Effects of combined training with different intensities on vascular health in patients with type 2 diabetes : a 1-year randomized controlled trial

Magalhãese al. Ca dio asc Diabe ol (2019) 18:34 h ps://doi.o g/10.1186/s12933-019-0840-2 ORIGINAL INVESTIGATION E ec s o combined aining wi hdi e en in ensi ies on ascula heal h inpa ien s wi h ype 2 diabe es: a1-yea andomized con olled ial João P. Magalhães1, Xa ie Melo1,8, Inês R. Co eia1, Rogé io T. Ribei o2, João Raposo2, Hélde Do es3,4,5, Manuel Bicho6,7 and Luís B. Sa dinha1* Abs ac Backg ound: Exe cise, when pe o med on a egula basis, is a well-accep ed s a egy o imp o e ascula unc ion in pa ien s wi h ype 2 diabe es. Howe e , he exe cise in ensi y ha yields maximal adap a ions on s uc u al and unc ional indices in pa ien s wi h ype 2 diabe es emains unce ain. Ou objec i e was o analyze he impac o a 1-yea andomized con olled ial o combined high-in ensi y in e al aining (HIIT) wi h esis ance aining (RT) s. a combined mode a e con inuous aining (MCT) wi h RT on s uc u al and unc ional a e ial indices in pa ien s wi h ype 2 diabe es. Me hods: Pa ien s wi h ype 2 diabe es (n = 80) we e andomized in o an exe cise in e en ion wi h h ee g oups: con ol, combined HIIT wi h RT and combined MCT wi h RT. The 1-yea in e en ion had 3 weekly exe cise sessions. High- esolu ion ul asonog aphy o he common ca o id a e y and cen al and pe iphe al applana ion onome y we e used o assess he changes in s uc u al and unc ional a e ial indices. Gene alized es ima ing equa ions we e used o model he co esponding ou comes. Resul s: A e adjus ing he models o sex, baseline mode a e- o- igo ous physical ac i i y, and mean a e ial p es- su e changes, while using he in en ion- o- ea analysis, a signi ican in e ac ion was obse ed on he ca o id in ima- media hickness (cIMT) o bo h he MCT (β = − 4.25, p < 0.01) and HIIT g oup (β = − 3.61, p < 0.01). Howe e , only he HIIT obse ed a o able changes om baseline o 1-yea on pe iphe al a e ial s i ness indices such as ca o id adial a e ial pulse wa e eloci y (β = − 0.10, p = 0.044), ca o id o dis al pos e io ibial a e y pulse wa e eloci y (β = − 0.14, p < 0.01), and on he dis ensibili y coe icien (β = − 0.00, p < 0.01). No e ec was ound o hemodynamic a iables a e he in e en ion. Conclusions: Following a 1-yea in e en ion in pa ien s wi h ype 2 diabe es, bo h he MCT and HIIT g oup educed hei cIMT, whe eas only he HIIT g oup imp o ed hei pe iphe al a e ial s i ness indices and dis ensibili y coe icien . Taken oge he , HIIT may be a meaning ul ool o imp o e long- e m ascula complica ions in ype 2 diabe es. T ial egis a ion clinical ials.go ID: NCT03144505 Keywo ds: High-in ensi y in e al aining, A e ial s i ness, Mode a e con inuous aining, In ima-media hickness, Dis ensibili y coe icien , Pulse wa e eloci y © The Au ho (s) 2019. This a icle is dis ibu ed unde he e ms o he C ea i e Commons A ibu ion 4.0 In e na ional License (h p://c ea i eco mmons .o g/licen ses/by/4.0/), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons license, and indica e i changes we e made. The C ea i e Commons Public Domain Dedica ion wai e (h p://c ea i eco mmons .o g/ publi cdoma in/ze o/1.0/) applies o he da a made a ailable in his a icle, unless o he wise s a ed. Open Access Ca dio ascula Diabe ology *Co espondence: [email p o ec ed] 1 Exe cise and Heal h Labo a o y, CIPER, Faculdade de Mo icidade Humana, Uni e sidade de Lisboa, Es ada da Cos a, 1499-002 C uz-Queb ada, Po ugal Full lis o au ho in o ma ion is a ailable a he end o he a icle Page 2 o 13 Magalhãese al. Ca dio asc Diabe ol (2019) 18:34 In oduc ion Fo mos pa ien s wi h diabe es melli us, mic o- and mac o- ascula complica ions a e he majo culp i o inc eased mo ali y and mo bidi y [1]. Wi h he onse o diabe es, subclinical mani es a ions o ca dio ascu- la pa hology occu , which in u n may lead o ischemic hea disease and ca o id s enosis [2, 3]. Among he sub- clinical ma ke s, ca o id in ima-media hickness (cIMT) and pulse wa e eloci y (PWV) a e well es ablished s uc u al [4] and a e ial s i ness measu emen s [5], associa ed wi h ca dio ascula disease (CVD) isk [6, 7]. Pa ien s wi h ype 2 diabe es ha e inc eased cIMT and PWV when compa ed wi h non-diabe ic pa ien s [5, 8]. P e en ion and ea men o hese ma ke s would likely e e se o delay he ascula changes ha occu in ype 2 diabe es, imp o ing endpoin ou comes [9, 10]. Cu en guidelines o pa ien s wi h ype 2 diabe es la gely ad oca e he impo ance o physical ac i i y as a he apeu ic ool o imp o e and con ol se e al CVD isk ac o s including glycemic con ol, blood p essu e, and endo helium unc ion. In line wi h hese indings, he Ame ican Diabe es Associa ion (ADA) s a es ha pa ien s wi h ype 2 diabe es should accumula e a leas 150min o mode a e-in ensi y physical ac i i y [40–60% peak oxygen up ake o 75min o igo ous-in ensi y phys- ical ac i i y (60–85% peak oxygen up ake)] pe week o main ain o imp o e heal h [11, 12]. Mo e ecen ly, s ud- ies ha e epo ed ha pe o ming high in ensi y in e al aining (HIIT) can elici he same o e en addi ional ca dio ascula and glycemic adap a ions when compa ed wi h mode a e con inuous aining (MCT) [13, 14]. While ou ecen ial [15] sugges ed ha a combina- ion o HIIT wi h RT had no impac on body composi- ion and glycemic con ol a iables ollowing a 1-yea in e en ion, he e ec o HIIT on a e ial s i ness and s uc u al indices in pa ien s wi h ype 2 diabe es emains o be de e mined. In ac , when conside ing he in e en ions ha included pa ien s wi h ype 2 diabe es and analyzed he impac o HIIT on s uc u al and a e- ial s i ness measu emen s, we only ound a single case add essing hese a iables wi h a ime span o 12-weeks [16]. Mo eo e , o he bes o ou knowledge, he e a e no in es iga ions compa ing he e ec s o di e en ypes o ae obic exe cise (HIIT s. MCT) alone o in combina ion wi h esis ance aining (combined exe cise) on a e ial s i ness and s uc u al indexes, which a e conside ed he mos e ec i e s a egies o achie ing glycemic con ol [17]. The e o e, he pu pose o he p esen 1-yea and- omized con olled ial was o in es iga e he e ec s o a combined HIIT and RT s. a combined MCT and RT on cen al and pe iphe al a e ial s i ness indices in pa ien s wi h ype 2 diabe es. We hypo hesized ha 1-yea o a combined HIIT and RT p o ocol will induce mo e imp o emen s in cIMT, and on cen al and pe iph- e al PWV, as well as o he s i ness measu emen s, when compa ed o a combined MCT wi h RT p o ocol. Ma e ials andme hods Rec ui men p ocess A andomized con olled ial conduc ed in he egion o g ea e Lisbon, be ween Feb ua y 2014 o July 2016, included pa ien s wi h ype 2 diabe es and an exe - cise in e en ion wi h a 1-yea du a ion (D2FIT p o- jec ) (Fig.1). The numbe and he cha ac e is ics o his sample a e he same as he one used in ou p e ious published s udy [15], hence a o al o 80 pa ien s we e andomized o h ee dis inc g oups. In o de o be eli- gible, pa icipan s had o be adul s diagnosed wi h ype 2 diabe es [18], ha e no majo mac o o mic o ascula complica ions, ha e a body mass index (BMI) < 48 kg/ m2, and ha e no physical limi a ions ha would p e- en hem om pa icipa ing in an exe cise p og am. Powe and sample size calcula ions (G-Powe , Ve sion 3.1.3) we e based on a p edic ed glyca ed hemoglobin (HbA1c) di e ence o 0.66 HbA1c uni s wi h a SD o e ec o 1.2 HbA1c uni s, α = 0.05, 1 − β = 0.80 and an expec ed d opou a e o 10% [19]. Howe e , o his sec- onda y analysis he powe and sample size calcula ions we e based on changes in ao ic PWV. Gi en a p edic ed PWV di e ence o 1.21ms−1 wi h a SD o 1.4ms−1, α = 0.05, 1 − β = 0.80, he sample used in his s udy was powe ed o his seconda y analysis [20]. This in es iga- ion was ca ied ou in acco dance wi h he ecommen- da ions o he Decla a ion o Helsinki o Human S udies. The p o ocol was app o ed by he E hics Commi ee o he Po uguese Diabe es Associa ion (app o al numbe : 07/17/2013). W i en in o med consen s we e ob ained om all pa icipan s be o e and p io o any p o ocol- speci ic p ocedu es. Resea ch design The cu en in es iga ion is a seconda y analysis o a 1-yea andomized con ol ial (D2FIT) de eloped o analyze he impac o exe cises wi h di e en in en- si ies on glyca ed hemoglobin (clinical ials.go ID: NCT03144505) [15]. The D2FIT had wo in e en ion g oups (MCT wi h RT, and HIIT wi h RT) and a con ol g oup. An ex e nal esea che used a compu e -gene - a ed lis o andom numbe s, o alloca e he pa ien s o he g oups in a 1:1:1 a io. The obse e s om each assessmen we e blinded o g oup andomiza ion. The changes o a e ial s i ness, s uc u al indexes, and hemodynamic a iables we e assessed as second- a y ou comes a baseline and a 1-yea ollow-up. All e alua ions we e pe o med du ing a single isi , excep Page 3 o 13 Magalhãese al. Ca dio asc Diabe ol (2019) 18:34 Fig. 1 S udy low cha Page 4 o 13 Magalhãese al. Ca dio asc Diabe ol (2019) 18:34 ca dio espi a o y i ness (CRF) assessmen , which was e alua ed on a sepa a e day. Pa icipan s we e equi ed o as o a leas 8h p io o he isi , a oid alcohol con- sump ion o 24h, and consume a no mal e ening meal he nigh be o e he isi . Pa icipan s ha we e eligi- ble we e andomized a e comple ing all he in ended assessmen s. Exe cise aining The non-exe cise g oup (con ol) had an ini ial o ien a- ion session, wi h s anda d counseling and in o ma ion ega ding gene al physical ac i i y guidelines. Addi ion- ally, once in e e y 4weeks, he con ol g oup, alongside wi h he MCT and HIIT g oup, me o hema ic sessions wi h b oad opics such as nu i ion, physical ac i i y, and clinical complica ions om diabe es. All pa icipan s om he in e en ion g oups (MCT and HIIT) pe - o med 1-yea o supe ised exe cise sessions h ee imes pe week while moni o ed by ce i ied exe cise physiolo- gis and he use o a hea a e pola band (Pola T-31, USA). Bo h MCT and HIIT we e designed o ha e he same ene gy expendi u e. The du a ion o he exe cise sessions was calcula ed using a weekly a ge o 10kcal/ kg and conside ing indi idual peak oxygen up ake. Fo example, conside ing a pa ien wi h a measu ed VO2 peak o 24.2ml/kg/min, a body weigh o 81.2kg, a s anda d 3.5ml/kg/min o es ing VO2, while exe cise a 60% o VO2 ese e (15.9ml/kg/min) du ing ha mon h, one could expec an ene gy expendi u e o 6.5 kcal/min. When mul iplying he body weigh o 10kcal/week we would ha e 812.5kcal/week, meaning ha a a a e o 6.5kcal/ min, his pa ien would need o spend 125.5min/week o 41.8min o cycling pe session. Fo he HIIT, he in en- si y calcula ions we e pe o med wi h a simila app oach as desc ibed abo e, conside ing ha 50% o he exe cise sessions we e pe o med a 70–90% o he VO2 ese e, and he emaining exe cise pe o med a an in ensi y equi a- len o 40–60% o he VO2 ese e. Conside ing he example abo e, his is equi alen o app oxima ely 34min/session, including 17 HIIT 1-min bou s a 90% o he VO2 ese e. Th oughou he whole yea o in e en ion bo h g oups wen h ough a planned pe iodiza ion exe cise p esc ip- ion wi h indi idualized in ensi y based upon hea a e ese e (HRR) o g adually in oduce he exe cise p e- sc ip ions. In phase 1 (p epa a ion phase, weeks 1–4), which was simila o bo h g oups, pa icipan s pe - o med con inuous exe cise o mode a e in ensi y (40– 60% o he HRR). Fo he MCT g oup, which only had an addi ional phase ( aining phase, weeks 5–52), pa ici- pan s pe o med con inuous cycling a 40 o 60% o he HRR. In he HIIT g oup, he objec i e o phase 2 ( ain- ing phase wi h lowe in ensi y phase, weeks 5–8) was o p og essi ely in oduce he HIIT p og am. Du ing weeks 5–6, pa icipan s pe o med bou s o 2min a 70% o he HRR ollowed by 1min a 40–60% o he HRR and inc eased o bou s o 80% o he HRR ollowed by 1min a 40–60% o he HRR du ing weeks 7–8. In phase 3 ( aining phase wi h highe in ensi y, weeks 9–52), pa - icipan s pe o med 1 min o exe cise a 90% o hei HRR ollowed by 1min es ing a 40–60% o he HRR. Th oughou he in e en ion, pa icipan s in bo h g oups we e ins uc ed o exe cise in he uppe limi o he p e- sc ibed exe cise in ensi y. In bo h g oups, a e he ae o- bic componen , pa icipan s pe o med a whole-body RT, which included 1 se o 10–12 epe i ions o uppe and lowe limbs exe cises. A ull desc ip ion o he exe cise p esc ip ion o bo h MCT and HIIT can be ound else- whe e [15]. An h opome y Pa icipan s we e weighed o he nea es 0.01kg while wea ing minimal clo hes and wi hou shoes on an elec- onic scale (Seca, Hambu g, Ge many). Heigh was measu ed o he nea es 0.1cm wi h a s adiome e (Seca, Hambu g, Ge many) acco ding o he s anda dized p o- cedu es desc ibed elsewhe e [21]. BMI was calcula ed as body mass (kg)/heigh 2 (m). BMI was u he ca ego ized in o no mal (< 25 kg/m2), o e weigh (25–29.9kg/m2), and obese (≥ 30kg/m2). Wais ci cum e ence measu e- men was aken wi h he pa icipan in a s anding posi- ion o e he naked skin o he nea es 0.1cm. The ape was applied ho izon ally jus abo e he uppe mos la e al bo de o he igh ilium a he end o no mal expi a ion [22]. The mean o wo measu emen s was conside ed. I he wo measu emen s di e ed by mo e han 1cm, a hi d measu emen was aken, and he wo closes meas- u emen s we e a e aged. B achial blood p essu e The igh and le b achial SBP and DBP we e measu ed ollowing a leas 15 min wi h he pa icipan s in he supine posi ion using an au oma ed oscillome ic cu (HEM-907-E, Om on, Tokyo, Japan). Two measu emen s we e aken and i hese alues de ia ed by > 5mmHg, a hi d measu emen was pe o med [23]. Condui a e y in ima‑media hickness The dis ance be ween he leading edge o he lumen– in ima in e ace and he leading edge o he media– ad en i ia in e ace o he a wall o he igh ca o id a e y was used o de ine cIMT. This measu emen was pe o med using an ul asound scanne equipped wi h a linea 13MHz p obe (MyLab One, Esao e, I aly) [24], and dis ension cu es we e acqui ed wi hin a segmen o he ca o id a e y abou one cm be o e he low di ide . Page 5 o 13 Magalhãese al. Ca dio asc Diabe ol (2019) 18:34 The CV o epea ed measu emen s in ou labo a o y o cIMT and ca o id diame e a e 3.02% and 1.49%, espec i ely. Ca o id blood p essu e The ca o id blood p essu e was es ima ed by assuming a linea ela ionship wi h he dis ension wa e o m [25], in which he mean a e ial p essu e (MAP) and b achial DBP a e cons an o e he a e ial ee. This enables he calcula ion o a scaling ac o (δ), conside ing ha he in eg al o e ime o he dis ension cu e is au oma ically calcula ed by he quali y a e ial s i ness so wa e. The local p essu e was assessed using he ollowing o mula: whe e ΔD( ) is he dis ension wa e o m. Ca o id a e ial s i ness indices The ca o id a e ial s i ness measu emen was conduc ed on he igh side, wi h he pa ien in he supine posi ion a e a leas a 15min es ing pe iod. An ul asound scan- ne equipped wi h a linea 13MHz p obe (MyLab One, Esao e, I aly) wi h Quali y A e ial S i ness echnology, was used app oxima ely one cm be o e he bi u ca ion. This allows he calcula ion o ca o id s i ness indices: PWV (m/s), dis ensibili y coe icien (1/KPa), compli- ance coe icien (mm2/kPa), s i ness index α and β. The coe icien s o a ia ion o epea ed measu emen s in ou labo a o y o ca o id dis ensibili y, compliance, s i - ness index α and β, and ca o id SBP a e 0%, 2.87%, 3.70%, 3.18% and 2.15%, espec i ely. Con ala e al pulse wa e eloci y Pulse wa e eloci y was measu ed by applana ion onom- e y immedia ely a e ul asound imaging. A single ope a o loca ed he ca o id, emo al, adial, and dis al pos e io ibial a e ies on he le side o he body and ma ked he poin o cap u ing he co esponding p es- su e cu es wi h wo speci ic p essu e sensi i e ansduc- e s. The dis ance be ween he ca o id and emo al and adial and dis al pos e io ibial a e ies we e measu ed di ec ly in o he Complio Analyse so wa e (ALAM Medical, Pa is, F ance). PWV alues ob ained om he ca o id o emo al a e y (CF PWV), ca o id o adial a e y (CR PWV), and ca o id o dis al pos e io ibial a e y (CD PWV) we e aken as indices o cen al/ao - ic and pe iphe al a e ial s i ness o uppe and lowe limb, espec i ely. A second obse e immedia ely e alu- a ed he quali y o he PWV eco ds. Whene e a con- inuous dec ease be o e he sha p sys olic ups oke was no clea ly seen, o he ole ance was abo e 5ms, a second measu e was aken. The coe icien s o a ia- ion o epea ed measu emen s in ou labo a o y o cSBP( ) = δ · �D( ) + bDBP, ao ic, uppe limb and lowe limb PWV a e 2.95%, 9.10%, espec i ely. Physical ac i i y Pa icipan s we e asked o wea an accele ome e (Ac i- g aph, model GT1M model, Pensacola, Flo ida) on he igh hip, nea he iliac c es du ing 4consecu i e days, including 2weekdays and 2weekend days. The de ices we e ac i a ed on aw mode wi h a 100Hz equency, and pos e io ly downloaded in o 15-s epochs (Ac ili e .6.9.1). The T oiano e al. cu poin s and wea ime ali- da ion c i e ia we e used o de ine he ime spen in each in ensi y and o de ine alid measu emen s [26]. Ca dio espi a o y i ness Ca dio espi a o y i ness was de e mined using a B uce s anda d p o ocol on a mo o ized eadmill o exhaus- ion (model Q-65, Quin on, Ca diac Science Co p; Bo h- ell, WA, USA). All g aded exe cise es s we e moni o ed using a 12-lead elec oca diog am PC-based acquisi ion module (model Qua k C12, Cosmed, Rome, I aly) wi h Cosmed so wa e (Cosmed, Rome, I aly). Inspi ed and expi ed gases we e con inuously analyzed, b ea h-by- b ea h, h ough a po able gas analyze (K4b2, Cosmed, Rome, I aly). Pa icipan s exe cised un il a leas wo o he ollowing es e mina ion c i e ia we e eached: (1) pa icipan s oli ional a igue; (2) espi a o y exchange a io eached 1.1 o highe ; (3) pa icipan s eached p e- dic ed maximal hea a e; (4) oxygen up ake did no inc ease in spi e o inc easing wo kload. The highes 20s alue o peak oxygen consump ion (ml/kg/min) a ained in he las minu e was used in he analysis, and e med CRF om he e on. Labo a o y measu emen s Pa icipan s unde wen biochemical assessmen s, includ- ing he analysis o glyca ed hemoglobin (HbA1c). Blood samples we e collec ed om an indwelling ca he e and d awn in o chilled, hepa inized ubes and cen i uged apidly o a oid glycolysis. HbA1c was analyzed by immunoassay (au o analyze Hb9210 P emie ). S a is ical analysis The da a ha suppo he indings o his s udy a e a ail- able om he co esponding au ho upon easonable eques . Da a analyses we e pe o med using IBM SPSS S a is ics e sion 22.0 (SPSS Inc., an IBM Company, Chicago, Illinois, USA). Desc ip i e s a is ics including mean ± SD we e calcula ed o all he main and second- a y ou come a iables. No mali y was es ed using Q–Q plo s. Compa isons be ween g oups we e pe o med using independen sample ANOVA es s o he non- pa ame ic Mann–Whi ney–Wilcoxon app oach. Due o Page 6 o 13 Magalhãese al. Ca dio asc Diabe ol (2019) 18:34 he co ela ed na u e o he da a and epea ed measu e- men s aken on each assessmen , gene alized es ima ing equa ions we e used o model ou comes while allowing us o con ol o po en ial con ounde s (i.e. sex, baseline mode a e- o- igo ous physical ac i i y (MVPA), MAP changes). A leas signi ican di e ence pos hoc es was used o es ima e he be ween-g oup and wi hin-g oup e ec s on se e al ca diome abolic ou comes. A linea dis ibu ion o he esponse was assumed and an au o e- g essi e co ela ion ma ix was se o he da a. Fo all he ou comes an in en ion- o- ea analysis (ITTA) was pe o med using all pa icipan s ha we e ini ially an- domized. Since he D2FIT was designed as an e ec i e- ness in es iga ion, an addi ional pe -p o ocol analyses (PPA) was pe o med, which included only a subg oup o pa icipan s ha comple ed he in es iga ion and hose in he in e en ion g oups ha had a leas 70% o adhe - ence o he o al numbe o ainings [27]. Resul s Baseline desc ip i e cha ac e is ics o he pa icipan s a e epo ed in Table1 by in e en ion g oup and o he ITTA and PPA. The p e alence o o e weigh and obesi y was 83.8%, wi h 46.3% o he o al sample ha ing uncon- olled HbA1c, as de ined by ADA c i e ia (> 7%). A baseline he e we e no di e ences be ween he in e en ion g oups, in bo h he ITTA and PPA, excep o baseline MVPA, which was highe in he HIIT g oup. A o al o 55 pa icipan s comple ed he in e en ion, wi h mean adhe ence pe cen age alues o 86% and 87% o he MCT and HIIT g oup, espec i ely. The d opou a es we e 11%, 18%, and 24% o he con ol, MCT and HIIT, espec i ely (Fig.1). Table 2 p esen s he PPA esul s o hemodynamic a iables and s uc u al and a e ial s i ness indices a baseline and ollowing 12mon hs, as well as he in e - ac ion e ec o ime wi h each g oup (MCT s. HIIT s. con ol). Following adjus men s o baseline MVPA, sex and MAP, we ound an in e ac ion e ec o he cIMT in bo h he MCT (β = − 5.02, p = 0.032) and he HIIT (β = − 3.68, p = 0.045) in e en ion g oups s. he con- ol g oup. Howe e , o he dis ensibili y coe icien (β = 0.00, p = 0.0.46) and CD PWV (β = − 0.20, p > 0.01), only he HIIT g oup had a signi ican in e ac ion e ec ollowing a 1-yea o in e en ion. Hemodynamic a i- ables, as assessed by b achial blood p essu e and ca o id blood p essu e, did no change h oughou he in e en- ion in bo h exe cise g oups. Following he same end, we obse ed no in e ac ion e ec o he CF PWV o all in e en ion g oups (p > 0.05). Figu e2 depic s da a om he changes ha occu ed be ween baseline and 1-yea ollow-up o he s uc u al and a e ial s i ness indices using he PPA. Pa icipan s om he HIIT in e en ion g oup dec eased hei cIMT, CR PWV, and CD PWV alues by, 1.1%, 10.0% and 11.2%, espec i ely. Wi h simila a o able changes, he HIIT g oup also inc eased he dis ensibili y coe icien by 8.9%. When conside ing he MCT g oup, we obse ed changes only o he cIMT a iable, wi h a dec ease o 1.4% om p e- o pos -in e en ion. Table 1 Baseline cha ac e is ics o  hepa icipan s byg oup in heITTA andin he PPA MCT mode a e con inuous aining, HIIT high in ensi y in e al aining, BMI body mass index, MVPA mode a e- o- igo ous physical ac i i y, HbA1c glyca ed hemoglobin, WC wais ci cum e ence, VO2peak peak oxygen up ake * Di e ences be ween g oup a baseline alues (p < 0.05) a Skewed alues a e p esen ed as median ± in e qua ile ange In en ion o ea baseline alues ( alues a e p esen ed mean ± SD) Pe ‑p o ocol baseline alues ( alues a e p esen ed mean ± SD) Con ol (n = 27) MCT (n = 28) HIIT (n = 25) p‑ alue Con ol (n = 22) MCT (n = 16) HIIT (n = 13) p‑ alue Age (y s) 59.0 ± 8.1 59.7 ± 6.5 56.7 ± 8.3 0.575 60.8 ± 7.5 60.4 ± 6.8 58.9 ± 7.5 0.814 Woman (%) 48.1 53.6 40.0 0.612 50.0 56.3 30.8 0.367 Hype ension medica ion (%) 48.1 50.0 52.0 0.579 54.5 37.5 53.8 0.538 O al an idiabe ic medica ion (%) 96.3 92.9 84.0 0.388 95.5 93.8 92.3 0.512 Diabe es Diagnosis (y s)a5.0 ± 3.0 8.0 ± 9.0 5.0 ± 6.0 0.086 4.5 ± 3.25 8.0 ± 9.0 6.0 ± 6.0 0.091 Weigh (kg) 84.1 ± 15.8 82.7 ± 13.3 81.6 ± 16.8 0.906 85.9 ± 15.7 82.0 ± 13.8 84.2 ± 19.2 0.799 Heigh (cm) 165.5 ± 9.4 163.2 ± 8.4 164.8 ± 8.1 0.545 164.5 ± 9.5 162.9 ± 9.2 166.6 ± 8.1 0.615 BMI (kg/m2) 30.7 ± 5.0 31.1 ± 5.0 30.1 ± 5.7 0.722 31.7 ± 4.7 31.0 ± 5.5 30.2 ± 5.9 0.506 WC (cm) 103.0 ± 12.4 103.8 ± 11.3 102.7 ± 14.3 0.914 103.3 ± 15.8 103.5 ± 12.2 103.3 ± 15.8 0.946 MVPA (min/day)a18.4 ± 26.4 30.5 ± 4.8 38.9 ± 29.4 0.008* 15.9 ± 23.1 38.1 ± 41.6 38.9 ± 30.1 0.012* VO2peak (ml/kg/min) 25.9 ± 5.5 24.1 ± 3.2 27.1 ± 6.3 0.143 25.1 ± 5.6 23.9 ± 3.7 26.6 ± 5.3 0.345 HbA1c (mmol/mol)a49.7 ± 20.7 53.2 ± 22.7 49.0 ± 12.3 0.545 48.1 ± 16.7 47.2 ± 22.1 50.8 ± 12.6 0.828 Page 7 o 13 Magalhãese al. Ca dio asc Diabe ol (2019) 18:34 Table 2 Hemodynamic, s uc u al and unc ional a e ial indices a baseline and ollowing12 mon hs: wi hinandbe ween g oup changes using hepe - p o ocol analysis Be as a e p esen ed as uns anda dized coe icien s adjus ed o sex, baseline MVPA, and Map changes, wi h he espec i e 95% con idence in e als DC dis ensibili y coe icien , CD PWV ca o id dis al pulse wa e eloci y, CF PWV ca o id emo al pulse wa e eloci y, CR PWV ca o id adial pulse wa e eloci y, DBP dias olic blood p essu e, HIIT high in ensi y in e al aining, IMT in ima media hickness, MCT mode a e con inuous aining, SBP sys olic blood p essu e, SI s i ness index, VO2peak peak oxygen up ake *Be ween-g oup changes signi ican a p < 0.05 † Wi hin-g oup changes signi ican a p < 0.05 Ou come Con ol (n = 22) MCT (n = 16) HIIT (n = 13) MCT*Con ol HIIT*Con ol MCT*HIIT Baseline 12mon hs Baseline 12mon hs Baseline 12mon hs β (95% CI) β (95% CI) β (95% CI) SBP (mmHg) 136.5 ± 12.6 130.6 ± 21.4 135.6 ± 13.6 130.9 ± 19.2 137.8 ± 17.0 130.7 ± 16.1†0.08 (− 0.79; 0.94) 0.09 (− 0.73; 0.90) − 0.01 (− 0.85; 0.83) DBP (mmHg) 80.1 ± 9.3 77.4 ± 10.8 81.2 ± 9.6 78.2 ± 9.1 80.2 ± 9.1 74.5 ± 6.3†− 0.01 (− 0.50; 0.47) − 0.22 (− 0.61; 0.16) 0.21 (− 0.29; 0.72) Ca o id IMT (mm) 714.9 ± 130.7 751.2 ± 119.4†737.9 ± 158.4 712.3 ± 110.8 733.6 ± 159.0 724.1 ± 119.2 − 5.04 (− 9.57; − 0.50)* − 3.70 (− 7.38; − 0.01)* − 1.34 (− 6.62; 3.93) Ca o id DC 0.018 ± 0.007 0.015 ± 0.007 0.019 ± 0.009 0.018 ± 0.009 0.018 ± 0.006 0.019 ± 0.007 0.00 (− 0.00; 0.00) 0.00 (0.00; 0.00)* 0.00 (− 0.00; 0.00) Ca o id β SI 11.9 ± 4.5 14.2 ± 6.8†11.2 ± 4.1 12.3 ± 4.9 11.9 ± 5.1 12.6 ± 6.2 − 0.11 (− 0.31; 0.09) − 0.15 (− 0.35; 0.06) 0.04 (− 0.19; 0.27) Ca o id SBP (mmHg) 120.9 ± 15.3 117.7 ± 13.9 124.2 ± 13.0 117.2 ± 11.9†123.8 ± 14.3 121.4 ± 12.3 − 0.31 (− 0.85; 0.23) 0.08 (− 0.57; 0.73) − 0.39 (− 1.07; 0.29) Ca o id DBP (mmHg) 73.7 ± 7.0 70.9 ± 7.7 77.3 ± 9.4 73.1 ± 5.9†75.9 ± 9.3 74.9 ± 6.2 − 0.13 (− 0.55; 0.28) 0.15 (− 0.41; 0.71) − 0.29 (− 0.84; 0.27) CF PWV (m/s) 13.1 ± 4.8 14.0 ± 4.3 13.3 ± 3.8 14.3 ± 3.9 12.8 ± 4.0 13.5 ± 4.7 0.01 (− 0.15; 0.18) − 0.02 (− 0.17; 0.13) 0.03 (− 0.14; 0.19) CD PWV (m/s) 9.0 ± 1.8 10.3 ± 1.7†9.9 ± 2.0 9.7 ± 1.4 9.7 ± 1.5 8.6 ± 2.0†− 0.12 (− 0.24; 0.00) − 0.20 (− 0.31; − 0.09)* 0.08 (− 0.03; 0.18) CR PWV (m/s) 9.2 ± 1.9 9.3 ± 1.5 9.6 ± 1.6 9.0 ± 2.1 9.5 ± 1.4 8.3 ± 1.9 − 0.06 (− 0.18; 0.06) − 0.11 (− 0.25; 0.03) 0.05 (− 0.11; 0.20) VO2peak (ml/kg/min) 25.5 ± 5.5 24.4 ± 5.7 24.0 ± 3.6 25.1 ± 4.9 28.0 ± 7.0 27.0 ± 6.9 0.21 (0.05; 0.37) * 0.02 (− 0.13; 0.17) 0.19 (0.04; 0.35)* Page 8 o 13 Magalhãese al. Ca dio asc Diabe ol (2019) 18:34 Table3 summa izes he esul s o he ITTA o hemo- dynamic a iables and s uc u al and a e ial s i - ness indices. When conside ing he ITTA, and a e adjus ing o sex, MAP and baseline MVPA, he esul s emained simila as he PPA o all he ou comes, wi h MCT (β = − 4.25, p < 0.01) and HIIT (β = − 3.61, p < 0.01) in e en ion g oups dec easing hei cIMT alues om baseline o pos -in e en ion. The HIIT g oup also had a a o able e ec on he CD PWV (β = − 0.14, p < 0.01) and on he dis ensibili y coe icien (β = 0.00, p < 0.01), simila o hose obse ed in he PPA, while ha ing an addi ional e ec on CR PWV (β = − 0.10, p = 0.044). As a as all o he a iables a e conce ned, no in e ac ion e ec s we e obse ed o bo h in e en ion g oups. Discussion To ou knowledge, his is he i s andomized con olled ial spanning a 1-yea in e en ion wi h supe ised exe - cise sessions analyzing he e ec i eness o a MCT com- bined wi h RT s. HIIT combined wi h RT on s uc u al and unc ional a e ial indices in pa ien s wi h ype 2 dia- be es. This in es iga ion a o ds expe imen al e idence ha a long- e m MCT combined wi h RT and HIIT com- bined RT imp o es cIMT. Mo eo e , he esul s o he s udy highligh s HIIT as a p omising long- e m exe cise s a egy o delay and coun e he changes in a e ial s i - ness indices, mo e speci ically on CD PWV, CR PWV, and on he dis ensibili y coe icien , which a e ypically comp omised in ageing and in ype 2 diabe es, wi h likely implica ions on he p og ession o CVD. Type 2 diabe es is s ongly linked o cen al obesi y, which in u n is associa ed wi h inc eased a e ial s i - ness [28]. Indeed, pa ien s wi h ype 2 diabe es ha e highe alues o a e ial s i ness when compa ed o ma ched con ols [29–31]. Rega ding he bene i s o HIIT on ascula heal h in pa ien s wi h ype 2 diabe es, mos o he li e a u e a ailable de i es om low medi- a ed dila ion (FMD) s udies. Recen e iews and me a- analysis ha e ound di e en esul s on he bene i s o HIIT on FMD in pa ien s wi h ype 2 diabe es when compa ed o MCT [32–34]. Unlike FMD, PWV p o ides s uc u al alongside wi h unc ional heal h in o ma ion o he a e ial wall and can be used as a complemen a y measu emen o ha o FMD. In ou in es iga ion, base- line alues o CF PWV and CD PWV we e 13.0 ± 4.0 and 9.6 ± 1.9, espec i ely, which a e sligh ly highe han he ones obse ed in o he s udies, especially o he CF PWV [5, 16]. Exe cise seems o a enua e a e ial s i ness in heal hy subjec s and in pa ien s wi h ype 2 diabe es, bu he e ec o di e en exe cise in ensi ies s ill emain con o e sial. Epidemiological e idence sugges s ha he la ges impac on ascula isk occu s when p ac icing exe cise a lowe olumes and in ensi ies [35, 36]. How- e e , mos o he s udies included in hese me a-analyses and e iews used high-in ensi y con inuous aining o analyze he impac o exe cise in ensi y on ascula isk [37]. Engaging in igo ous PA o p olonged pe iods o Fig. 2 Changes in s uc u al and hemodynamic a iables using he pe -p o ocol analysis. Dashed lines ep esen mean alues o each in e en ion g oup Page 9 o 13 Magalhãese al. Ca dio asc Diabe ol (2019) 18:34 Table 3 In en ion- o- ea analysis onhemodynamic, s uc u al and unc ional a e ial indices Be as a e p esen ed as uns anda dized coe icien s adjus ed o sex, baseline MVPA, and MAP changes, wi h he espec i e 95% con idence in e als CD ca o id dis ensibili y, CD PWV ca o id dis al pulse wa e eloci y, CF PWV ca o id emo al pulse wa e eloci y, CR PWV ca o id adial pulse wa e eloci y, DBP dias olic blood p essu e, HIIT high in ensi y in e al aining, IMT in ima media hickness, MCT mode a e con inuous aining, SBP sys olic blood p essu e, SI s i ness index, VO2peak peak oxygen up ake * Be ween-g oup changes signi ican a p < 0.05 † Wi hin-g oup changes signi ican a p < 0.05 Ou come Con ol (n = 22) MCT (n = 16) HIIT (n = 13) MCT*Con ol HIIT*Con ol MCT*HIIT Baseline 12mon hs Baseline 12mon hs Baseline 12mon hs β (95% CI) β (95% CI) β (95% CI) SBP (mmHg) 136.8 ± 13.4 131.5 ± 20.6 139.9 ± 13.5 134.6 ± 18.0 142.2 ± 18.3 135.7 ± 19.3†− 0.04 (− 0.74; 0.66) 0.04 (− 0.65; 0.73) − 0.08 (− 0.75; 0.60) DBP (mmHg) 81.2 ± 10.5 77.5 ± 11.1†82.0 ± 8.8 79.3 ± 10.1 82.6 ± 10.3 78.4 ± 10.1†0.07 (− 0.34; 0.48) − 0.03 (− 0.35; 0.29) 0.10 (− 0.29; 0.49) Ca o id IMT (mm) 716.5 ± 120.6 746.7 ± 109.7†723.1 ± 142.5 703.1 ± 106.8 713.2 ± 175.8 700.2 ± 151.6 − 4.25 (− 7.38; − 1.12)* − 3.61 (− 6.15; − 1.07)* − 0.64 (− 4.06; 2.78) Ca o id DC 0.019 ± 0.006 0.016 ± 0.006†0.018 ± 0.008 0.018 ± 0.008 0.017 ± 0.006 0.018 ± 0.006 0.00 (− 0.00; 0.00) 0.00 (0.00; 0.00)* 0.00 (− 0.00; 0.00) Ca o id β SI 11.3 ± 4.2 13.4 ± 6.2†11.7 ± 4.1 12.6 ± 4.8 11.8 ± 4.3 12.2 ± 4.9 − 0.09 (− 0.23; 0.05) − 0.14 (− 0.28; 0.01) 0.05 (− 0.10; 0.19) Ca o id SBP (mmHg) 121.5 ± 16.0 119.4 ± 14.8 126.2 ± 12.5 121.8 ± 14.7†126.0 ± 17.6 124.0 ± 16.4 − 0.20 (− 0.65; 0.25) 0.01 (− 0.50; 0.52) − 0.21 (− 0.75; 0.33) Ca o id DBP (mmHg) 75.4 ± 9.0 73.6 ± 9.8 77.7 ± 8.3 74.9 ± 7.3†76.9 ± 8.7 76.4 ± 9.3 − 0.11 (− 0.43; 0.22) 0.12 (− 0.28; 0.51) − 0.22 (− 0.60; 0.16) CF PWV (m/s) 12.9 ± 4.4 13.5 ± 4.1 13.0 ± 3.3 14.0 ± 3.5†13.2 ± 3.7 13.9 ± 4.1 0.03 (− 0.09; 0.14) − 0.00 (− 0.11; 0.10) 0.03 (− 0.07; 0.13) CD PWV (m/s) 9.2 ± 2.0 10.1 ± 1.8 10.1 ± 1.8 10.1 ± 1.5 10.2 ± 2.7 9.5 ± 2.7 − 0.08 (− 0.17; 0.02) − 0.14 (− 0.24; − 0.04)* 0.06 (− 0.03; 0.15) CR PWV (m/s) 8.9 ± 2.3 9.0 ± 2.1 9.4 ± 1.4 9.2 ± 1.7 10.3 ± 2.2 9.3 ± 2.3 − 0.03 (− 0.11; 0.06) − 0.10 (− 0.19; − 0.00)* 0.07 (− 0.03; 0.17) VO2peak (ml/kg/min) 25.9 ± 5.5 24.4 ± 5.4 24.1 ± 3.2 24.9 ± 4.1 27.1 ± 6.3 26.5 ± 6.0 0.19 (0.03; 0.34)* 0.05 (− 0.076; 0.64) 0.12 (0.01; 0.22)*