Table 5 Drugs effects on EPCs in DM patients

Insulin

Insulin glargine versus insulin detemir (dose adjusted)

Randomized cross-over study (6 months)

T2DM (n:42)

cEPCs: CD133⁺ KDR⁺/CD34⁺ CD133⁺ KDR⁺

↑Number

Fadini, G.P. (2011)

[160]

Insulin glargine and NPH insulin (dose adjusted) versus oral medication

Partially double-blind, randomized, three-arm unicentre study (4 weeks)

T2DM (n:55)

EPCs: CD34⁺ KDR⁺

↑Number

Oikonomou, D. (2014)

[161]

Insulin pump versus multiple daily insulin injections

Observational (2 years)

T1DM (n:204)

CPCs: CD34⁺/CD133⁺/CD34⁺ CD133⁺ cEPCs: CD34⁺ KDR⁺/CD133⁺ KDR⁺/CD34⁺ CD133⁺ KDR⁺

↑Number

Longo, M. (2020)

[162]

Continuous subcutaneous insulin infusion versus multiple daily injections (dose adjusted)

Open controlled study (6 months)

T1DM (n:106)

EPCs: CD34⁺ KDR⁺/CD34⁺ KDR⁺ CD133⁺

↑Number

Maiorino, M.I. (2016)

[163]

Intensive insulin therapy (dose adjusted)

Open controlled study

T2DM (n:36)

EPCs: CD34⁺ KDR⁺ CD133⁺

↓Number

Zhang, W. (2022)

[164]

Sulfonylurea

Gliclazide (30–90 mg/day)

Open controlled study (12 weeks)

T2DM (n:33)

EPCs: CD45^dim CD34⁺ KDR⁺

↑Number

Chen, L-L. (2011)

[165]

Metformin

Metformin (500 mg OD–1 g BID)

Open label and parallel standard treatment study

T1DM (n:23)

cEPCs: CD45d^im CD34⁺ KDR⁺ cECs: CD45^dim CD133⁻ CD34⁺ CD144⁺ KDR⁺

↑Number

↓Number

Ahmed, F.W. (2016)

[169]

Metformin (250–1000 mg/day) + Gliclazide (30–60 mg/day) versus Metformin (500–2500 mg/day)

Randomized open study (16 weeks)

T2DM (n:47)

cEPCs: CD45^dim CD34⁺ KDR⁺

↑Number

Chen, L.L. (2010)

[170]

Insulin + metformin versus Metformin monotreatment

Open controlled study

T2DM (n:95)

cEPCs: CD34⁺ CD133⁺ KDR⁺

↑Number

Asadian, s. (2019)

[171]

Thiazolidinediones

Rosiglitazone (4 mg BID)

Open controlled study (12 weeks)

T2DM (n:10)

EPCs: CD34⁺/CD34⁺ CD133⁺

↑Number

↑Migration

Pistrosch, F. (2005)

[172]

Rosiglitazone (4 mg BID)

Open placebo-controlled study (2 weeks)

T2DM (n:30)

EPCs: Dil-acLDL⁺ UEA-1⁺ CD31⁺ vWF⁺ KDR⁺ CD14⁺

↑Revascularization

Sorrentino, S.A. (2007)

[174]

Pioglitazone (30 mg)

Randomized controlled study (8 weeks)

T2DM patients on metformin monotherapy (n:36)

EPCs: Dil-acLDL⁺ UEA-1⁺ vWF + Tie-2⁺

↑Number

↑Functionality

Wang, C.H. (2006)

[176]

DPP-4 inhibitors

Sitagliptin (100 mg/day)

Open controlled study (4 weeks)

T2DM (n:32)

EPCs: CD34⁺/CD34⁺ KDR⁺

↑Number

Fadini, G.P. (2010)

[179]

Sitagliptin (50 mg/day) versus Placebo (Glimepiride,1 mg/day)

Prospective, randomized, open label clinical trial (12 weeks)

T2DM (n:30)

EPCs: CD34⁺ CXCR4⁺

↑Number

Aso, Y. (2015)

[180]

Sitagliptin and metformin combined therapy versus monotherapies

Randomized controlled clinical trial (3 days)

T2DM (n:60)

EPCs: CD34⁺ KDR⁺/CD34⁺CD133⁺KDR⁺

↑Number

Xu, M. (2014)

[182]

Sitagliptin (50 mg/day) versus Voglibose (0.6 mg/day)

Randomized prospective multicentre study (12 weeks)

T2DM (n:66)

EPCs: CD34⁺

↑Number

Nakamura, K. (2014)

[183]

Vildagliptin (100 mg/day) versus Glibenclamide (2.5–5 mg BID)

Randomized open-label trial (12 months)

T2DM (n:64)

EPCs: CD34⁺ CD133⁺ KDR⁺

↑Number

Dei Cas, A. (2017)

[166]

Alogliptin (25 mg/day) versus Gliclazide (30 mg/day)

Randomized clinical trial (4 months)

T2DM (n:80)

EPCs: CD133⁺ KDR⁺ CD45⁻/CD34⁺ KDR⁺/CD45⁻

↑Number

Negro, R. (2019)

[184]

Saxagliptin (5 mg/day) versus Metformin (1500 mg/day)

Controlled, randomized, open-label clinical trial (12 weeks)

T2DM (n:27)

EPCs: CD34⁺ CD133⁺ KDR⁺

↑Number

Li, F. (2017)

[185]

Saxagliptin (5 mg/day) and metformin (1–2 g/day) versus Metformin (1–2 g/day)

Phase 4, single-site, double-blind, placebo-controlled, randomized clinical trial (12 weeks)

T2DM (n:42)

cEPCs: CD34⁺/CD34⁺ CXCR4⁺ cECs: CD31⁺

↑ Proportion

↓Number

Dore, F.J. (2018)

[186]

Linagliptin (5 mg/day)

Randomized, Placebo-controlled trial (12 weeks)

T2DM (n:40)

EPCs: 20 subpopulations based on CD34, CD133, KDR, and CD45 expression

NC

Baltzis, D. (2016)

[188]

Linagliptin (5 mg/day)

Subanalysis from a randomized, placebo-controlled trial (RELEASE study) (26 weeks)

T2DM (n:41)

EPCs: CD34⁺ CD133⁺ KDR⁺ Tang cells: CD3⁺ CD31⁺ CXCR4⁺

NC

↑Number

de Boer, S.A. (2020)

[189]

Teneligliptin (20 mg/day)

Single-centre, open-label, prospective, randomized controlled trial (28 weeks)

T2DM (n:17)

EPCs: CD34⁺

↑Number

↓ SDF-1α

Akashi, N. (2023)

[190]

GLP-1 Receptor Agonists

Exenatide (5 μg BID-10 μg TID) versus Liraglutide (0.6 mg OD-1.2 mg OD)

Comparative study (4–7 weeks)

T2DM (n:11)

EPCs: CD34⁺ KDR⁺

↑Number

De Ciuceis C. (2018)

[191]

Liraglutide (1.2 mg/day)

Randomized open label trial (4 weeks)

T2DM (n:49)

HPCs: CD34⁺ CD45^dim HPCs with angiogenic activity: CD34⁺ CD45^dim CD133⁺ CD31⁺

NC

Gaborit, B. (2019)

[192]

Liraglutide (1.8 mg OD) versus Sitagliptin (100 mg OD)

Randomized, active-comparator trial (26 week)

T2DM and obesity (n:61)

CPCs: CD34⁺/CD34⁺ CD133⁺/CD34⁺ CD45^dim/CD34⁺ CD45^dim CD133⁺ EPCs: KDR coexpression

NC

Ahmad, E. (2021)

[193]

Dulaglutide (1.5 mg/day) and metformin (1000 mg/day) versus Metformin (2000 mg/day)

Randomized controlled trial (12 weeks)

T2DM (n:60)

EPCs: CD34⁺ CD133⁺ KDR⁺

↑Number

↑Functionality

Xie, D. (2022)

[195]

SGLT2 inhibitors

Canagliflozin (100 mg OD)

Phase 4 (post-marketing), two arm, single site, parallel group, double blind, placebo controlled randomized clinical trial (16 weeks)

T2DM (n:29)

EPCs: CD34⁺

↑Functionality

Nandula, S.R. (2021)

[196]

Dapagliflozin (10 mg) and empagliflozin (10 mg)

Randomized placebo open trial (Dapagliflozin, 12 weeks and 1.5 years, n:33) and open-label observational study (Empagliflozin, 12 weeks, n:15)

T2DM

CSC: CD34⁺

EPCs: CD34⁺ KDR⁺

↓Number

↓Number (12 weeks)

↑Number (1.5 years)

Bonora, B.M. (2018)

[197]

Statins

Atorvastatin (80 mg/day)

Open-labelled prospective trial (10 weeks)

DM (n:14) and non-DM (n:10) with CVDs

CPCs: CD45⁻ CD34⁺ CD133⁺

↑Number

Jaumdally, R.J. (2010)

[199]

Pitavastatin (2 mg/day) versus Atorvastatin (10 mg/day)

Prospective, double-blind, randomized (12 weeks)

DM (n:19) and non-DM (n:7) with hyperlipidemia

EPCs: CD34⁺ KDR⁺

↑Number

↑Functionality

Lin, L.Y. (2014)

[200]

Statins discontinuation

Randomized controlled trial (5 days)

T2DM (n:34)

EPCs: CD34⁺ KDR⁺/CD133⁺ KDR⁺/CD34⁺ CD133⁺ KDR⁺/CD34⁺ CD45⁻

↑Number

Fadini, G.P. (2015)

[201]

High (80 mg/day)—or moderate (20 mg/say)—intensity atorvastatin therapy

Randomized trial (3 months)

DM with drug-eluting stent implantation (n:130)

EPCs: CD34⁺ KDR + 133⁺/CD34⁺ KDR⁺

↑Number

Briguori, C. (2017)

[202]

Statins

Prospective observational study (3 months)

DM (n:62) and non-DM (n:38) with AMI and 2-years follow up period

EPCs: CD45^dim CD34⁺ KDR⁺CXCR4⁺/CD45^dim CD34⁺ KDR⁺ CD133⁺

↑Number

António, N. (2014)

[203]

High-to-moderate intensity statin (atorvastatin 40–20 mg, fluvastatin 80 mg, simvastatin 80–20 mg) versus low intensity statin (fluvastatin 40–20 mg, pravastatin 20 mg, simvastatin 10 mg)

Monocentric prospective all-comers trial

DM (n:60) and non-DM (n:45) with coronary angiography

EPCs: CD34⁺ KDR⁺

↓Number

Florescu, R. (2022)

[204]

Statins

Open labelled trial (3 months)

T2DM (n:45) and non-DM (n:37) at high cardiovascular risk

Total EPCs: CD45⁻ CD34⁺ eEPCs: CD45⁻ CD34⁺ CD146⁻

↓Number

↑PCSK9

Tripaldi, R. (2021)

[207]

PCSK9 inhibitors

Alirocumab (140 mg/ml twice a week) or evolocumab (75–150 mg/ml twice a week)

Open labelled trial (12 weeks)

DM (n:10) and non-DM (n:16) with PAD-CAD

cEPCs: CD34⁺ KDR⁺/CD133⁺ KDR⁺

↑Number

↑Functionality

Itzhaki Ben Zadok, O. (2022)

[206]

RAS inhibitors

Olmesartan (40 mg/day) versus Irbesartan (300 mg/day)

Double-blind placebo-controlled study (12 weeks)

T2DM (n:18)

EPCs: Dil-LDL⁺ UEA-1⁺

↑Number

Bahlmann, F.H. (2005)

[208]

Angiotensin-2 receptor blocker

Valsartan (adjusted dose)

Open study (52 weeks)

DM with asymptomatic CAD (n:86)

CD14⁺ KDR⁺

↑Number

Berezin, A.E. (2015)

[209]

Angiotensin-converting enzyme inhibitor

Perindopril (4 mg/day)

Open randomized controlled study (6 months)

T2DM with PCI (n:68)

cEPCs: CD34⁺ CD133⁺ KDR⁺

↑Number

Sun, J.Y. (2013)

[210]

Renin inhibitor

Aliskiren (150–300 mg/day) versus Hydrochlorothiazide (12.5-25 mg/day)

Open study (3 months)

T2DM with hypertension (n:20)

EPCs: acLDL⁺ UEA-1⁺

↑Number

Raptis, A.E. (2014)

[214]

P2Y12 receptor antagonists

Ticagrelor versus Prasugrel

Longitudinal study (AngioSafe 1) and randomized open label trial (AngioSafe 2) (10 weeks)

T2DM with non–ST-segment elevation acute coronary syndrome

EPCs: CD34⁺ KDR⁺/CD34⁺ CD117⁺/CD34 + CD133⁺

↑Number

Jeong, H.S. (2017)

[217]

Multifactorial treatment

Metformin, aspirin, statins and angiotensin II blockers

Open controlled study (90 days)

T2DM (n:28)

EPCs: Dil-acLDL⁺ UEA-1⁺

↑ Number

Reinhard, H. (2010)

[218]