Some of Mary-Elizabeth Patti’s patients with diabetes are in a bind. Careful to practice social distancing, they tell her during telehealth visits they don’t feel safe exercising outdoors in their congested neighborhoods — though they know staying active and maintaining good blood sugar levels may be their best defense against severe Covid-19.
“I’m always happy when patients say, yes, I’m not going out, I’m wearing a mask, I’m doing as much as I can. But it makes it harder for people to meet their fitness goal, which is such a critical element of overall health and metabolic health,” said Patti, an adult endocrinologist at Joslin Diabetes Center in Boston. “It underscores the health inequity problem,” she added: “Their exposures may be increased due to living in a densely populated neighborhood with multigenerational families [and] more essential workers who cannot work from home.”
There are no easy answers to the coronavirus pandemic, but for people with diabetes, it’s dismayingly difficult to untangle the thicket of biological and socioeconomic factors that make them more likely to suffer severe illness and die should they catch the virus that causes Covid-19. That leaves prevention — controlling blood sugar through diet, exercise, monitoring, and medication — as the leading tactic to protect people, until a successful vaccine proven to work in people with diabetes, too, reaches a population bearing multiple burdens of chronic illness.
The numbers are alarming. A Lancet Diabetes & Endocrinology study mining 61 million medical records in the U.K. pinned the mortality rate at 30% for people with diabetes who are infected with the coronavirus. After accounting for potentially relevant risk factors such as social deprivation, ethnicity, and other chronic medical conditions, the risk of dying from Covid-19 was still almost three times higher for people with type 1 diabetes and almost twice as high for type 2, versus those without diabetes.
Data from the U.S. Centers for Disease Control and Prevention show more than three-quarters of people who died from Covid-19 had at least one preexisting condition. Overall, diabetes was noted as an underlying condition for approximately 4 in 10 patients. Among people younger than 65 who died from the infection, about half had diabetes.
Juliana Chan, director of the Hong Kong Institute of Diabetes and Obesity and leader of the U.K. study, said the pandemic has intertwined with and exposed two other widespread problems: diabetes and disparities triggered by social determinants of health.
“What we are seeing is nothing new, but it is really just on a massive and global scale,” she said in an interview. “I hope that there is something positive out of this, that people understand that we are hit by three epidemics.”
While urging prevention as the first and best course, doctors and scientists are testing hypotheses to understand the biology behind the collision of a new infectious disease with an old metabolic one. The exact molecular mechanisms make for an emerging story, and there is disagreement about why, as case reports from around the world suggest, some people develop type 1 diabetes after their coronavirus infection clears. But clinicians and scientists told STAT there is no question that unless people with diabetes have their glucose under control, Covid-19 poses much more danger to them than to other people.
In people with type 1 diabetes, the insulin-producing pancreatic islet cells have been destroyed, meaning they cannot process the glucose their bodies need for fuel and the sugar accumulates in the blood. In type 2 diabetes, people can’t make enough insulin to convert glucose into energy, or they grow insensitive to the insulin they do make.
Over a lifetime, problems with too much or too little glucose inflict widespread damage in the kidney, heart, and liver, as well as around nerves. Stroke, heart attack, kidney failure, eye disease, and limb amputations can be the legacy of poor glucose control. The linings of blood vessels throughout the body become so fragile they can’t ferry needed nutrients as well as they should. Inflammation rises and the immune system does not perform well. Obesity, which is more common in type 2 diabetes but can also occur in type 1, makes all these conditions worse.
“Once someone with diabetes or obesity became infected with Covid-19, then their outcomes were generally not as good,” said Daniel Drucker, of the Lunenfeld-Tanenbaum Research Institute at Mt. Sinai Hospital in Toronto. “They were more likely to be hospitalized, more likely to be intubated, more likely to have higher rates of death.”
People with obesity as a rule have lower cardiorespiratory fitness, meaning they can’t move as well due to poorer lung function, possibly severe sleep apnea, and blood vessel disease.
“All of these things are important for when you become ill. You need to be able to breathe. You need to have optimal circulatory function,” Drucker said. “When we develop obesity, we have excess energy storage and the presence of that fat is inflammatory. And so once we get coronavirus infection, we are less able to mount an appropriate immune response because our immune system is already being set off in an inappropriate manner by the presence of obesity.”
Some studies add support to the idea that it’s not just obesity, but also the downstream hypertension and other cardiovascular diseases that pose greater risk. Drucker said. “It’s those comorbidities that seem to be affecting the increased risk or poor outcomes.”
It isn’t clear at what point those comorbidities take their toll. Does the course of disease become severe because of those comorbidities, or is there a difference in the biology of early infection, which may lead to increased viral burden in patients with both uncontrolled glucose and obesity?
For years doctors, patients, and scientists have known from epidemiologic data that infections of any kind — viral, bacterial, or fungal — can do more harm to people with diabetes because their bodies do not process glucose as well during illness, their immune response is weaker, and their circulation is impaired.
Covid-19’s impact on people with diabetes fits that pattern. Janelle Ayres, a professor at the Salk institute in La Jolla, Calif., points to what diabetes and Covid-19 have in common.
“The organ systems that the virus targets are the same organ systems that are compromised in diabetic patients, so having both may have synergistic effects that push patients down a more severe disease trajectory,” she said. “This makes it incredibly difficult to parse out the cause and effect of what’s going on in these patients.”
People with diabetes tend to live in a chronic inflammatory state, setting them up for a more severe inflammatory response to Covid-19 that can culminate in a life-threatening cytokine storm. That immune overreaction is thought to harm some people more through organ damage than via the actual viral infection. But diabetes can also weaken how well the immune system fights viruses. People with type 2 diabetes also have more ACE2 receptors in many tissues, including those lining blood vessels, Ayres pointed out, opening many more doors to Covid-19 invasion. ACE2 is one receptor that the coronavirus’s spike protein uses to gain entry into cells.
There is only one target to control in hospitalized Covid-19 patients with diabetes, Drucker and others said: glucose.
“People who have really poorly controlled diabetes are more susceptible to more severe infection, whether it’s influenza or tuberculosis,” he said. “Elevated blood sugar directly impairs our immune function.”
Age and poor glucose control are the two major drivers of poor outcomes in Covid-19. Someone under 65, not obese, and whose glucose control is good is unlikely to have as much increased risk.
“It’s very difficult to reverse obesity or to meaningfully lose a sufficient amount of weight during the pandemic. It’s very difficult for me to take away your coronary artery disease — same thing with hypertension,” Drucker said. “But if you have poorly controlled diabetes, I can fix that in days to weeks if I had the resources.”
Not every person with diabetes and Covid-19 needs to be hospitalized, but if they do require that level of care, controlling — and monitoring — glucose levels are key. There aren’t any results from controlled clinical trials yet, Joslin’s Patti pointed out, but lowering glucose safely to as normal a range as possible is the goal she and other doctors pursue. That can be challenging in the hospital, where typically glucose levels are measured in drops of blood obtained from patients’ fingertips.
“You don’t want to ask nursing staff to go in repeatedly to be doing fingerstick glucoses for someone who’s severely ill and having to use more PPE,” Patti said. “So there’s more and more use of what’s called continuous glucose monitors, which allow frequent — every five minutes — remote monitoring of glucose levels from outside the room.”
Vaccines promise prevention in a shot (or two), but clinical trials will have to answer questions about how well they work in people with diabetes, given differences in immune function. There is some evidence in the scientific literature that flu vaccination is not quite as effective in older people with diabetes, or in people of any age with poorly controlled diabetes.
“Will the vaccines that are being developed [provide] equal immunity and equal protection to people with diabetes and obesity?” Drucker asked. ”When you have the added complication of a preexisting abnormal state of inflammation and immune response in people with diabetes and obesity who are not very healthy, that’s an additional unknown.”
Tight glucose control is number one, but healthy people with diabetes must also remain vigilant about masks and social distancing. That’s been more effective in Hong Kong than in Western countries, Chan said.
“Seventeen years ago, when Hong Kong and China were first hit by the SARS-1 virus, we already knew that people with diabetes were three times more likely to die,” she said. “That’s a painful memory for us. We have 100% compliance on masks now. … We never really had a lockdown.”
Even with such caution, and even in countries that offer citizens universal health care, disparities driving the social determinants of health persist, she said. Income will always divide those who are homeless, live in crowded conditions, or work in jobs that place them at risk, even if Covid-19 subsides. That makes prevention essential, especially for those who don’t have the luxury of protecting themselves.
“Currently a lot of the care is focused on acute care, not on educating patients, protecting them, supporting them so that they never come to the hospital,” she said about Covid-19.
“We must not forget. We have to learn from this.”