Antidiabetic drugs in patients with Covid-19 infection

J Atherosclerosis Prev Treat. 2022 Jan-Apr;13(1):36-42 | doi:10.53590/japt.02.1032

REVIEW ARTICLE

Konstantinos Theocharis1, Christina Antza1, Georgios Kostopoulos2, Vasilios Kotsis1

1Hypertension Center, 3rd Department of Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Greece
2Department of Endocrinology, 424 Military Hospital of Thessaloniki, Greece

 

 

Abstract

The COVID-19 pandemic has posed new challenges to the management of the ever-growing group of patients with Diabetes Mellitus (DM). An important question to be answered is which, if any, specific glucose-lowering therapy is associated with worse or better COVID-19 related outcomes for patients with DM. Physicians had to make such management decisions in the absence of robust scientific evidence so far. After nearly two years into the pandemic, there are now a fair number of published studies comparing the premorbid or in-hospital use of certain anti-diabetic medications and relating them to certain COVID-19 outcomes, and there are also a number of published recommendations for the management of people with DM during the pandemic. The purpose of this review is to examine the relationship between the different classes of antidiabetic medications and COVID-19 related outcomes, as well as to make evidence-based recommendations regarding the use of glucose-lowering therapies during acute COVID-19 infection.

Key words: Diabetes, Type 2 Diabetes Mellitus, Antidiabetic agents, Covid-19, mortality, morbidity

Corresponding author: Prof. Vasilios Kotsis, MD, PhD, 3rd Department of Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Greece, E-mail: vkotsis@auth.gr, Tel.: +30 6974 748860

INTRODUCTION

The COVID-19 pandemic has undoubtedly created a new era in medicine, to which physicians had to be adapted in a short period of time. As of December 2021, the number of SARS-CoV-2 infections worldwide exceed 270 million1. The corresponding number in Europe is about 93 million, and in Greece the total cases so far have reached over a million2,3.The real number could actually be much higher (10-fold or more),since many infections go undiagnosed due to a lack of symptoms or due to low disease severity which does not prompt a timely viral test4,5. The Case Fatality Rate (deaths/ confirmed cases) is 1,95%, while the Infection Fatality Rate (deaths/total cases) is estimated at 0,15-1,0%, although this number varies greatly depending on age and certain comorbidities6,7. In the U.S. , COVID-19 is now the third leading cause of death after cardiovascular events and cancer8.

On the other hand, Type 2 Diabetes Mellitus (T2DM) has also been characterized as a modern day “pandemic”, with over 470 million people worldwide living with the disease9. In Europe, the number of people with T2DM is about 61 million, accounting for 9,2% of the adult population, with estimates that this percentage will rise to more than 13% by 204510. Greece is in the 22th place of Europe, with 7,4% of the adult population living with T2DM. The vascular, cardiac, renal and other complications of diabetes have been well established, with the disease ranking 9th as a cause of death worldwide11.

It has been observed early in the course of the pandemic that People with Diabetes (PWD) had an increased chance of having severe COVID-19 compared to non-diabetics, and also had a higher chance of being hospitalized or dying due to COVID-1912-17. The OR for severe COVID-19 or in-hospital death varied by study, but generally was between 2.0 and 3.0 for people with T2DM, compared to people without diabetes. The importance of adequate glycemic control has also been highlighted, since an elevated HbA1c% (>7,5%) has been correlated to an increased in-hospital mortality compared to lower values13.

What is less well established, however, is the optimal care of PWD during the pandemic. There are a number of published studies (mostly observational ones), comparing the premorbid or in-hospital use of certain diabetes medications in order to identify possible COVID-19 related outcomes, such as need for hospitalization and death18-27. There are also several published recommendations regarding the management of PWD during the pandemic28-35, but unfortunately the level of disagreement is high, creating confusion regarding the best management options. Hence, the aim of this review was to investigate the literature and provide evidence for the use of antidiabetic medications in patients infected with COVID-19, hopefully shedding light onto this tangled topic.

EVIDENCE FOR THE USE OF SPECIFIC CLASSES OF DIABETES MEDICATIONS

Most studies so far have compared the premorbid (and less frequently, the in-hospital) use of metformin, dipeptidyl-peptidase 4 inhibitors (DPP4-i), sodium glucose transporter-2 inhibitors (SGLT2-i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), sulfonylureas, thiazolidinediones and insulin regarding different mortality and morbidity outcomes for PWD and SARS-CoV-2. It should be noted, however, that most of the studies are observational (with the exception of the DARE-19 trial23) and the results should be treated with caution, as it is likely that confounders have played an important role.

METFORMIN

Many studies have shown that the premorbid use of metformin is associated with a decreased COVID-19 related mortality, compared to no metformin18,22,24,26. The largest one, a nationwide observational study in England with over 2.800.000 participants and 13.500 COVID-19 deaths, demonstrated a hazard ratio (HR) of 0·77 (95% CI 0·73-0·81) for metformin versus no metformin, regarding COVID-19 related death18. Data from the US have shown a decreased in-hospital COVID-19 related mortality with the premorbid use of metformin, but only in women (HR 0·785, 95% CI 0·650-0·951)26. Contrasting these outcomes is the SEMI-COVID study, which showed no reduced mortality with metformin use after propensity matching21. However, the sample size was much smaller compared to the other studies, rising queries about the statistical strength. There is also a published meta-analysis of five studies comparing the preadmission use of metformin with no metformin use, where the pooled analysis revealed significantly reduced odds for mortality with the use of metformin (pooled odds ratio [OR] = 0.62; 95% CI: 0.43–0.89)24. Overall, the premorbid use of metformin seems to be predictive of better outcomes and reduced mortality for PWD and COVID-19, compared to no metformin. One possible explanation for this includes the anti-inflammatory effects of metformin on the endothelium36,37, which may dampen the systemic inflammation and cytokine storm provoked by SARS-CoV-2. It is possible, however, that these results are affected by confounders, since PWD on metformin are more likely to be younger and earlier in the course of T2DM.

Regarding the use of metformin during acute COVID-19, it should generally be withdrawn when the illness is severe or critical28-35. Hypoxia, haemodynamic instability and acute kidney injury (AKI) secondary to dehydration can all significantly increase the chance of lactic acidosis38. Metformin-associated lactic acidosis (MALA) is a very serious condition, with reported mortality rates of 30-50%38. When it comes to mild or moderate disease, opinions start to diverge, with some advocating for discontinuation of metformin with any level of illness28,34, and others recommending that it is continued29,30,35. The Hellenic Diabetes Association recommends that metformin is discontinued during acute illness, especially in patients with concurrent dehydration39.

SODIUM-GLUCOSE TRANSPORTER -2 INHIBITORS (SGLT2-i)

This widely used class of anti-diabetic medications has also shown a benefit for PWD and COVID-19. According to the UK Cohort study, the premorbid use of SGLT-2i was associated with a HR of 0·82 (95% CI 0·74-0·91), compared to no SGLT-2i use, regarding COVID-19 related death18. A different study (N3C) compared the premorbid use of SGLT-2i to the use of DPP-4i and found lower rates of 60-day mortality (OR 0.66 [95% CI 0.50-0.86]), Emergency Room (ER) visits and hospitalization with SGLT-2i use19. DARE-19 (DApagliflozin in REspiratory failure in patients with COVID-19), a multicenter, randomized, double-blind, placebo-controlled study involving 1.250 participants, compared the use of dapagliflozin (10 mg once daily for 30 days) to matching placebo for patients with COVID-19 requiring hospitalization, that had at least one cardiometabolic risk factor, such as T2DM or cardiovascular disease. Regarding the primary outcomes of the study, there was no significant difference between the two groups, but there was a trend towards reduced mortality and organ failure in the dapagliflozin group. This study also demonstrated the absence of a safety signal, since both groups had the same frequency of serious adverse events23.

Most published recommendations still suggest that the discontinuation of SGLT-2i in hospitalized patients with COVID-19 is preferred due to the risk of dehydration, AKI, and Diabetic Ketoacidosis (DKA)28-35. However, the results of the DARE-19 trial actually showed that dapagliflozin was safe and well tolerated amongst inpatients, allowing for the continuation of the drug when clinically indicated23. Regarding outpatient use, the recommendations, as with metformin, are mixed. Some advocate for the discontinuation of SGLT-2i with any level of illness28,34, while others recommend that they should be continued in mild to moderate illness, because of their significant cardiorenal benefits29,32. The position of the Hellenic Diabetes Association is to withhold this drug class during acute illness and that therapy should be re-initiated after clinical improvement39.

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS (GLP-1 RA)

Evidence from the UK shows overall no mortality difference with the premorbid use of GLP-1 RA compared to their non-use (HR 0·94 [95% CI 0·83-1·07])18. However, when compared to DPP-4i, the N3C study found lower rates of 60-day mortality (OR 0.54 [95% CI 0.37-0.80]), ER visits and hospitalization with GLP-1 RA use19.

During acute COVID-19, the use of GLP-1 RA remains controversial. Due to the possibility of Gastrointestinal (GI) adverse effects (nausea/vomiting) and the resulting dehydration, some recommend against their use, especially in patients with severe disease that require hospitalization31-33,35. On the other hand, GLP-1 RA have been cited as the preferred treatment option for hospitalized patients34. This lack of consistency highlights the need for more robust data. If the use of GLP-1 RA is decided, the patient should be monitored for signs of dehydration, and adequate fluid and food intake should be encouraged28. As a side note, fixed formulations of either a GLP-1 RA or a SGLT-2i with basal insulin have been proven to be equally effective, and even safer (less hypoglycemic episodes), to a basal-bolus insulin regimen  for PWD and inadequate glycemic control40. If this could be applied for PWD and COVID-19 remains unanswered.

DIPEPTIDYL-PEPTIDASE 4 INHIBITORS (DPP4-i)

Observational studies show either a negative or a neutral effect regarding the premorbid use of DPP4-i for PWD and COVID-1918-22,25. As discussed above, the premorbid use of the DPP4-i class compared poorly to both SGLT-2i and GLP-1 RA regarding the rates of 60-day mortality, ER visits and hospitalization19. A meta-analysis of nine studies looked into the effects of the premorbid, but also the in-hospital use of DPP4-i. The results revealed no significant difference in mortality with preadmission use of DPP4-i (adjusted OR 0.89, 95% CI 0.73-1.09), but interestingly found that their in-hospital use was associated with a significant reduction in mortality (adjusted OR 0.27, 95% CI 0.13-0.55)25. The reasons for this are not fully understood, but it may be due to the role of DPP4/CD26  acting as a co-receptor for the binding of SARS-CoV-2 to the ACE2-R of human cells, with the use of DPP4-i possibly inhibiting the adherence of the virus41-43. Although the decrease in mortality appears important, large randomized, placebo-controlled studies are needed to confirm these findings.

Most recommendations agree that the use of DPP4-i may be continued during acute infection with COVID-19, both in the outpatient and the inpatient setting. The safety profile of these drugs is very favorable and they can be used across a wide range of renal function28-30,33,34.

SULFONYLUREAS

The premorbid use of sulfonylureas (such as gliclazide) has shown no significant difference in COVID-19 related mortality (adjusted HR 0·94 [95% CI 0·89-0·99]), according to the UK Cohort study18. In line with these findings is a study from the US involving 35.000 veterans with T2DM and COVID-19, which also demonstrated a neutral effect of the premorbid use of sulfonylureas on 30-day mortality (OR 1.00, 95% CI 0.92–1.10) 27. The study also found no difference in the rates of hospitalization and ICU admission(OR 1.02,95% CI 0.96–1.08 and 1.04,95% CI 0.95–1.14, respectively.)27

The use of sulfonylureas during acute COVID-19 has not been thoroughly tested, but they should generally be discontinued when oral intake of food is poor, due to the risk of hypoglycemia32,33.

THIAZOLIDINEDIONES

As with sulfonylureas, the US Veterans study demonstrated a neutral effect with the premorbid use of thiazolidinediones on hospitalization, ICU admission and 30-day mortality for PWD and COVID-19 (OR 1.04 [95% CI 0.93–1.17], 0.97 [95% CI 0.80–1.19] and 1.07 [95% CI 0.88–1.30], respectively)27. Evidence from the UK also showed no difference in COVID-19 related mortality with the premorbid use of this drug class (adjusted HR 0·94 [95% CI 0·82–1·07])18.

Published recommendations generally suggest that pioglitazone may be continued in mild to moderate COVID-19. However, it should be discontinued in hospitalized individuals with severe or critical disease, due to the risk of fluid retention and possible exacerbation of heart failure29,30,32,33.

INSULIN

The routine pre-admission use of insulin is associated with an increased COVID-19 mortality18,22,27. CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes), a nationwide observational study in France demonstrated an age-adjusted OR of 1.72 (95% CI 1.41, 2.08) with the premorbid use of insulin, regarding the 28-day mortality of PWD hospitalized with COVID-1922. The use of insulin was also associated with a reduced chance of hospital discharge within 28 days (age-adjusted OR 0.78 [95% CI 0.67, 0.92])22. Similar results have been published by the UK Cohort study, with the premorbid use of insulin being correlated to an increased chance of COVID-19 related death (HR 1·42 [95% CI 1·35–1·49])18. A causal relationship between routine insulin use and COVID-19 mortality has not been established, and it is likely that confounders, such as longer diabetes duration, have played an important role in these outcomes44.

Insulin seems to be the preferred treatment option for hospitalized patients with COVID-1928-34. Regular glucose monitoring, or even continuous glucose monitoring is advised to quickly identify hypoglycemia28,31. For non-critically ill patients, subcutaneous basal/bolus/sliding scale insulin is the go-to regimen31,33. For patients that are critically ill (ICU), insulin is best given as an intravenous infusion28,30,34. Evidence shows that the use of insulin (as an infusion) and the resulting control of hyperglycemia leads to lower IL-6 and D-dimer values, as well as improved clinical outcomes for PWD hospitalized with COVID-1945.

SUMMARY

Table 1 summarizes the recommendations regarding the use of diabetes medications during acute COVID-19. For PWD at risk of infection, but not currently infected, the recommendation is that patients continue on their usual therapeutic regimen. This recommendation is due to the lack of sufficient evidence to guide a change in treatment in this setting18,30.

CONCLUSION

Although the COVID-19 pandemic may be receding, with many countries slowly entering the endemic phase of the infection, it remains crucial for PWD to get the best available care, since SARS-CoV-2 infections will continue to appear. Most recommendations regarding the use of diabetes medications are based on observational studies and clinical experience with the use of the various drugs, and thus should be adapted with caution. It would be nice to have more randomized, placebo-controlled studies be conducted, for example regarding the use of GLP-1 RA or DPP4-i in the hospital setting. Common goal is that PWD should have the best available treatment when infected with COVID-19, thus reducing mortality and adding to their quality of life.

Acknowledgment

None

Conflict of Interests

The authors have no conflicts of interest related to this publication.

REFERENCES

  1. Worldometers. COVID Live – Coronavirus Statistics. 2021 [Internet] [Accessed 2021 Dec 17]. Available from: https://www.worldometers.info/coronavirus/.
  2. Eody. Covid Greece Daily Report. 2021 [Internet] [Accessed 2021 Dec 17]. Available from: https://eody.gov.gr/wp-content/uploads/2021/12/covid-gr-daily-report-20211217.pdf.
  3. World Health Organization. Covid19. 2021 [Internet] [Accessed 2021 Dec 17]. Available from: https://covid19.who.int/table.
  4. Havers FP, Reed C, Lim T, Montgomery JM, Klena JD, Hall AJ, et al. Seroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States, March 23-May 12, 2020. JAMA Intern Med. 2020 Jul (ahead of print). Available from: https://pubmed.ncbi.nlm.nih.gov/32692365/
  5. Stringhini S, Wisniak A, Piumatti G, Azman AS, Lauer SA, Baysson H, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study. Lancet (London, England). 2020 Aug;396(10247):313-9.
  6. Ioannidis JPA. Reconciling estimates of global spread and infection fatality rates of COVID-19: An overview of systematic evaluations. Eur J Clin Invest. 2021 May;51(5):e13554.
  7. Meyerowitz-Katz G, Merone L. A systematic review and meta-analysis of published research data on COVID-19 infection fatality rates. Int J Infect Dis. 2020 Dec;101:138-48.
  8. Statista. Leading causes of death U.S. 2020-2021. 2021 [Internet] [Accessed 2021 Dec 17]. Available from: https://www.statista.com/statistics/1254560/leading-causes-of-death-in-the-us-average-number-daily/.
  9. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of Type 2 Diabetes – Global burden of disease and forecasted trends. J Epidemiol Glob Health. 2020 Mar;10(1):107-11.
  10. Diabetesatlas. Europe diabetes report 2000 — 2045. 2021 [Internet] [Accessed 2021 Dec 19]. Available from: https://diabetesatlas.org/data/en/region/3/eur.html. .
  11. World Health Organization. The top 10 causes of death. 2021 [Internet] [Accessed 2021 Dec 19]. Available from: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death. Accessed December 19,2021.
  12. Barron E, Bakhai C, Kar P, Weaver A, Bradley D, Ismail H, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. The lancet Diabetes & endocrinology. 2020 Aug;8(10):813-22.
  13. Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020 Aug;584(7821):430-6.
  14. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020 May;94:91-95.
  15. Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clinical research in cardiology: official journal of the German Cardiac Society. 2020 May;109(5):531-8.
  16. Chen Y, Gong X, Wang L, Guo J. Effects of hypertension, diabetes and coronary heart disease on COVID-19 diseases severity: A systematic review and meta-analysis. medRxiv [Internet]. 2020 Mar [cited 2020 Mar 30]. Doi: https://doi.org/10.1101/2020.03.25.20043133. Available from: https://www.medrxiv.org/content/10.1101/2020.03.25.20043133v1.full.pdf+html
  17. Fadini GP, Morieri ML, Longato E, Avogaro A. Prevalence and impact of diabetes among people infected with SARS-CoV-2. J Endocrinol Invest. 2020 Jun;43(6):867-9.
  18. Khunti K, Knighton P, Zaccardi F, Bakhai C, Barron E, Holman N, et al. Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: A nationwide observational study in England. Lancet Diabetes Endocrinol. 2021 May;9(5):293-303
  19. Kahkoska AR, Abrahamsen TJ, Alexander GC, Bennett TD, Chute CG, Haendel MA, et al. Association between Glucagon-Like Peptide 1 Receptor Agonist and Sodium-Glucose Cotransporter 2 Inhibitor use and COVID-19 Outcomes. Diabetes Care. 2021;44(7):1564-72.
  20. Israelsen SB, Pottegård A, Sandholdt H, Madsbad S, Thomsen RW, Benfield T. Comparable COVID-19 outcomes with current use of GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors among patients with diabetes who tested positive for SARS-CoV-2. Diabetes, obesity & metabolism. 2021 Jun;23(6):1397-1401.
  21. Pérez-Belmonte LM, Torres-Peña JD, López-Carmona MD, Ayala-Gutiérrez MM, Fuentes-Jiménez F, Jorge Huerta L, et al. Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: A nationwide cohort study. BMC Medicine. 2020 Nov;18(1):359.
  22. Wargny M, Potier L, Gourdy P, Pichelin M, Amadou C, Benhamou P-Y, et al. Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study. Diabetologia. 2021 Apr;64(4):778-94.
  23. Kosiborod MN, Esterline R, Furtado RHM, Oscarsson J, Gasparyan SB, Koch GG, et al. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2021 Sep;9(9):586-94.
  24. Kow CS, Hasan SS. Mortality risk with preadmission metformin use in patients with COVID-19 and diabetes: A meta-analysis. Journal of medical virology. 2021 Feb;93(2):695-7.
  25. Pal R, Banerjee M, Mukherjee S, Bhogal RS, Kaur A, Bhadada SK. Dipeptidyl peptidase-4 inhibitor use and mortality in COVID-19 patients with diabetes mellitus: an updated systematic review and meta-analysis. Ther Adv Endocrinol Metab [Internet]. 2021 Feb;12:2042018821996482. Available from: https://pubmed.ncbi.nlm.nih.gov/33680425/
  26. Bramante CT, Ingraham NE, Murray TA, Marmor S, Hovertsen S, Gronski J, et al. Metformin and risk of mortality in patients hospitalised with COVID-19: A retrospective cohort analysis. Lancet Healthy Longev. 2021 Jan;2(1):e34-e41.
  27. Wander PL, Lowy E, Beste LA, Tulloch-Palomino L, Korpak A, Peterson AC, et al. Prior Glucose-Lowering medication use and 30-day outcomes among 64,892 veterans with diabetes and COVID-19. Diabetes Care. 2021 Dec;44(12):2708-13.
  28. Bornstein SR, Rubino F, Khunti K, Mingrone G, Hopkins D, Birkenfeld AL, et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol. 2020 Jun;8(6):546-50.
  29. Sun B, Huang S, Zhou J. Perspectives of Antidiabetic Drugs in Diabetes With Coronavirus Infections. Front Pharmacol [Internet]. 2020 Jan [cited 2021 Jan 29];11:592439. Available from: https://pubmed.ncbi.nlm.nih.gov/33584268/
  30. Lim S, Bae JH, Kwon HS, Nauck MA. COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat Rev Endocrinol. 2021 Jan;17(1):11-30.
  31. Korytkowski M, Antinori-Lent K, Drincic A, Hirsch IB, McDonnell ME, Rushakoff R, et al. A Pragmatic Approach to Inpatient Diabetes Management during the COVID-19 Pandemic. J Clin Endocrinol Metab. 2020 Sep;105(9):dgaa342.
  32. Koliaki C, Tentolouris A, Eleftheriadou I, Melidonis A, Dimitriadis G, Tentolouris N. Clinical Management of Diabetes Mellitus in the Era of COVID-19: Practical Issues, Peculiarities and Concerns. J Clin Med. 2020 Jul;9(7):2288.
  33. Katulanda P, Dissanayake HA, Ranathunga I, Ratnasamy V, Wijewickrama PSA, Yogendranathan N, et al. Prevention and management of COVID-19 among patients with diabetes: an appraisal of the literature. Diabetologia. 2020 Aug;63(8):1440-52.
  34. Hartmann-Boyce J, Morris E, Goyder C, Kinton J, Perring J, Nunan D, et al. Diabetes and COVID-19: Risks, management, and learnings from other national disasters. Diabetes Care. 2020 Aug;43(8):1695-1703.
  35. Futatsugi H, Iwabu M, Okada-Iwabu M, Okamoto K, Amano Y, Morizaki Y, et al. Blood glucose control strategy for Type 2 Diabetes patients With COVID-19. Front Cardiovasc Med [Internet]. 2020 Oct [cited 28 Oct 2020];7(231):593061.
  36. Davis BJ, Xie Z, Viollet B, Zou MH. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes. 2006 Feb;55(2):496-505.
  37. Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension (Dallas, Tex: 1979). 2006 Jun;47(6):1183-8.
  38. DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. 2016 Feb;65(2):20-9.
  39. Hellenic Diabetes Association [Internet]. Updated HDA Guidelines for Protecting People with Diabetes from Coronavirus (Covid-19). 2020.
  40. Giugliano D, Longo M, Caruso P, Di Fraia R, Scappaticcio L, Gicchino M, et al. Feasibility of simplification from a basal-bolus insulin regimen to a fixed-ratio formulation of basal insulin plus a GLP-1RA or to basal insulin plus an SGLT2 inhibitor: BEYOND, a randomized, pragmatic trial. Diabetes Care. 2021 Jun;44(6):1353-60.
  41. Iacobellis G. COVID-19 and diabetes: Can DPP4 inhibition play a role? Diabetes Res Clin Pract. 2020 Apr;162:108125.
  42. Solerte SB, Di Sabatino A, Galli M, Fiorina P. Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19. Acta Diabetol. 2020 Jul;57(7):779-83.
  43. Strollo R, Pozzilli P. DPP4 inhibition: Preventing SARS-CoV-2 infection and/or progression of COVID-19? Diabetes Metab Res Rev. 2020 Nov;36(8):e3330.
  44. Hadjadj S, Wargny M. Glucose-lowering treatments and COVID-19 mortality in T2DM. Nat Rev Endocrinol. 2021Jul;17(7):387-8.
  45. Sardu C, D’Onofrio N, Balestrieri ML, Barbieri M, Rizzo MR, Messina V, et al. Outcomes in Patients With Hyperglycemia Affected by COVID-19: Can We Do More on Glycemic Control? Diabetes Care. 2020 Jul;43(7):1408-15.