Editorial Current Vascular Pharmacology, 2020, Vol. 18, No.

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EDITORIAL

Pharmacological Management of Type 2 Diabetes Complications

Michael Doumas1,2, Konstantinos Imprialos1, Konstantinos Stavropoulos1 and Vasilios G. Athyros1,*

1
Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocra-
tion Hospital, Thessaloniki, Greece; 2George Washington University, Washington, DC, USA; and Veteran Affairs Medi-
cal Center and Georgetown University, Washington, DC, USA

Keywords: Dyslipidaemia, expert consensus, lipid management, comorbidities, cardiovascular risk factors.

Diabetes mellitus (DM) is a very prevalent disease worldwide [1-3]. It holds an outstanding position among non commut-
able diseases with an increasing prevalence trend and mortality [1-3]. In particular:
• 1 in 11 adults has diabetes (425 million).
• 1 in 2 adults with diabetes is undiagnosed (212 million).
• 1 in 6 births is affected by hyperglycaemia in pregnancy.
• Over 1 million children and adolescents have type 1 diabetes.
• Two-thirds of people with diabetes live in urban areas (279 million).
• Two-thirds of people with diabetes are of working age (327 million).
• In 2012 alone diabetes caused 1.5 million deaths.
• 3/4 of people with diabetes live in low and middle income countries.
• 12% of global health expenditure is spent on diabetes ($727 billion) [1-3].
Diabetes is associated with micro- and macrovascular complication. Microvascular complications include diabetic neph-
ropathy, neuropathy, and retinopathy [4]. Macrovascular complications of DM include peripheral vascular disease, myocardial
infarction, stroke, and congestive heart failure [5, 6]. The epidemic of DM, its complications, and their impact on morbidity and
mortality have become a massive global problem and need effective control [4-7].
There is a significant deficit in understanding the risk of DM‐related complications, both by a lot of patients and by some
physicians [8]. Patients with DM, mainly those from ethnic minorities, were often unaware of the risks of complications, espe-
cially for macrovascular events [8]. In a large study, nearly 70% of people with T2DM did not know that they were at increased
risk for developing CVD more than the general population [9].
The aim of this special issue of Current Vascular Pharmacology is to provide an up-to-date overview about the risks of DM
complications and the effect of newer antidiabetic dugs, the new kids on the block, to avoid them, improving the quality of life
at the same time. These drugs range from selective PPAR modulators [SPPARMs] and dual PPAR agonists to the available
glucagon like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i).
Thiazolidinediones (TZDs) are useful, especially the novel selective PPAR-γ modulators, which increase adiponectin with-
out significant weight gain [10]. SPPARMs and dual PPAR agonists may play an important role in the treatment of CVD disor-
ders due to lipid-modifying, anti-inflammatory and insulin-sensitizing effects [11]. INT131, a SPPARM-γ with predominantly
insulin-sensitizing actions, may also have favourable lipid-modifying effects [12]. INT131 achieved a high level of antidiabetic
action by an increase in insulin sensitivity that led to reduction in substantial glucose and insulin levels, without noteworthy
adverse effects [12]. Besides SPPARMs, there are dual PPAR agonists too. Elafibranor is a PPAR-α/δ agonist, which was in-
vestigated in a phase 2 trial in 274 (107 with T2DM) patients with biopsy-proven non-alcoholic steatohepatitis (NASH) [13].
Elafibranor and lobeglitazone [14], resolved NASH in a significant percentage of patients without fibrosis and improved the
hepatic and metabolic profile, glucose and lipids levels [15].
_______________________________
*Address correspondence to this author at the Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, 15
Marmara St, Thessaloniki, 55 132, Greece; Τel: +30 2313 312606; Fax: +30 2310 835955; E-mail: vathyros@gmail.com

1875-6212/20 $65.00+.00 © 2020 Bentham Science Publishers

102 Current Vascular Pharmacology, 2020, Vol. 18, No. 2 Editorial

Microvascular complications are common and are mainly related to glycemic control [16]. The new antidiabetic drugs con-
tribute to glycemic control and have their share in preventing or treating microvascular complications [17].
In regard to macrovascular complications the new antidiabetics GLP-1 RA, commercially available, include liraglutide, ex-
enatide, lixisenatide, and dulaglutide, which are used for the treatment of T2DM [18]. In the Liraglutide Effect and Action in
Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, liraglutide reduced the composite endpoint of all
CVD events (mainly myocardial infarction and stroke) and CVD death as well as all-cause mortality in comparison with pla-
cebo [19]. Patients with a GFR < 60 ml/min/1.73 m2 benefited the most. Since NAFLD was not evaluated in this study, a post-
hoc analysis would be important [19]. In animal models, administration of the GLP-1 Exendin-4 reduced systemic hypertension
and albuminuria as well as ameliorated biopsy-proven renal damage [20].
In the EMPA REG study, the primary composite endpoint (death from CVD causes, myocardial infarction, or stroke) was
reduced by 15% with empagliflozin, p=0.04 for superiority [21]. The hospitalization for heart failure had a 35% and death from
all causes a 32% risk reduction [21]. In the EMPA-REG Renal study, renal function (diabetic nephropathy, a microvascular
complication of DM) was substantially improved (less nephropathy worsening, less doubling of the serum creatinine level and
less renal kidney replacement therapy) [22].
The above suggest that there are indeed new kids on the block that might substantially control glycemic control, micro-, and
macrovascular complications, leading to a considerable reduction in morbidity and (for the first time) mortality. These drugs
are commercially available to be used and all we need is a better education of patients and physicians.
Towards this direction, this issue of Current Vascular Pharmacology covers several topics in the fields of prevalence, identi-
fication, scouting, and mainly treatment of diabetes mellitus complications.
Lovic et al. [23] describe the growing epidemic of diabetes mellitus according to its types, discuss the contributors for the
continuous increase in its prevalence, and critically evaluate existing epidemiological data. Viigimaa and colleagues [24] report
the macrovascular complications of type 2 diabetes mellitus (T2DM), including the heart and brain consequences of long-term
hyperglycemia. Faselis et al. reviewed the microvascular complications of T2DM [25], including the traditional ones (diabetic
nephropathy, neuropathy, and retinopathy) and critically discussing sexual dysfunction as an emerging multifactorial microvas-
cular complication of diabetes mellitus. Patoulias and colleagues [26] report the current status and the future perspectives on the
treatment of pharmacological management of cardiac disease in diabetic patients. They provide a really fresh look of this topic,
since they initially discuss the effects of intensive versus standard therapy of its cardiovascular risk factor, and then they criti-
cally evaluate the cardiac effects of each class of therapeutic agents. Papademetriou and colleagues [27] report recent data on
pharmacological management of diabetic nephropathy, the most prominent microvascular complication of diabetes mellitus,
critically evaluating all available evidence in this field and providing their own expert opinion on the advantages and disadvan-
tages of relevant trials. Didangellos, Kantartzis [28] review whether insulin for the treatment of diabetes in patients with heart
failure is an enemy or a friend? They provide available experimental and clinical evidence on the effects of hyperglycemia and
hyperinsulinemia on heart failure, and they conclude that hyperglycemia seems to be the main contributor for heart failure,
while insulin does not seem to be the main contributor. Didangelos, Veves [29] report the recent data on the treatment of dia-
betic neuropathy, and they provide their expert opinion on available and future therapeutic options for this devastating mi-
crovascular complication of diabetes mellitus. Alvaro-Afonso and colleagues [30] report the existing data on the advances in
dermoepidermal skin substitutes for diabetic foot ulcers. They systematically reviewed 28 randomized controlled trials compar-
ing the effects of dermal substitutes (either cellular or acellular) on the course of diabetic foot ulcers. Athyros and colleagues
[31] analyzed the recent developments on pharmacological management of non-alcoholic fatty liver disease in T2DM, a fre-
quently overlooked comorbidity in patients with type 2 diabetes mellitus. They discuss the effects of traditional and new an-
tidiabetic drugs on steatohepatitis, and they critically evaluate available evidence on emerging drugs such as SPPARMs.
We hope that this special issue if CVP will contribute to the improvement of physicians approach for the management of
diabetes to offer a proper and evidence-based treatment that will ameliorate the CV profile of the diabetic patient.

REFERENCES
[1] Gowshall M, Taylor-Robinson SD. The increasing prevalence of non-communicable diseases in low-middle income countries: the view from Malawi.
Int J Gen Med 2018; 11: 255-64.
[2] International Diabetes Federation. IDF Diabetes Atlas. 8th edition. Brussels, Belgium: International Diabetes Federation 2017. [Accessed July 22,
2018]. Available from http://www.diabetesatlas.org.
[3] WHO Global Report on Diabetes. 2016. [Accessed July 22, 2018]. Available from http://www.who.int/diabetes/global-report/en/.
[4] Forbes J M, Fotheringham AK. Vascular complications in diabetes: old messages, new thoughts. Diabet Med 2017; 60: 2129-38.
[5] Einarson TR, Acs A, Ludwig C, Panton UH. Economic burden of cardiovascular disease in type 2 diabetes: A systematic review. Value Health 2018;
21: 881-90.
[6] Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007; 115: 3213-23.
[7] Zghebi SS, Steinke DT, Carr MJ, Rutter MK, Emsley RA, Ashcroft DM. Examining trends in type 2 diabetes incidence, prevalence and mortality in
the UK between 2004 and 2014. Diabetes Obes Metab 2017; 19: 1537-45.
[8] Rouyard T, Kent S, Baskerville R, Leal J, Gray A. Perceptions of risks for diabetes‐related complications in Type 2 diabetes populations: a systematic
review. Diabet Med 2017; 34: 467-77.
[9] Merz C, Buse J, Tuncer D, Twillman G. Physician attitudes and practices and patient awareness of the cardiovascular complications of diabetes. J Am
Coll Cardiol 2002; 40: 1877-81.
[10] Polyzos SA, Bugianesi E, Kountouras J, Mantzoros CS. Nonalcoholic fatty liver disease: Updates on associations with the metabolic syndrome and
lipid profile and effects of treatment with PPAR-γ agonists. Metabolism 2017; 66: 64-68.
Editorial Current Vascular Pharmacology, 2020, Vol. 18, No. 2 103

[11] Sahebkar A, Chew GT, Watts GF. New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-
alcoholic fatty liver disease. Expert Opin Pharmacother 2014; 15: 493-503.
[12] Higgins LS, Mantzoros CS. The development of INT131 as a selective PPARgamma modulator: Approach to a safer insulin sensitizer. PPAR Res
2008; 2008: 936906.
[13] Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution
of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150: 1147-59.
[14] Lee YH, Kim JH, Kim SR, et al. Lobeglitazone, a novel thiazolidinedione, improves non-alcoholic fatty liver disease in type 2 diabetes: its efficacy
and predictive factors related to responsiveness. J Korean Med Sci 2017; 32: 60-9.
[15] Choung S, Joung KH, You BR, Park SK, Kim HJ, Ku BJ. Treatment with lobeglitazone attenuates hepatic steatosis in diet-induced obese mice. PPAR
Res 2018; 2018: 4292509.
[16] Gibbons CH, Goebel-Fabbri A. Microvascular complications associated with rapid improvements in glycemic control in diabetes. Curr Diab Rep
2017; 17(7): 48.
[17] Doumas M, Imprialos Κ, Stavropoulos K, Reklou A, Sachinidis A, Athyros VG. Combination of SGLT-2 inhibitors and GLP-1 receptor agonists:
potential benefits in surrogate and hard endpoints. Curr Pharm Des 2018; 24(17): 1879-86.
[18] Jespersen MJ, Knop FK, Christensen M. GLP-1 agonists for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug
Metab Toxicol 2013; 9: 17-29.
[19] Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-22.
[20] Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob
mice. Hepatology 2006; 43: 173-81.
[21] Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-28.
[22] Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323-34.
[23] Lovic D, Piperidou A, Zografou I, et al. The growing epidemic of diabetes mellitus. Curr Vasc Pharmacol 2020; 18(2): 104-9.
[24] Viigimaa M, Sachinidis A, Toumpourleka M, et al. Macrovascular complications of type 2 diabetes mellitus. Curr Vasc Pharmacol 2020; 18(2): 110-
16.
[25] Faselis C, Katsimardou A, Imprialos K, et al. Microvascular complications of type 2 diabetes. Curr Vasc Pharmacol 2020; 18(2): 117-24.
[26] Patoulias D, Stavropoulos K, Imprialos K, et al. Pharmacological management of cardiac disease in patients with type 2 diabetes: insights into clinical
practice. Curr Vasc Pharmacol 2020; 18(2): 125-38.
[27] Papademetriou V, Alataki S, Stavropoulos K, et al. Pharmacological management of diabetic nephropathy. Curr Vasc Pharmacol 2020; 18(2): 139-47.
[28] Didangellos T, Kantartzis K. Diabetes and heart failure: is it hyperglycemia or hyperinsulinemia? Curr Vasc Pharmacol 2020; 18(2): 148-57.
[29] Didangelos T, Veves A. Treatment of diabetic cardiovascular autonomic, peripheral and painful neuropathy. Focus on the treatment of Cardiovascular
Autonomic Neuropathy with ACE inhibitors. Curr Vasc Pharmacol 2020; 18(2): 158-71.
[30] Alvaro-Afonso FJ, Garcia-Alvarez Y, Lazaro-Martinez JL, et al. Advances in dermoepidermal skin substitutes for diabetic foot ulcers. Curr Vasc
Pharmacol 2020; 18(2): 182-92.
[31] Athyros VG, Polyzos SA, Kountouras J, et al. Non-alcoholic fatty liver disease treatment in patients with type 2 diabetes mellitus; new kids on the
block. Curr Vasc Pharmacol 2020; 18(2): 172-81.