J Endocrinol Metab

Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access

Article copyright, the authors; Journal compilation copyright, J Endocrinol Metab and Elmer Press Inc

Journal website https://www.jofem.org

Review

Volume 11, Number 1, February 2021, pages 1-7

The Optimal Medical Therapy for Glycemic Control in COVID-19

**Table 1.** Putative Beneficial and Harmful Effects, and Clinical Outcomes of Metformin Use in Glycemic Control Among COVID-19 Patients
Putative beneficial effects	Putative harmful effects	Clinical outcomes
COVID-19: coronavirus disease 2019; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; RR: relative risk; IL: interleukin; CI: confidence interval.
Metformin improves insulin resistance which is induced by increased inflammatory cytokines.	Development of lactic acidosis in hypoxic situation.	In a case-control study, the incidence of life-threatening complications was significantly higher in the metformin group than the non-metformin group (28.6% vs. 7.4%, P = 0.004) [9].
Reduced production of proinflammatory cytokines, and alleviation of lung injuries in animals. Direct inhibition of SARS-CoV-2 infection [7].		Metformin was significantly associated with a higher incidence of acidosis, especially in severe COVID-19 patients, however, not with 28-day mortality [10].
Suppression of IL-1β-induced secretion of IL-6 in macrophages, vascular smooth muscle and endothelial cells [8].		A health record data analysis of 25,326 subjects showed that metformin was independently associated with a significant reduction in mortality among COVID-19 individuals with diabetes (OR, 0.33; 95% CI, 0.13 - 0.84; P = 0.0210) [11].
		Metformin was associated with reduced mortality in women by propensity matching (OR, 0.759; 95% CI, 0.601 - 0.960) [12].
		The in-hospital mortality was significantly lower in the metformin group (2.9%) than in the non-metformin group (12.3%) [13].
		The meta-analysis (5 studies, n = 6,937) elucidated that metformin was associated with reduction in mortality (RR, 0.54; 95% CI 0.32 - 0.90, P = 0.02) [14].

Table 1. Putative Beneficial and Harmful Effects, and Clinical Outcomes of Metformin Use in Glycemic Control Among COVID-19 Patients

Putative beneficial effects

Putative harmful effects

Clinical outcomes

COVID-19: coronavirus disease 2019; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; RR: relative risk; IL: interleukin; CI: confidence interval.

Metformin improves insulin resistance which is induced by increased inflammatory cytokines.

Development of lactic acidosis in hypoxic situation.

In a case-control study, the incidence of life-threatening complications was significantly higher in the metformin group than the non-metformin group (28.6% vs. 7.4%, P = 0.004) [9].

Reduced production of proinflammatory cytokines, and alleviation of lung injuries in animals. Direct inhibition of SARS-CoV-2 infection [7].

Metformin was significantly associated with a higher incidence of acidosis, especially in severe COVID-19 patients, however, not with 28-day mortality [10].

Suppression of IL-1β-induced secretion of IL-6 in macrophages, vascular smooth muscle and endothelial cells [8].

A health record data analysis of 25,326 subjects showed that metformin was independently associated with a significant reduction in mortality among COVID-19 individuals with diabetes (OR, 0.33; 95% CI, 0.13 - 0.84; P = 0.0210) [11].

Metformin was associated with reduced mortality in women by propensity matching (OR, 0.759; 95% CI, 0.601 - 0.960) [12].

The in-hospital mortality was significantly lower in the metformin group (2.9%) than in the non-metformin group (12.3%) [13].

The meta-analysis (5 studies, n = 6,937) elucidated that metformin was associated with reduction in mortality (RR, 0.54; 95% CI 0.32 - 0.90, P = 0.02) [14].

Table 2. Putative Beneficial and Harmful Effects, and Clinical Outcomes of Incretin-Related Drugs Use in Glycemic Control Among COVID-19 Patients

Putative beneficial effects

Putative harmful effects

Clinical outcomes

GLP-1 RA: glucagon-like peptide-1 receptor agonist; HR: hazard ratio; COVID-19: coronavirus disease 2019; DPP4: dipeptidyl peptidase-4; CRP: C-reactive protein.

DPP4 inhibitors are unlikely to develop hypoglycemia.

No applicable data

Sitagliptin use during hospitalization was associated with reduced mortality (HR, 0.44; 95% CI, 0.29 - 0.66; P = 0.0001), with clinical improvement (60% vs. 38%; P = 0.0001) and with more hospital discharges (120 vs. 89; P = 0.0008) as compared with the standard care [19].

DPP4 inhibitors increase secretion of insulin, anabolic hormone, which may be beneficial for the treatment of severe infection.

The identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, therefore, DPP4 was proposed as an important putative target for the treatment of COVID-19 [15].

A meta-analysis reported a significant reduced CRP levels by DPP4 inhibitors as compared with placebo [2].

Sitagliptin was reported to improve inflammatory status by affecting on NF-kappa-B signaling [16].

The S1 domain of SARS-CoV-2 spike glycoprotein potentially interacts with DPP4 [17]. DPP4 inhibitors can be the therapeutic candidate for COVID-19 by blocking the entry of SARS-CoV-2 into human body [18].

In type 2 diabetic patients, liraglutide (GLP-1 RA) significantly reduced serum CRP levels [2].

Table 3. Putative Beneficial and Harmful Effects, and Clinical Outcomes of Pioglitazone and Sulfonylurea in Glycemic Control Among COVID-19 Patients

Putative beneficial effects

Putative harmful effects

Clinical outcomes

COVID-19: coronavirus disease 2019; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; IL: interleukin; hs-CRP: high-sensitivity C-reactive protein.

Pioglitazone

IL-6 expression was suppressed by pioglitazone in monocytes, white adipose tissue and cardiomyocytes. Pioglitazone significantly reduced serum CRP levels. A meta-analysis demonstrated that pioglitazone significantly lowered serum hs-CRP levels in type 2 diabetic patients [2].

As my opinion, pioglitazone may possibly exacerbate pulmonary congestion or acute respiratory distress syndrome (ARDS) which need critical management of body fluid by increasing fluid retention.

No applicable data

Progressive atherosclerosis is associated with the development of severe COVID-19. Oxidized LDL (Ox-LDL) plays an important role for atherogenesis. Uptake of ox-LDL by macrophages activates the reprogramming of innate immunity, “trained immunity.” Ox-LDL-trained macrophages infected with SARS-CoV-2 increase cytokine release, which leads to lung injury. Inhibition of macrophage training by pioglitazone may suppress the cytokine storm induced by SARS-CoV-2 infection [21].

Sulfonylurea

Sulfonylurea increases secretion of insulin, anabolic hormone, which may be beneficial for the treatment of severe infection.

Sulfonylurea is likely to develop hypoglycemia.

A combination therapy of metformin and sulfonylureas was most commonly associated with the development of hypoglycemia (65.75%) [24].

Channel activity was found for the envelope protein of coronaviruses, and the ion channel was inhibited by gliclazide [22].

Glibenclamide presented 3D similarity to known ligands, reasonable predicted binding modes and micromolar predicted binding affinity values for the SARS-CoV-2 main protease [23].

**Table 4.** Putative Beneficial and Harmful Effects, and Clinical Outcomes of SGLT2 Inhibitors in Glycemic Control Among COVID-19 Patients
Putative beneficial effects	Putative harmful effects	Clinical outcomes
COVID-19: coronavirus disease 2019; SGLT2: sodium-glucose cotransporter 2.
No applicable data	Owing to their pharmacological characteristics, SGLT2 inhibitors might cause adverse effects in patients with COVID-19 and so cannot be recommended [25].	A 52-year-old male with type 2 diabetes on empagliflozin and no history of diabetic ketoacidosis (DKA) presented with symptoms of COVID-19 as well as laboratory findings consistent with euglycemic DKA. SGLT2 inhibitors should be held as early as possible in COVID-19 patients due to the risk of euglycemic DKA [28].
	People with diabetes should be encouraged to continue medication prescribed for hypertension, diabetes or dyslipidemia. Furthermore, patients with diabetes and COVID-19 infection should follow their usual antidiabetic treatment with the exception of SGLT2 inhibitors [26].	The patient of euglycemic DKA due to empagliflozin use was initially suspected to be a case of COVID-19 [29].
	Avoidance of diabetic ketoacidosis associated with SGLT2 inhibitors is of particular medical importance during the COVID-19 pandemic [27].

Table 4. Putative Beneficial and Harmful Effects, and Clinical Outcomes of SGLT2 Inhibitors in Glycemic Control Among COVID-19 Patients

Putative beneficial effects

Putative harmful effects

Clinical outcomes

COVID-19: coronavirus disease 2019; SGLT2: sodium-glucose cotransporter 2.

No applicable data

Owing to their pharmacological characteristics, SGLT2 inhibitors might cause adverse effects in patients with COVID-19 and so cannot be recommended [25].

A 52-year-old male with type 2 diabetes on empagliflozin and no history of diabetic ketoacidosis (DKA) presented with symptoms of COVID-19 as well as laboratory findings consistent with euglycemic DKA. SGLT2 inhibitors should be held as early as possible in COVID-19 patients due to the risk of euglycemic DKA [28].

People with diabetes should be encouraged to continue medication prescribed for hypertension, diabetes or dyslipidemia. Furthermore, patients with diabetes and COVID-19 infection should follow their usual antidiabetic treatment with the exception of SGLT2 inhibitors [26].

The patient of euglycemic DKA due to empagliflozin use was initially suspected to be a case of COVID-19 [29].

Avoidance of diabetic ketoacidosis associated with SGLT2 inhibitors is of particular medical importance during the COVID-19 pandemic [27].