.
From the Article
Introduction
Spanning over 20 years, the UK Prospective Diabetes Study (UKPDS) was a randomised, multicentre trial among people with newly diagnosed type 2 diabetes. Findings from the UKPDS showed relative risk reductions with an intensive glycaemic control strategy with sulfonylurea or insulin therapy, compared with a conventional glycaemic control strategy (primarily with diet), of 12% for any diabetes-related endpoint (p=0·029) and 25% for clinically evident microvascular complications (p=0·0099).
The 16% relative risk reduction for myocardial infarction did not achieve conventional statistical significance (p=0·052). In participants with more than 20% of their ideal bodyweight (which equates approximately to a BMI of >27 kg/m), relative risk reductions with an intensive glycaemic control strategy with metformin, compared with a conventional glycaemic control strategy, were 32% for any diabetes-related endpoint (p=0·0023), 36% for death from any cause (p=0·01), and 39% for myocardial infarction (p=0·01).
Discussion
This follow-up of UKPDS participants for up to 42 years is perhaps the longest for any clinical trial to date, with more than 80 000 person-years accrued. Following up to 14 more years of post-trial monitoring using routinely collected NHS administrative data, analyses show that the previously identified glycaemic and metformin legacy effects do not wane for up to 24 years after the trial ended. The legacy benefits from early intensive glycaemic control with sulfonylurea or insulin led to overall relative risk reductions from baseline of 10% for death, 17% for myocardial infarction, and 26% for microvascular complications. Early intensive glycaemic control with metformin led to numerically larger overall relative risk reductions than with sulfonylurea or insulin, from baseline of 20% for death and 31% for myocardial infarction. These landmark findings emphasise the importance of achieving good glycaemic control for people with type 2 diabetes as early as possible. By contrast, the substantial within-trial relative risk reductions seen with tight blood pressure control in the UKPDS waned rapidly during the post-trial monitoring study, with all HRs moving towards unity. The pathophysiological mechanisms responsible for persisting glycaemic and metformin legacy effects remain unclear. Perhaps the glycaemic legacy effect is in reality a hyperglycaemic legacy effect, whereby initial poor glycaemic control induces irreversible pathophysiological changes, permanently increasing the risks of diabetes-related complications and death. Post-hoc UKPDS analyses have shown that glycaemic legacy effects can be explained predominately by historical HbA- Each percentage point higher HbAdecrease for 10 years, compared with an immediate decrease, would mean a drop in the estimated relative risk reduction for death from 18·6% to 6·6%. An observational study using the Kaiser Permanente Northern California Diabetes Registry data has shown that for patients with newly diagnosed type 2 diabetes who survived for at least 10 years,
HbA The glycaemic legacy effect first described by the UKPDS is akin to the metabolic memory first described in people with type 1 diabetes by the Epidemiology of Diabetes Interventions and Complications follow-up of the Diabetes Control and Complications Trial. The type 2 diabetes legacy effect and the type 1 diabetes metabolic memory effect might share similar mechanisms. Proposed mechanisms include increased intracellular formation of advanced glycation end products, oxidative stress, and epigenetic changes enhancing expression of proinflammatory genes.
UKPDS has shown that establishing and maintaining near normoglycaemia from the time of diagnosis of type 2 diabetes minimises the risk of complications and prolongs life, and early metformin therapy reduces the risk of complications and of dying. The numerically greater magnitude of the metformin legacy effect suggests additional metformin-related protective mechanisms might exist, such as inhibition of the inflammatory pathway.
Modern management of type 2 diabetes includes the use of newer glucose-lowering agents that have been shown to reduce the risk of diabetes-related complications such as GLP-1 receptor agonists and SGLT2 inhibitors.
However, their glucose lowering properties appear to explain only part of their ability to prevent or delay cardiovascular and kidney diseases, suggesting that non-glycaemic mechanisms might largely be responsible.
We support the major role GLP-1 receptor agonists and SGLT2 inhibitors have in helping to reduce the risk of the complications of diabetes, but would emphasise the importance of avoiding hyperglycaemia however this outcome is achieved. Notably, all the therapies used in the UKPDS are off patent, have been shown previously to be cost-effective or indeed cost-saving, are widely available globally at low cost, and are on the WHO List of Essential Medicines. The glycaemic legacy effect is likely to strengthen the economic case for the use of these therapies in low-income settings, as this study has demonstrated additional enduring health benefits long beyond the trial period.
Our study has some limitations. Additional clinical event data could be obtained only for participants who could be linked to routinely collected NHS administrative data, and we could not obtain non-fatal clinical event data for the 130 participants in the two Northern Ireland centres. However, because of the similar patterns of death across the three nations, we believe that had we obtained the Northern Ireland non-fatal event data our conclusions would not have changed. During this extended follow-up period, we did not have access to information about biochemical measures, including HbA1cand plasma creatinine values, nor information about pharmacotherapy. Most participants not randomly assigned to the metformin group will likely have received this medication over time, suggesting that the true relative risk reductions for metformin could be even greater than we report. Non-fatal events that did not require admission to hospital or an outpatient procedure, for example blindness in one eye, might not have been captured. Events identified via routinely collected NHS administrative data could not be adjudicated, although a post-hoc analysis of the ASCEND trial suggests that routinely collected UK hospital admission and death registry data can be used as the sole method to follow up cardiovascular outcomes in primary prevention cardiovascular trials without needing to verify them by clinical adjudication.
Nevertheless, any misclassification of outcomes is unlikely to be related to previous randomisation. The number of participants (n=753) in the metformin comparison is small by modern trial standards, but sufficient to show the differences in complication risks of the magnitude we report. This sample size was also nearly five times greater than the 160 participants in the highly regarded Steno-2 study, which first showed the beneficial effects of multifactorial intervention on morbidity and later on mortality in type 2 diabetes.
As in previous UKPDS papers, no statistical adjustment was made for multiple testing of aggregate outcomes, and the dwindling cohort size secondary to mortality potentially limits the ability to detect new treatment-related differences. Competing risk methods were not used as cause-specific hazard models are appropriate when addressing aetiological questions.
In conclusion, our results demonstrate near-lifelong legacy effects of early intensive glycaemic control with sulfonylurea or insulin and with metformin. Achieving near-normal glycaemia immediately after type 2 diabetes is diagnosed appears to be essential to minimise the lifetime risk of diabetes-related complications to the greatest extent possible.
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https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00537-3/fulltext
