15 August COVID and diabetes

Dear colleagues,

We are all aware in the meantime that diabetes is considered as an important risk factor and “co-morbidity” for COVID-19.  I was wondering what exactly are the risks, the pathophysiological mechanisms, the role of type 1 versus type 2, confounding factors etc.  You find some proposed answers and still many interesting research questions to tackle below.   

1. Prevalence and pathophysiology…

• Evidence that diabetes increases risk of morbidity and mortality in other infections, including H1N1 Influenza, SARS-COV-1 and MERS…
• Diabetes is second most important risk factor for COVID disease (after hypertension, but before CVD and COPD see Table 1)
• In over 40,000 Chinese COVID-19 patients, the case fatality rate (CFR) was 2.3 overall, but it was 10.5% in patients with CVD, 7.3% in diabetes and 6.0% in hypertension. 
• Underlying mechanisms: increased ACE-2 and furin, increased interleukin-6, decreased T cell and neutrophil function.
• Modulatory role of anti-diabetic drugs: metformin may have some beneficial effects, whereas thiazolidinediones may be disfavorable.  Only “circumstantial evidence”. 
• COVID-19 diabetics are best treated with insulin and frequent glucose monitoring, which is challenging in view of safety for HCW
• Known controversy about potential favorable or disfavorable effect of ACE inhibitors and angiotensin receptor blockers (ARB) on COVID.  If they are part of the patient’s pre-COVID treatment, it should not be changed.
• Statins and Ca++channel blockers may be beneficial; aspirin may be dangerous in view of DIC, but should be continued if indicated for coronary heart disease.
• For non-COVID diabetics the pandemic is disadvantageous, like for other medical conditions.   Diet, exercise, antidiabetic drugs should be continued.  Telemedicine may be helpful

2. Prognostic factors for poor outcome in diabetic COVID patients: CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) = prospective multicenter in France March 2020

Primary outcome = tracheal intubation (20%)  or death (10%)  within 7 days after admission

Significant factors:

• Increased BMI
• Age
• Microvascular complications e.g. decreased glomerular filtration
• Macrovascular events
• Co-morbidities such as treated sleep-apnoe

Non-significant (in multivariate analysis):

• HbA1c (as marker of long-term control
• Drugs acting on Renin-Angiostensin system (ACE-inhibitors and Arb), nor DPP-IV inhibitors
• Glycemia at admission was predictive in univariate, but not in multivariate   

Why is obesity associated with poor outcome: (hypotheses)

• Poor respiratory mechanics;
• Visceral fat produces adipokines and inflammatory cytokines
• Fat may be a reservoir for the virus
• Obesity associated with comorbidities such as hypertension, renal impairment, sleep apnoea, non-alcoholic fatty liver (NAFL)
• In fact raised (> 40 IU) aspartate transaminases (AST) at admission is one of the strongest predictors of bad prognosis.  This observation is not only made in the context of (pre-existing) NAFLD, but may be an early indication of widespread organ damage. 

3. The relation between COVID-19, obesity and diabetes is further worked out in the next paper, with the following conclusion:

Both SARS-CoV-2 infection and obesity seem to share some common metabolic and inflammatory reaction pathways.

• On the one hand, obesity causes hyperglycemia via insulin resistance whereas SARS-CoV-2 may cause hyperglycemia as well (via mechanisms that are not elucidated yet).
• On the other hand, obesity represents a state of low grade inflammation, sharing many common molecules and pathways with those observed in SARS-CoV-2 infection.

There is a nice figure to illustrate the relationships

Selected metabolic pathways for obesity and SARS-CoV-2 infection; their common elements are shown in grey boxes. In obesity, resistance to leptin (along with resistin) leads to insulin resistance (both in the brain and in peripheral tissues) and eventually to hyperglycemia and T2DM.

Moreover, adipose tissue releases ATG, which, via ACE is converted to AT II and increases blood pressure.

SARS-CoV-2 attaches to cells via ACE2 and may provoke hyperglycemia (see text for more details);

FFA: free fatty acids, ATG: angiotensinogen, ACE: angiotensin converting enzyme, AT II: angiotensin II, AT1e7: angiotensin 1-7 (vasodilatory), NO: Nitric Oxide, T2DM: type 2 diabetes mellitus, ACE2: angiotensin converting enzyme 2,

*: is usually upregulated in subjects with hypertension on ACE-inhibitors and AT receptor blockers (ARB),

**hyperglycemia has been reported in patients with SARS-CoV-2 infection

4. The next review “COVID-19 and DM: An unholy interaction of two pandemics, a potential vicious circle is described:

• Compromised innate immunity, pro-inflammatory cytokine milieu, reduced expression of ACE2and use of renin-angiotensin-aldosterone system antagonists in people with diabetes mellitus contribute to poor prognosis in COVID-19.
• On the contrary, direct β-cell damage, cytokine-induced insulin resistance, hypokalemia and drugs used in the treatment of COVID-19 (like corticosteroids, lopinavir/ritonavir) can contribute to worsening of glucose control in people with diabetes mellitus.

5. With regard to type 1 diabetes (T1D),  there is little formally published information:

• A short report in  Diabetes Care on a multicenter study, a group of 64 T1D with COVID-like admissions is described: half of them turned out COVID(+).  As you can see in Table 1 there are not so many differences between both: most obvious is a hogh risk of keto-acidosis in the COVID (+) group. 
• A review on keto-acidosis in COVID-19 by Palermo shows that this complication is rather common and certainly not restricted to type 1.
• The good news is that in Flanders there is no indication of increased hospitalization for cOVID-19 in community-dwelling T1D
• A video by Prof Chantal Mathieu on diabetes care in times of COVID-19: https://www.facebook.com/intdiabetesfed/videos/2563478910558340

6. Marijana Tadic et al argue that the evidence for an independent effect of diabetes on morbidity and mortality is limited,n because of the many confoundiung factors (obesity, age, hypertension) etc.

7. Finally a research agenda set by Rubino et al in NEJM in order to better understand if/ how SARS-CoV-2 induces or facilitates diabetes.  To answer the following questions:

• How frequent is the phenomenon of new-onset diabetes during/ after COVID-19 , and is it classic type 1 or type 2 diabetes or a new type of diabetes?
• Do these patients remain at higher risk for diabetes or diabetic ketoacidosis?
• In patients with preexisting diabetes, does Covid-19 change the underlying pathophysiology and the natural history of the disease?