Glucose-Regulating Drugs Like GLP-1R Agonists – DPP-4 Inhibitors and Pioglitazone Reduces Risk Of COVID-19 Severity


A new multinational retrospective cohort study by researchers from Penn State College of Medicine, Pennsylvania-USA shows that glucose-regulating medications used to treat obesity and type-2 diabetes may improve outcomes in COVID-19 patients with type-2 diabetes.

It has already been known that individuals with type 2 diabetes mellitus (T2DM) are at increased risk of severe COVID-19 outcomes possibly due to dysregulated inflammatory responses.

The study findings showed that glucose-regulating medications such as glucagon-like peptide-1 receptor (GLP-1R) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and pioglitazone are known to have anti-inflammatory effects that may improve outcomes in patients with SARS-CoV-2 infection.

The study team in a multinational retrospective cohort study used the TriNetX COVID-19 Research Network of 56 large healthcare organizations to examine these medications in relation to the incidence of hospital admissions, respiratory complications, and mortality within 28 days following a COVID-19 diagnosis.

After matching for age, sex, race, ethnicity, body mass index, and significant comorbidities, use of GLP-1R agonists and/or pioglitazone was associated with significant reductions in hospital admissions (GLP-1R: 15.7% vs 23.5%; RR, 0.67 [95% CI, 0.57-0.79] P <.001; pioglitazone: 20.0% vs 28.2%; RR, 0.71 [95% CI, 0.54-0.93]; P =.01). Use of GLP-1R agonists was also associated with reductions in respiratory complications (15.3% vs 24.9%; RR, 0.62 [95% CI, 0.52-0.73]; P <.001) and incidence of mortality (1.9% vs 3.3%; RR, 0.58 [95% CI, 0.35-0.97]; P =.04). Use of DPP-4 inhibitors was associated with a reduction in respiratory complications (24.0% vs 29.2%; RR, 0.82 [95% CI, 0.74-0.90];P <.001), and continued use of DPP-4 inhibitors after hospitalization was associated with a decrease in mortality compared with those who discontinued use (9% vs 19%; RR, 0.45 [95% CI, 0.28-0.72]; P <.001).

The study findings concluded that use of glucose-regulating medications such as GLP-1R agonists, DPP-4 inhibitors, or pioglitazone may improve outcomes for COVID-19 patients with T2DM.

The study findings were published in the peer reviewed journal: Diabetes (A journal of the American Diabetes Association.)

As of April 14th, 2021, there were 137,811,552 confirmed cases and 2,964,835 (2.2%) deaths worldwide due to coronavirus infection 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These figures include 31,375,111 confirmed cases and 563,873 (1.8%) deaths in the United States alone.1

Given the time required to distribute a vaccine, an expedient solution to reduce morbidity and mortality due to COVID- 19 is to rapidly identify therapeutics utilizing highly scalable agents that show promise. A randomized, placebo controlled trial found remdesivir, a broad-spectrum antiviral with activity against SARS-CoV-2, reduced median recovery time from 15 to 11 days, but did not reduce mortality.2,3

An open-label trial with the synthetic glucocorticoid dexamethasone suggested a reduction in mortality by one-third in patients requiring ventilator support and by one-fifth in patients requiring oxygen.4 trials. Together, these interventions are proving helpful, however, the number of deaths due to COVID-19 continues to climb in the US and around the world.1 Moreover, mortality for at-risk populations such as those with type 2 diabetes mellitus (T2DM) is much higher.5-7

In China, risk of mortality was reported to be 7.2% for patients with T2DM,8 and a recent study in England found that patients with T2DM made up 31.4% of the COVID-19 related deaths.9 One hypothesis is that patients with T2DM are more susceptible to a dysregulated inflammatory response, or ‘cytokine storm,’ which has been hypothesized to lead to severe outcomes in a subset of patients with COVID-19.10,11 Additionally, recent data indicate dysregulation of glycometabolic control in patients with COVID-19.12

As SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as its receptor, we selected medications that are used to treat type 2 diabetes, and that have been shown to increase ACE2 and have anti-inflammatory effects. The GLP-1 agonist liraglutide has been shown to increase ACE2 expression in the lungs of rats, and reduce acute lung injury due to influenza virus in mice, which is particularly relevant to COVID-19 induced pulmonary disease.13-16

Dipeptidyl peptidase-4 (DPP-4) inhibitors may have similar effects as they increase endogenous GLP-1 levels by inhibiting the breakdown of GLP-1 by the DPP-4 enzyme. The DPP-4 inhibitor linagliptin has been shown to increase ACE2 activity, and has the potential to exert anti- inflammatory effects.17 Finally, thiazolidinediones (TZDs) were selected because they have been shown to increase ACE2 levels in the aorta, liver, adipose tissue, and skeletal muscle.18,19

As GLP-1 agonists, DPP-4 inhibitors, and TZDs increase ACE2, we hypothesized that these drugs would have protective effects in patients with COVID-19 and diabetes. Increased ACE2 leads to increased production of angiotensin-(1–7), which exhibits anti-inflammatory effects and prevents end-organ damage due to diabetes, and may potentially also prevent end-organ damage due to COVID-19.

Several medications used to regulate blood glucose have been hypothesized to improve COVID- 19 related outcomes in patients with T2DM;20-28 however, there currently are no data to support these hypotheses or to provide rationale for a randomized trial. The objective of this multinational retrospective cohort study was to investigate whether the use of T2DM medications is associated with improved outcomes in patients with COVID-19 and T2DM.

One such class of medications includes glucagon-like peptide-1 receptor (GLP-1R) agonists. GLP-1 is a hormone produced by L cells in the small intestine that increases insulin release, decreases glucagon release, and decreases gastric emptying.29 GLP-1R agonists are an approved and effective treatment for obesity and T2DM,30-32 and may have a protective effect for severe

outcomes of COVID-19 in patients with fatty liver disease.33 In patients with T2DM, GLP-1R agonists control blood glucose, reduce elevated glycated hemoglobin (HbA1c), and decrease both cardiovascular risk34 and the frequency of major adverse cardiac events.35,36 GLP-1R agonists also have positive effects on body weight, body mass index (BMI), blood pressure, and cholesterol.29,37

Of particular interest, GLP-1R agonists have been shown to decrease inflammatory cytokines in animals38 and humans.37,39 Other medications for T2DM that have anti-inflammatory effects include dipeptidyl peptidase-4 (DPP-4) inhibitors which block the breakdown of GLP-1 and have been shown to regulate other coronaviruses,40 and pioglitazone which is a thiazolidinedione.23,41

We hypothesized that the use of GLP-1R agonists, DPP-4 inhibitors or pioglitazone within 6 months prior to the diagnosis of COVID-19 would reduce hospital admissions, respiratory complications, and mortality within 28 days following the diagnosis of COVID-19 in patients with T2DM.


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