Minireviews
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Aug 15, 2019; 10(8): 446-453
Published online Aug 15, 2019. doi: 10.4239/wjd.v10.i8.446
Development of therapeutic options on type 2 diabetes in years: Glucagon-like peptide-1 receptor agonist’s role intreatment; from the past to future
Hakan Dogruel, Mustafa Kemal Balci
Hakan Dogruel, Department of Internal Medicine, Antalya Ataturk State Hospital, Antalya 07040, Turkey
Mustafa Kemal Balci, Akdeniz University Faculty of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, Antalya 07070, Turkey
ORCID number: Hakan Dogruel (0000-0002-6204-9796); Mustafa Kemal Balci (0000-0002-6494-3249).
Author contributions: Dogruel H and Balci MK conceived of and designed the study; Dogruel H searched the literature and drafted the article; both authors revised the article and Balci MK gave final approval for the article.
Conflict-of-interest statement: No potential conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Mustafa Kemal, MD, Doctor, Department of Internal Medicine, Antalya Ataturk State Hospital, Anafartalar street, No. 100, Antalya 07070, Turkey. mkbalci@msn.com
Telephone: +90-505-4789010 Fax: +90-242-2496040
Received: March 22, 2019
Peer-review started: March 22, 2019
First decision: May 31, 2019
Revised: June 13, 2019
Accepted: July 27, 2019
Article in press: July 27, 2019
Published online: August 15, 2019

Abstract

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hypergly-cemia. Type 2 diabetes (T2DM) accounting for 90% of cases globally. The worldwide prevalence of DM is rising dramatically over the last decades, from 30 million cases in 1985 to 382 million cases in 2013. It’s estimated that 451 million people had diabetes in 2017. As the pathophysiology was understood over the years, treatment options for diabetes increased. Incretin-based therapy is one of them. Glucagon-like peptide-1 receptor agonist (GLP-1 RA) not only significantly lower glucose level with minimal risk of hypoglycemia but also, they have an important advantage in themanagement of cardiovascular risk and obesity. Thus, we will review here GLP-1 RAsrole in the treatment of diabetes.

Key Words: Incretin-basedtherapy, Incretin mimetics, Glucagon-like peptide-1 receptor agonist, Dipeptidyl peptidase-4 inhibitor

Core tip: The prevalence of type 2 diabetes and its complications rising dramatically over the last years. It is well known that diabetes and its complications; especially cardiovascular complications lead to increased morbidity and mortality. Treatment options for diabetes have increased as the pathophysiology was understood. We discuss the incretin-based therapy, especially Glucagon-like peptide-1 receptor agonistsand the beneficial effects on comorbidities besides glucose lowering effect.



INTRODUCTION

Diabetes Mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia. Depending on etiology; decreased insulin secretion, decreased glucose utilization and increased glucose production contribute to hyperglycemia[1]. There are several distinct types of DM. Type 2 DM (T2DM) accounting for 90% of cases globally[2]. T2DM demonstrate insulin resistance in peripheral tissues, defective insulin secretion particularly in response to glucose stimuli and increased glucose production by the liver as three cardinal abnormalities[2]. Increased lipolysis in fat tissue, increased production of glucagon, incretin hormone deficiency and resistance, increased renal tubular glucose reabsorption and central nervous system role in metabolic regulation also contribute to the pathophysiology of T2DM[3]. The worldwide prevalence of DM is rising dramatically over the last decades, from 30 million cases in 1985 to 382 million cases in 2013[1]. It’s estimated that 451 million people had diabetes in 2017[4]. As the pathophysiology was understood over the years, treatment options for diabetes increased. Thus, we will review here Glucagon-like peptide-1 receptor agonist (GLP-1 RAs) role in the treatment of diabetes. We aimed to summarize not only their glucose lowering effect but also their efficacy on the comorbidities come along with diabetes, such as obesity and cardiovascular disease (CVD).

We selected the articles by searching an electronic database (PubMed) with the following terms; glucagon-like peptide 1 agonists, glucagon-like peptide 1 agonists and CVD, glucagon-like peptide 1 agonists and obesity, dipeptidyl peptidase-4 (DPP-4) inhibitors. The articles not related to diabetes, the case reports, abstract only, comments and conference papers were excluded. Only studies in English language were included. Cardiovascular safety trial of each molecule (GLP-1 RA and DPP-4 inhibitor) were also included. All the included articles reviewed for full text.

ROLE OF INCRETINS IN GLUCOSE HOMEOSTASIS

Glucose is the most important physiologic substance involved in the regulation of insulin secretion from the pancreas[5-7]. Glucose has a dose-dependent effect on the beta cells. It’s well known that oral glucose administration has a greater effect on insulin release than intravenous glucose administration[8-10]. Known as the incretin effect. In a study, insulin secretion was detected 26% lower in response to IV administration than oral administration[10]. This increased response to oral glucose shows that glucose absorption from the gastrointestinal tract may cause secretion of some hormones which have an effect on B-cell sensitivity[5-10]. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are the major incretin hormones in humans[11]. GIP is produced in the K-cells and these cells are located predominantly in the proximal parts of the intestine, especially in the duodenum. GLP-1 is produced by the L-cells which distally situated especially in the ileum. L-cells also found in the colon in high density[12]. Both K-cells and L-cells can be situated throughout all parts of the intestine. It’s also detected that there is a population of cells which contain both GLP-1 and GIP[13]. Secretion of incretin hormones is correlated with food intake and the driving factor is the presence of nutrients in the lumen, not distension since loading of water does not cause a significant increase in GLP-1 and GIP concentrations[14-16]. The incretins are cleaved by the enzymeDPP-4 and lose their biologic activity[1,2].

INCRETIN EFFECT IN DIABETES MELLITUS

The incretin effect found substantially reduced or even absent in patients who have T2DM and hyperglycemia[17-19]. As the fasting plasma glucose level increases above the level defining diabetic state (126 mg/dL), incretin effect seems to start to reduce[20]. This reduced effect is universal with the possible exception of East Asians[21].

T2DM patients almost completely lost response to GIP[22]. Because much of the incretin effect in healthy individuals is mediated by GIP, lack of activity may explain the reduced incretin effect in T2DM patients[20]. Besides this; the substantial insulinotropic activity of GLP-1 retains in these patients and GLP-1 activity related to dose and concentration, linearly[23-25]. However, GLP-1 insulinotropic effect is reduced compared with healthy individuals; a result of reduced B-cell mass, most likely[25,26]. The effects of GLP-1 on appetite, gastrointestinal motility, food intake, and suppression glucagon secretion are retained[23,27]. Parenterally given GLP-1 significantly increase insulin secretion, suppress glucagon secretion and normalize glucose concentration[22].

INCRETIN-BASED THERAPY IN T2DM

As the research in the field of diabetes progressed and the pathophysiologic processes were understood, new therapeutic options were invented. Incretin-based treatment is one of them. Practically, DPP-4 inhibitors or GLP-1 RAs can be used for this therapeutic approach. Besides that, GLP-1 gene transferring has studied in animal models and it was showed that GLP-1 gene transfer may be an alternative to GLP-1 infusion or multiple daily or weekly injections, in the future[28,29].

There are several GLP-1 agonists used in daily clinical practice. Some of them are listed below in Table 1[30]. All of the GLP-1 agonists administered by subcutaneous injection but semaglutide also has an oral form[31]. On the other site, all of the DPP-4 inhibitors are given orally. Alogliptin (25 mg, once daily), linagliptin (5 mg, once daily), saxagliptin (5 mg once daily), sitagliptin (100 mg, once daily) and vildagliptin (50 mg, twice daily) are the DPP-4 inhibitors used in daily clinical practice[32].

Table 1 Glucagon-like peptide-1 receptor agonist.
DrugAdministrationPhase 3 clinical trial
ExenatideTwice daily (5 µg or 10 µg)Amigo
LiraglutideDaily (0.6 mg or 0.8 mg or 1.2 mg)Leader
Exenatide ERWeekly (2 mg)Duration
LixisenatideDaily (10 µg or 20 µg)Getgoal
DulaglutideWeekly (0.75 mg or 1.5 mg)Award
SemaglutideWeekly (0.5 mg or 1.5 mg)Sustain
AlbiglutideWeekly (30 mg or 50 mg)Harmony

GLP-1 RA and DPP-4 inhibitors are important therapeutic options for patients with T2DM[33]. European Association for the Study of Diabetes and the American Diabetes Association recommend these agents as the second line for the treatment of T2DM[34]. The glucose-lowering effect of these agents with minimal risk of hypoglycemia is well studied. They also have a favorable effect on body weight and blood pressure[35-43]. The efficacy of GLP-1 RAs is greater than DPP-4 inhibitors, in general[44]. While patients who receive GLP-1 RA experience significant weight loss, the effect of DPP-4 inhibitors on body weight is neutral[44,45]. In a systematic review of comparative effectiveness of GLP-1 RAs, it was concluded that GLP-1 RAs are similar or more effective than oral glucose-lowering agents in improving glycemic parameters. In the same review, GLP-1 RAs found to provide similar or less decrease in Hba1c level compared with insulin therapy, with less hypoglycemia[46].

CARDIOVASCULAR OUTCOMES OF INCRETIN-BASED THERAPY IN T2DM

After the meta-analysis, published by Nissen and colleagues in 2007, suggesting that rosiglitazone (an anti-diabetic agent) was associated with increased risk of myocardial infarction (MI) among T2DM patients, United States Food and Drug Administration (FDA) mandated the conduct of large, randomized, placebo-controlled cardiovascular safety trials for all new anti-diabetic agents[47,48]. FDA defined the standards of these studies[48]. Several large randomized controlled trials (RCT) have been completed since that time. The RCT examined saxagliptin for cardiovascular safety established an unexpected increased risk of hospitalization for heart failure among patients randomized to saxagliptin[49,50]. The RCT’s examined other DPP-4 inhibitors didn’t establish such results[51-59]. Vildagliptin haven’t been studied in RCT for examining cardiovascular safety.

Because the GLP-1 RAs promote weight loss, reduce blood pressure, decrease myocardial and vascular inflammation and decrease platelet aggregation behind their effect on blood glucose level, they thought to reduce cardiovascular risk[60,61]. Cardiovascular safety was established for the whole class in the RCTs of cardiovascular outcomes with GLP-1 RAs (liraglutide, semaglutide, lixisenatide, and extended-release exenatide). Besides that, the results for cardiovascular efficacy was mixed[62-65]. Among these RCTs in two studies (SUSTAIN 6 and LEADER) a significant reduction in three-point major adverse cardiovascular events (non-fatal stroke, non-fatal MI and cardiovascular mortality) was shown[63,64]. Questions emerged after these varying findings about the generalizability of the trials to the drug class. The data available from the RCTs of cardiovascular outcomes with GLP-1 RAs was synthesized in a meta-analysis to examine the overall effect on cardiovascular efficacy and safety[66]. According to this meta-analysis; cardiovascular safety appointed for all GLP-1 RAs, use of GLP-1 RAs was associated with a significant 10% relative risk reduction for the three-point major adverse cardiovascular events, also associated with risk reduction in cardiovascular mortality of 13% and all-cause mortality of 12% compared with placebo[66]. Likewise, it was determined in a retrospective epidemiological study that patients who treated with exenatide were less likely to have CVD, CVD related and all-cause hospitalizations[67]. The trial of cardiovascular outcomes in patients with T2DM on albiglutide was completed in 2018 and it was shown that albiglutide was both as safe as placebo in terms of cardiovascular outcomes and superior to placebo in efficacy even in short period of time (1.6 years)[68].

The effect of incretin-based therapy on atherosclerosis was examined in a meta-analysis of RCTs. Incretin-based therapy showed significant improvement of carotid intima media thickness in the long term (2 years) but it has failed to show this effect in 1 year follow up[69].

Certain experimental studies examined incretin receptors on vascular smooth muscle cells and showed their role in causing atherosclerosis[70,71]. Also, the efficacy of DPP-4 inhibitors on improvement of endothelial function was shown[72].

It was generally shown in observational studies that there is a relationship between hyperglycemia and CVD but reduced CVD by reducing hyperglycemia haven’t confirmed in clinical trials[73-78]. Moreover, one trial terminated early because in the intensive glycemic treatment arm, all-cause mortality was increased and, in each subgroup, it was associated with hypoglycemia[74,79]. It’s an important point that GLP-1 RAs and DPP-4 inhibitors have a glucose lowering effect with less hypoglycemia (GLP-1 RAs are more potent than DPP-4 inhibitors)[35-44].

According to the recent meta-analysis, GLP-1 RAs are seemed to be cardio-protective as a whole class[80]. They have pleiotropic actions on cardiovascular risk factors with a direct effect on the cardiovascular system (Table 2)[69,80,81].

Table 2 Cardiovascular effect of glucagon like peptide-1 receptor agonists.
Anti-atherosclerotic effectDecrease matrix metalloproteinase 2; decrease vascular smooth muscle cell proliferation
Improves endothelial functionIncrease nitric oxide-induced vasodilation; decrease oxidative stress
Anti-inflammatory effectSuppress human macrophagesby inhibition of protein kinase C
Decrease infarct/injury sizeDecrease glucose-induced apoptosis; decrease intracellular calcium overload
Modifies risk factorsImprove glycemic control; decrease body weight; decrease blood pressure; decrease low-density lipoprotein

A recently published review in which several preclinical studies were examined, it was concluded that using GLP-1 agonists improve functional outcome after ischemic stroke. It’s unknown whether these results are valid for humans in clinical practice[82].

THE EFFECT OF INCRETIN-BASED THERAPY ON BODY WEIGHT

Obesity is an important risk factor and comorbidity of T2DM, and it also elevates cardiovascular risk. Obesity must also be managed for effective treatment of T2DM. GLP-1 RAs were studied in several trials and it was established that GLP-1 RAs cause significant weight loss in T2DM patients with obesity[46,83,84]. The effect of DPP-4 inhibitors on weight in neutral[44,45,83]. Although GLP-1 RA’s cost and administration route may be limitations for generalized acceptance, they may also offer a reasonable alternative choice for obese patients (liraglutide 3 mgr.) without diabetes who don’t achieve weight-loss goals with lifestyle modification alone[84].

CONCLUSION

T2DM is a chronic disorder which comes along with several comorbidities like obesity, CVD, kidney disease, hypertension, etc. As long as the pathophysiologic process of DM was understood over the years, several new therapeutic options emerged. Individualizing care gained importance in the last years for the management of DM. It’s important to manage obesity, hypertension, hyperlipidemia and total cardiovascular risk together with lowering glucose level with minimal risk of hypoglycemia. GLP-1 RAs not only significantly lower glucose level with minimal risk of hypoglycemia but also, they have an important advantage in the management of cardiovascular risk and obesity.

All GLP-1 RAs are administered parenterally but semaglutide also can be given orally by now. Besides that, it was showed that GLP-1 gene transfer may be an alternative to GLP-1 injections, in the future.

Footnotes

Manuscript source: Unsolicited manuscript

Specialty type: Endocrinology and metabolism

Country of origin: Turkey

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B, B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Koch TR, Samasca G S-Editor:Dou Y L-Editor: A E-Editor: Xing YX

References
1.  Powers AC. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. 19th ed. New York: McGraw-Hill, 2015. .  [PubMed]  [DOI]
2.  PolonskyKS, BurantCF. In: Shlomo Melmed KS, Polonsky PR, Larsen HM. Kronenberg Williams Textbook of Endocrinology. 13th ed. 2016. .  [PubMed]  [DOI]
3.  Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795.  [PubMed]  [DOI]
4.  International Diabetes Federation. IDF Diabetes Atlas, 8th ed. Brussels: International Diabetes Federation, 2017. .  [PubMed]  [DOI]
5.  Porte D, Pupo AA. Insulin responses to glucose: evidence for a two pool system in man. J Clin Invest. 1969;48:2309-2319.  [PubMed]  [DOI]
6.  Chen M, Porte D. The effect of rate and dose of glucose infusion on the acute insulin response in man. J Clin Endocrinol Metab. 1976;42:1168-1175.  [PubMed]  [DOI]
7.  Ward WK, Beard JC, Halter JB, Pfeifer MA, Porte D. Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care. 1984;7:491-502.  [PubMed]  [DOI]
8.  Faber OK, Madsbad S, Kehlet H, Binder C. Pancreatic beta cell secretion during oral and intravenous glucose administration. Acta Med Scand Suppl. 1979;624:61-64.  [PubMed]  [DOI]
9.  Madsbad S, Kehlet H, Hilsted J, Tronier B. Discrepancy between plasma C-peptide and insulin response to oral and intravenous glucose. Diabetes. 1983;32:436-438.  [PubMed]  [DOI]
10.  Shapiro ET, Tillil H, Miller MA, Frank BH, Galloway JA, Rubenstein AH, Polonsky KS. Insulin secretion and clearance. Comparison after oral and intravenous glucose. Diabetes. 1987;36:1365-1371.  [PubMed]  [DOI]
11.  Deacon CF, Ahrén B. Physiology of incretins in health and disease. Rev Diabet Stud. 2011;8:293-306.  [PubMed]  [DOI]
12.  Eissele R, Göke R, Willemer S, Harthus HP, Vermeer H, Arnold R, Göke B. Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest. 1992;22:283-291.  [PubMed]  [DOI]
13.  Mortensen K, Christensen LL, Holst JJ, Orskov C. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine. Regul Pept. 2003;114:189-196.  [PubMed]  [DOI]
14.  Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V. Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol. 1993;138:159-166.  [PubMed]  [DOI]
15.  Orskov C, Wettergren A, Holst JJ. Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day. Scand J Gastroenterol. 1996;31:665-670.  [PubMed]  [DOI]
16.  Ahrén B, Carr RD, Deacon CF. Incretin hormone secretion over the day. Vitam Horm. 2010;84:203-220.  [PubMed]  [DOI]
17.  Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46-52.  [PubMed]  [DOI]
18.  Knop FK, Vilsbøll T, Højberg PV, Larsen S, Madsbad S, Vølund A, Holst JJ, Krarup T. Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes. 2007;56:1951-1959.  [PubMed]  [DOI]
19.  Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsbøll T. Impaired regulation of the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:737-745.  [PubMed]  [DOI]
20.  Meier JJ, Nauck MA. Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired beta-cell function? Diabetes. 2010;59:1117-1125.  [PubMed]  [DOI]
21.  Oh TJ, Kim MY, Shin JY, Lee JC, Kim S, Park KS, Cho YM. The incretin effect in Korean subjects with normal glucose tolerance or type 2 diabetes. Clin Endocrinol (Oxf). 2014;80:221-227.  [PubMed]  [DOI]
22.  Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016;4:525-536.  [PubMed]  [DOI]
23.  Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301-307.  [PubMed]  [DOI]
24.  Mentis N, Vardarli I, Köthe LD, Holst JJ, Deacon CF, Theodorakis M, Meier JJ, Nauck MA. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes. 2011;60:1270-1276.  [PubMed]  [DOI]
25.  Kjems LL, Holst JJ, Vølund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes. 2003;52:380-386.  [PubMed]  [DOI]
26.  Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102-110.  [PubMed]  [DOI]
27.  Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741-744.  [PubMed]  [DOI]
28.  Tasyurek HM, Altunbas HA, Balci MK, Griffith TS, Sanlioglu S. Therapeutic Potential of Lentivirus-Mediated Glucagon-Like Peptide-1 Gene Therapy for Diabetes. Hum Gene Ther. 2018;29:802-815.  [PubMed]  [DOI]
29.  Lee Y, Kwon MK, Kang ES, Park YM, Choi SH, Ahn CW, Kim KS, Park CW, Cha BS, Kim SW, Sung JK, Lee EJ, Lee HC. Adenoviral vector-mediated glucagon-like peptide 1 gene therapy improves glucose homeostasis in Zucker diabetic fatty rats. J Gene Med. 2008;10:260-268.  [PubMed]  [DOI]
30.  Sharma D, Verma S, Vaidya S, Kalia K, Tiwari V. Recent updates on GLP-1 agonists: Current advancements & challenges. Biomed Pharmacother. 2018;108:952-962.  [PubMed]  [DOI]
31.  Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA. 2017;318:1460-1470.  [PubMed]  [DOI]
32.  Sesti G, Avogaro A, Belcastro S, Bonora BM, Croci M, Daniele G, Dauriz M, Dotta F, Formichi C, Frontoni S, Invitti C, Orsi E, Picconi F, Resi V, Bonora E, Purrello F. Ten years of experience with DPP-4 inhibitors for the treatment of type 2 diabetes mellitus. Acta Diabetol. 2019;56:605-617.  [PubMed]  [DOI]
33.  Liu J, Li L, Deng K, Xu C, Busse JW, Vandvik PO, Li S, Guyatt GH, Sun X. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ. 2017;357:j2499.  [PubMed]  [DOI]
34.  Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140-149.  [PubMed]  [DOI]
35.  Kawalec P, Mikrut A, Łopuch S. The safety of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT-2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2014;30:269-283.  [PubMed]  [DOI]
36.  Tricco AC, Antony J, Khan PA, Ghassemi M, Hamid JS, Ashoor H, Blondal E, Soobiah C, Yu CH, Hutton B, Hemmelgarn BR, Moher D, Majumdar SR, Straus SE. Safety and effectiveness of dipeptidyl peptidase-4 inhibitors versus intermediate-acting insulin or placebo for patients with type 2 diabetes failing two oral antihyperglycaemic agents: a systematic review and network meta-analysis. BMJ Open. 2014;4:e005752.  [PubMed]  [DOI]
37.  Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ. 2012;344:e1369.  [PubMed]  [DOI]
38.  Katout M, Zhu H, Rutsky J, Shah P, Brook RD, Zhong J, Rajagopalan S. Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic meta-analysis and meta-regression. Am J Hypertens. 2014;27:130-139.  [PubMed]  [DOI]
39.  Aroda VR, Henry RR, Han J, Huang W, DeYoung MB, Darsow T, Hoogwerf BJ. Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin Ther. 2012;34:1247-1258.e22.  [PubMed]  [DOI]
40.  Karagiannis T, Liakos A, Bekiari E, Athanasiadou E, Paschos P, Vasilakou D, Mainou M, Rika M, Boura P, Matthews DR, Tsapas A. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2015;17:1065-1074.  [PubMed]  [DOI]
41.  Zhang X, Zhao Q. Effects of dipeptidyl peptidase-4 inhibitors on blood pressure in patients with type 2 diabetes: A systematic review and meta-analysis. J Hypertens. 2016;34:167-175.  [PubMed]  [DOI]
42.  Sun F, Chai S, Li L, Yu K, Yang Z, Wu S, Zhang Y, Ji L, Zhan S. Effects of glucagon-like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes: a systematic review and network meta-analysis. J Diabetes Res. 2015;2015:157201.  [PubMed]  [DOI]
43.  Esposito K, Mosca C, Brancario C, Chiodini P, Ceriello A, Giugliano D. GLP-1 receptor agonists and HBA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Curr Med Res Opin. 2011;27:1519-1528.  [PubMed]  [DOI]
44.  Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60:470-512.  [PubMed]  [DOI]
45.  Smilowitz NR, Donnino R, Schwartzbard A. Glucagon-like peptide-1 receptor agonists for diabetes mellitus: a role in cardiovascular disease. Circulation. 2014;129:2305-2312.  [PubMed]  [DOI]
46.  Levin PA, Nguyen H, Wittbrodt ET, Kim SC. Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research. Diabetes Metab Syndr Obes. 2017;10:123-139.  [PubMed]  [DOI]
47.  Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471.  [PubMed]  [DOI]
48.  US Food and Drug Administration. Guidance for Industry: Diabetes Mellitus-Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008.  Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf.  [PubMed]  [DOI]
49.  Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.  [PubMed]  [DOI]
50.  Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, Udell JA, Mosenzon O, Im K, Umez-Eronini AA, Pollack PS, Hirshberg B, Frederich R, Lewis BS, McGuire DK, Davidson J, Steg PG, Bhatt DL; SAVOR-TIMI 53 Steering Committee and Investigators. Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial. Circulation. 2015;132:e198.  [PubMed]  [DOI]
51.  White WB, Bakris GL, Bergenstal RM, Cannon CP, Cushman WC, Fleck P, Heller S, Mehta C, Nissen SE, Perez A, Wilson C, Zannad F. EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J. 2011;162:620-626.e1.  [PubMed]  [DOI]
52.  Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Lam H, White WB; EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-2076.  [PubMed]  [DOI]
53.  White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335.  [PubMed]  [DOI]
54.  Green JB, Bethel MA, Paul SK, Ring A, Kaufman KD, Shapiro DR, Califf RM, Holman RR. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J. 2013;166:983-989.e7.  [PubMed]  [DOI]
55.  Bethel MA, Green JB, Milton J, Tajar A, Engel SS, Califf RM, Holman RR; TECOS Executive Committee. Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Diabetes Obes Metab. 2015;17:395-402.  [PubMed]  [DOI]
56.  McGuire DK, Van de Werf F, Armstrong PW, Standl E, Koglin J, Green JB, Bethel MA, Cornel JH, Lopes RD, Halvorsen S, Ambrosio G, Buse JB, Josse RG, Lachin JM, Pencina MJ, Garg J, Lokhnygina Y, Holman RR, Peterson ED; Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS) Study Group. Association Between Sitagliptin Use and Heart Failure Hospitalization and Related Outcomes in Type 2 Diabetes Mellitus: Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2016;1:126-135.  [PubMed]  [DOI]
57.  Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR; TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373:232-242.  [PubMed]  [DOI]
58.  Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Espeland MA, Bluhmki E, Mattheus M, Ryckaert B, Patel S, Johansen OE, Woerle HJ. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diab Vasc Dis Res. 2015;12:164-174.  [PubMed]  [DOI]
59.  Rosenstock J, Marx N, Neubacher D, Seck T, Patel S, Woerle HJ, Johansen OE. Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol. 2015;14:57.  [PubMed]  [DOI]
60.  Secrest MH, Udell JA, Filion KB. The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors. Trends Cardiovasc Med. 2017;27:194-202.  [PubMed]  [DOI]
61.  Drucker DJ. The Cardiovascular Biology of Glucagon-like Peptide-1. Cell Metab. 2016;24:15-30.  [PubMed]  [DOI]
62.  Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, Solomon SD, Tardif JC; ELIXA Investigators. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373:2247-2257.  [PubMed]  [DOI]
63.  Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375:311-322.  [PubMed]  [DOI]
64.  Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375:1834-1844.  [PubMed]  [DOI]
65.  Ginterová A, Janotková O. A simple method of isolation and purification of cultures of wood-rotting fungi. Folia Microbiol (Praha). 1975;20:519-520.  [PubMed]  [DOI]
66.  Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, Pagidipati NJ, Chan JC, Gustavson SM, Iqbal N, Maggioni AP, Öhman P, Poulter NR, Ramachandran A, Zinman B, Hernandez AF, Holman RR; EXSCEL Study Group. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6:105-113.  [PubMed]  [DOI]
67.  Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M, Hussein MA. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care. 2011;34:90-95.  [PubMed]  [DOI]
68.  Hernandez AF. Green JB, Janmohamed S, D'Agostino RB Sr, Granger CB, Jones NP, Leiter LA, Rosenberg AE, Sigmon KN, Somerville MC, Thorpe KM, McMurray JJV, Del Prato S; Harmony Outcomes committees and investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392:1519-1529.  [PubMed]  [DOI]
69.  Barbarawi M, Aburahma A, Zayed Y, Osman M, Rashdan L, Swaid B, Bachuwa G. Anti-atherosclerotic effect of incretin mimetics: a meta-analysis of randomized controlled trials. J Community Hosp Intern Med Perspect. 2018;8:349-356.  [PubMed]  [DOI]
70.  Jojima T, Uchida K, Akimoto K, Tomotsune T, Yanagi K, Iijima T, Suzuki K, Kasai K, Aso Y. Liraglutide, a GLP-1 receptor agonist, inhibits vascular smooth muscle cell proliferation by enhancing AMP-activated protein kinase and cell cycle regulation, and delays atherosclerosis in ApoE deficient mice. Atherosclerosis. 2017;261:44-51.  [PubMed]  [DOI]
71.  Shi L, Ji Y, Jiang X, Zhou L, Xu Y, Li Y, Jiang W, Meng P, Liu X. Liraglutide attenuates high glucose-induced abnormal cell migration, proliferation, and apoptosis of vascular smooth muscle cells by activating the GLP-1 receptor, and inhibiting ERK1/2 and PI3K/Akt signaling pathways. Cardiovasc Diabetol. 2015;14:18.  [PubMed]  [DOI]
72.  Nakamura K, Oe H, Kihara H, Shimada K, Fukuda S, Watanabe K, Takagi T, Yunoki K, Miyoshi T, Hirata K, Yoshikawa J, Ito H. DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study. Cardiovasc Diabetol. 2014;13:110.  [PubMed]  [DOI]
73.  Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.  [PubMed]  [DOI]
74.  Action to Control Cardiovascular Risk in Diabetes Study Group. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.  [PubMed]  [DOI]
75.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.  [PubMed]  [DOI]
76.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.  [PubMed]  [DOI]
77.  Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.  [PubMed]  [DOI]
78.  ADVANCE Collaborative Group. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.  [PubMed]  [DOI]
79.  Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, Dudl RJ, Ismail-Beigi F, Kimel AR, Hoogwerf B, Horowitz KR, Savage PJ, Seaquist ER, Simmons DL, Sivitz WI, Speril-Hillen JM, Sweeney ME. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909.  [PubMed]  [DOI]
80.  Andrikou E, Tsioufis C, Andrikou I, Leontsinis I, Tousoulis D, Papanas N. GLP-1 receptor agonists and cardiovascular outcome trials: An update. Hellenic J Cardiol. 2018;.  [PubMed]  [DOI]
81.  Lim S, Kim KM, Nauck MA. Glucagon-like Peptide-1 Receptor Agonists and Cardiovascular Events: Class Effects versus Individual Patterns. Trends Endocrinol Metab. 2018;29:238-248.  [PubMed]  [DOI]
82.  Milonas D, Didangelos T, Hatzitolios AI, Tziomalos K. Incretin-Based Antihyperglycemic Agents for the Management of Acute Ischemic Stroke in Patients with Diabetes Mellitus: A Review. Diabetes Ther. 2019;10:429-435.  [PubMed]  [DOI]
83.  Ji Q. Treatment Strategy for Type 2 Diabetes with Obesity: Focus on Glucagon-like Peptide-1 Receptor Agonists. Clin Ther. 2017;39:1244-1264.  [PubMed]  [DOI]
84.  Ottney A. Glucagon-like peptide-1 receptor agonists for weight loss in adult patients without diabetes. Am J Health Syst Pharm. 2013;70:2097-2103.  [PubMed]  [DOI]