NY STUDIE. En intensiv behandling som kombinerar läkemedel med livsstilsförändringar kan eventuellt motverka flera negativa sjukdomsprocesser för personer med prediabetes. De försiktigt positiva resultaten kommer från ett europeiskt forskningssamarbete, där professor Marcus Lind medverkat.

Studiens resultat, publiceras av tidskriften Journal of Clinical Medicine. Resultaten gläntar på dörren till en ny möjlighet att fördröja utvecklingen av diabetes typ 2.

- Det är den första studien som kombinerar intensiva livsstilsinterventioner och läkemedel vid förstadium till typ 2 diabetes och utvärderar effekter på de komplikationer personer med diabetes typ 2 riskerar.

Marcus Lind, professor i diabetologi vid Göteborgs universitet, har medverkat i utformningen av studiens design. Han tycker att resultaten är intressanta och hoppingivande, men vill inte dra för stora växlar:

– Det är data från ettårsuppföljningen, vilket är en relativt kort period. Med det sagt indikerar resultaten att tidig intensiv kombinationsbehandling förbättrar både njurfunktion, nervfunktion och viktprofil.

- Men vi behöver konfirmera resultaten när studien fortsätter och vi följer upp patienterna under längre tid, säger Marcus Lind.

Läkemedel och livsstilsinterventioner

I denna randomiserade studie utvärderades 658 personer som uppfyller kriterierna för prediabetes i fyra olika grupper, som alla fick den livsstilsintervention som idag rekommenderas för personer som riskerar att utveckla diabetes typ 2. Den andra och den tredje gruppen fick dessutom behandling med var sitt etablerat diabetesläkemedel (metformin och linagliptin) och den fjärde gruppen behandlades med båda dessa läkemedel i kombination med livsstilsinterventionerna.

– Det kan låta som ett relativt litet antal personer för att vara en randomiserad klinisk prövning där organskador utvärderas, men ha då i åtanke att dessa personer ofta inte är registrerade patienter, utan riskpersoner från normalbefolkningen. Studiepersonerna får genomgå omfattande undersökningar, som fotografering av ögonbotten, neurologiska tester och mätning av njurens funktion, berättar Marcus Lind.

Ett akademiskt initiativ

Till skillnad från många andra kliniska prövningar är denna studie inte initierad av läkemedelsbolagen, utan är ett akademiskt initiativ, med finansiering från EU. Professor Marcus Lind var en av de delaktiga redan när studien initierades i ett större EU-samarbete. Huvudansvariga var professor Jaakko Tuomilehto vid universitetet i Helsingfors och Rafael Gabriel, forskare vid universitetssjukhuset La Paz i Madrid.

Bakgrunden är en annan studie, publicerad 2001 i tidskriften New England Journal of Medicine under ledning av Jaakko Tuomilehto, som visade att utveckling av typ 2 diabetes kan förhindras i högriskgrupper genom kraftfulla livsstilsförändringar.

Den aktuella studien, kallad ePREDICE, tar nästa steg. Den undersöker om inte bara typ 2 diabetes utan även organskador kan förebyggas med intensivbehandling på ett tidigt stadium, redan innan typ 2 diabetes utvecklats.

• Titel: Reduction in the Risk of Peripheral Neuropathy and Lower Decrease in Kidney Function with Metformin, Linagliptin or Their Fixed-Dose Combination Compared to Placebo in Prediabetes: A Randomized Controlled Trial; https://doi.org/10.3390/jcm12052035

• Bakgrundsartikel från 2001: Prevention of Type 2 Diabetes Mellitus by Changes in Lifestyle among Subjects with Impaired Glucose Tolerance; https://www.nejm.org/doi/full/10.1056/nejm200105033441801

Press release Elin Lindström Göteborgs universitet

https://www.mdpi.com/2077-0383/12/5/2035

Abstract

Objective:

To compare the effect of glucose-lowering drugs on peripheral nerve and kidney function in prediabetes. Methods: Multicenter, randomized, placebo-controlled trial in 658 adults with prediabetes treated for 1 year with metformin, linagliptin, their combination or placebo. Endpoints are small fiber peripheral neuropathy (SFPN) risk estimated by foot electrochemical skin conductance (FESC < 70 μSiemens) and estimated glomerular filtration rate (eGFR).

Results:

Compared to the placebo, the proportion of SFPN was reduced by 25.1% (95% CI:16.3–33.9) with metformin alone, by 17.3% (95% CI 7.4–27.2) with linagliptin alone, and by 19.5% (95% CI 10.1–29.0) with the combination linagliptin/metformin (p< 0.0001 for all comparisons). eGFR remained +3.3 mL/min (95% CI: 0.38–6.22) higher with the combination linagliptin/metformin than with the placebo (p= 0.03). Fasting plasma glucose (FPG) decreased more with metformin monotherapy −0.3 mmol/L (95%CI: −0.48; 0.12, p= 0.0009) and with the combination metformin/linagliptin −0.2 mmol/L (95% CI: −0.37; −0.03) than with the placebo (p= 0.0219). Body weight (BW) decreased by −2.0 kg (95% CI: −5.65; −1.65, p= 0.0006) with metformin monotherapy, and by −1.9 kg (95% CI: −3.02; −0.97) with the combination metformin/linagliptin as compared to the placebo (p= 0.0002).

Conclusions:

in people with prediabetes, a 1 year treatment with metformin and linagliptin, combined or in monotherapy, was associated with a lower risk of SFPN, and with a lower decrease in eGFR, than treatment with placebo.

Introduction

Type 2 diabetes (T2D) is a slowly progressive disease characterized by advancing hyperglycemia. Prediabetes, the intermediate stage between normoglycemia and T2D, is a heterogeneous condition with several pathophysiological phenotypes [1]. Progression from prediabetes to T2D ranges between 5–10% per year [2,3,4] and this rate depends on the sub-phenotype of prediabetes and the risk factor profile; for instance, the level of diabetes risk score [2,3,4].

People with prediabetes have an increased risk for macro- and microvascular (namely nephropathy, neuropathy and retinopathy), complications [5,6,7,8,9,10,11]. The Rotterdam study reported that people with prediabetes have generalized microvascular dysfunction and sequelae representing end-organ damage typical of diabetes [12]. Based on such evidence it has been proposed that the definition of prediabetes should not only be centered on glucose abnormalities but should also incorporate microvascular involvement among its criteria [13,14,15].

Lifestyle intervention studies have shown a reduction in the relative risk of diabetes by 40–70% in individuals with prediabetes [13]. The Finnish Diabetes Prevention Study (DPS) and the US Diabetes Prevention Program (DPP) showed how lifestyle intervention, as compared to the control group, was associated with a 58% reduction in the risk of diabetes after approximately three years. The benefits of lifestyle modification in delaying the onset of T2D in people with prediabetes have been confirmed in meta-analyses of clinical trials [16]. However, approximately half of the people with hyperglycemia in the DPP failed to achieve normal glycaemia with lifestyle interventions alone, and about 1/3 of them progressed to clinical T2D in an average of 10 years [3]. Several glucose-lowering drugs such as acarbose, metformin, rosiglitazone, pioglitazone, insulin glargine and liraglutide have also shown some benefits for the prevention of diabetes in people with prediabetes, but this benefit disappeared when the drug therapy was stopped [17,18,19,20,21]. The dipeptidyl peptidase-4 inhibitor (DPP4i) linagliptin has demonstrated its cardiovascular safety in placebo-controlled trials. It also demonstrated non-inferiority using a composite marker for cardiovascular outcome compared to glimepiride. Both cases happened when the drugs were administered as monotherapy in relatively early T2D [22]. Recently, the VERIFY study [23] has reported on the efficacy and safety of combining metformin with the DPP4i vildagliptin, compared with metformin monotherapy, in early–untreated T2D. Evidence of higher efficacy and safety of dual therapy versus monotherapy and/or lifestyle changes in people with prediabetes does not exist. Evidence for the prevention of microvascular complications is also limited in prediabetes. Few prevention trials have evaluated the potential benefits of lifestyle modification or drug treatment for preventing such complications. The Da Qing study in China was the first published trial reporting a significant long-term reduction in the incidence of diabetic retinopathy with lifestyle modification [24]. The evidence regarding the benefit of lifestyle changes or the use of metformin for the prevention of microvascular complications was also inconclusive in the US-DPP [17]. The DPS has reported that lifestyle intervention improved retinopathy status [25]. Experimental studies have reported that linagliptin has a protective effect on the microvasculature of the diabetic retina, most likely due to a combination of neuroprotective and antioxidative beneficial effects [26]. Several clinical trials have also shown that linagliptin may slow down the progression of albuminuria in patients with T2D and renal dysfunction [27,28].

So far, no trial has reported if microvascular function can be better preserved by combining lifestyle interventions with early glucose-lowering drug treatment (multiple or monotherapy) in people with either early diagnosed T2D [29] or with prediabetes [30]. Therefore, the primary objective of the Early Prevention of Diabetes Complications in People with Hyperglycaemia (ePREDICE) trial is to assess the effects of early intensive management of prediabetes on several microvascular parameters in comparison with placebo and lifestyle modification. The primary endpoint was a combination of three microvascular endpoints: retinal and peripheral nerve and kidney functions in adults with prediabetes. In this paper we report 1 year results on the intermediate independent effect of each glucose-lowering drug regimen and placebo (i.e., lifestyle intervention alone) only on the peripheral nerve (sudomotor function) and eGFR.

Läs abstract och hela studien pdf free

https://www.nejm.org/doi/full/10.1056/nejm200105033441801

Prevention of Type 2 Diabetes Mellitus by Changes in Lifestyle among Subjects with Impaired Glucose Tolerance

• Jaakko Tuomilehto, M.D., Ph.D., et al

• Abstract

  Background

  Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known.

  Methods

  We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years.

  Results

  The mean (±SD) amount of weight lost between base line and the end of year 1 was 4.2±5.1 kg in the intervention group and 0.8±3.7 kg in the control group; the net loss by the end of year 2 was 3.5±5.5 kg in the intervention group and 0.8±4.4 kg in the control group (P<0.001 for both comparisons between the groups). The cumulative incidence of diabetes after four years was 11 percent (95 percent confidence interval, 6 to 15 percent) in the intervention group and 23 percent (95 percent confidence interval, 17 to 29 percent) in the control group. During the trial, the risk of diabetes was reduced by 58 percent (P<0.001) in the intervention group. The reduction in the incidence of diabetes was directly associated with changes in lifestyle.

  Conclusions

  Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects.