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Shortening the duration of dual-antiplatelet therapy (DAPT) and continuing with a P2Y12 inhibitor alone after percutaneous coronary intervention (PCI) was associated with a similar rate of ischemic events but with less bleeding than prolonged DAPT after 3 years of follow-up in the SMART-CHOICE trial.

“The current results of extended follow-up from the SMART-CHOICE trial support evidence of an aspirin dropping strategy with indefinite use of P2Y12 inhibitor after minimum use of DAPT in patients who underwent PCI,” the investigators, with lead author Ki Hong Choi, MD, division of cardiology, department of medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, conclude.

The 3-year results from the study were published online in JAMA Cardiology.

The authors explain that although dual therapy with aspirin and a P2Y12 inhibitor after PCI with a drug-eluting stent (DES) is crucial to reduce the risk of ischemic events, it raises concerns about increased risk of bleeding, and the antiplatelet strategy after PCI is currently shifting to reduce the duration of DAPT.

Several recent randomized studies have consistently shown that a short duration of DAPT (1-3 months) followed by P2Y12 inhibitor monotherapy had ischemia protection effects comparable with that of DAPT of longer duration, and it was associated with a significantly reduced risk of bleeding events in patients who underwent PCI, they note. However, these studies have so far reported only 1-year outcomes, and long-term results are not yet available.

The SMART-CHOICE trial compared two antiplatelet strategies – 3 months of DAPT followed by long-term P2Y12 inhibitor monotherapy (mainly with clopidogrel) or prolonged DAPT for 12 months or longer – in 2,993 patients who had undergone PCI with a drug-eluting stent. Results at 12 months showed a similar rate of ischemic events with both strategies but a lower rate of bleeding in the group that received shortened DAPT.

The SMART-CHOICE investigators now report the 3-year results showing similar outcomes.

At 3 years, the primary endpoint, a composite of all-cause death, myocardial infarction, or stroke, had occurred in 6.3% of the shortened DAPT group and 6.1% in the prolonged DAPT group, giving a hazard ratio of 1.06 (95% confidence interval, 0.79-1.44).

But in the shortened DAPT group, the risk of bleeding was reduced. Bleeding Academic Research Consortium (BARC) types 2-5 bleeding had occurred in 3.2% of the shortened DAPT group and in 8.2% of the prolonged DAPT group (hazard ratio, 0.39; 95% CI, 0.28-0.55). Major bleeding, BARC types 3-5, occurred in 1.2% of the shortened DAPT group and in 2.4% of the prolonged DAPT group (HR, 0.56; 95% CI 0.31-0.99).

The landmark analyses between 3 months and 3 years and per-protocol analyses showed consistent results.

The researchers point out that this is the first trial to report on the long-term safety and efficacy of P2Y12-inhibitor monotherapy as long-term maintenance therapy for stable patients treated with PCI.

“Especially considering that extended DAPT significantly reduced the risks of ischemic events compared with aspirin monotherapy in a couple of trials, comparison between P2Y12-inhibitor monotherapy and prolonged DAPT for recurrent ischemic events over a longer period beyond 1 year is of great importance,” they say.

They cite two other trials – HOST-EXAM and GLOBAL LEADERS – which have shown P2Y12-inhibitor monotherapy to be superior to aspirin monotherapy in preventing both ischemic and bleeding events during the long-term maintenance period after PCI.

“Combining the results of the current study, HOST-EXAM trial, and landmark analysis of the GLOBAL LEADERS trial, long-term P2Y12-inhibitor monotherapy after a minimum period of DAPT might be the most reliable option from among aspirin monotherapy, P2Y12 monotherapy, and extended DAPT for maintenance therapy after stabilizing patients who have undergone PCI with a current-generation DES,” they conclude.

They note that the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guidelines for coronary artery revascularization newly recommends a shorter course of DAPT followed by P2Y12 monotherapy as a class IIa indication. The recommendation is based on results of five large, randomized clinical trials, including SMART-CHOICE, TWILIGHT, STOPDAPT-2, TICO, and GLOBAL LEADERS.

“The current results of extended follow-up from the SMART-CHOICE trial support evidence of aspirin-dropping strategy with indefinite use of P2Y12 inhibitor after minimum use of DAPT in patients who underwent PCI,” they say.

They point out that two further trials, A-CLOSE in high-risk patients and SMART-CHOICE III, will be helpful to confirm these findings.
 

P2Y12-inhibitor monotherapy ‘attractive concept’

In an accompanying editor’s note, Ajay Kirtane, MD, Columbia University Irving Medical Center/New York–Presbyterian Hospital, New York, and Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai and the Cardiovascular Research Foundation, New York, note that current guidelines recommend 3-6 months of DAPT following PCI with current-generation drug-eluting stents in stable patients and 6-12 months or longer for those with acute coronary syndromes. For patients at higher risk of bleeding, even shorter DAPT durations can be considered on a case-by-case basis.

Historically, the component of DAPT subject to discontinuation decisions was the P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), but more recent trials have further explored whether discontinuation of the aspirin component of DAPT can mitigate bleeding while preserving anti-ischemic efficacy.

The editorialists explain that the concept of P2Y1-inhibitor monotherapy is attractive because it may optimize antiplatelet effects through a single agent that can avoid the gastrointestinal toxicity of aspirin as well as the increased bleeding that comes with combing multiple antithrombotic agents.

They suggest that the long-term results from the SMART-CHOICE trial “should lead clinicians to consider a strategy of monotherapy after a short period of DAPT as a viable one to mitigate bleeding risk,” although they also point out that SMART-CHOICE was underpowered to rigorously assess ischemic differences, so caution is warranted.

“For patients at greatest risk for recurrent ischemic events, the role of continued DAPT is always an option, but these data (and other consistent trials) give clinicians more options to pursue individualized treatment decisions,” they write.

“To some, the continually moving field of post-PCI antiplatelet therapy has provided too many choices, which can at times be dizzying. To us, every patient is different, and thoughtful evidence-based consideration is increasingly possible for many of our treatment decisions,” they conclude.

The SMART-CHOICE study was supported by unrestricted grants from the Korean Society of Interventional Cardiology, Abbott Vascular, Biotronik, and Boston Scientific.

A version of this article first appeared on Medscape.com.

Shortening the duration of dual-antiplatelet therapy (DAPT) and continuing with a P2Y12 inhibitor alone after percutaneous coronary intervention (PCI) was associated with a similar rate of ischemic events but with less bleeding than prolonged DAPT after 3 years of follow-up in the SMART-CHOICE trial.

“The current results of extended follow-up from the SMART-CHOICE trial support evidence of an aspirin dropping strategy with indefinite use of P2Y12 inhibitor after minimum use of DAPT in patients who underwent PCI,” the investigators, with lead author Ki Hong Choi, MD, division of cardiology, department of medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, conclude.

The 3-year results from the study were published online in JAMA Cardiology.

The authors explain that although dual therapy with aspirin and a P2Y12 inhibitor after PCI with a drug-eluting stent (DES) is crucial to reduce the risk of ischemic events, it raises concerns about increased risk of bleeding, and the antiplatelet strategy after PCI is currently shifting to reduce the duration of DAPT.

Several recent randomized studies have consistently shown that a short duration of DAPT (1-3 months) followed by P2Y12 inhibitor monotherapy had ischemia protection effects comparable with that of DAPT of longer duration, and it was associated with a significantly reduced risk of bleeding events in patients who underwent PCI, they note. However, these studies have so far reported only 1-year outcomes, and long-term results are not yet available.

The SMART-CHOICE trial compared two antiplatelet strategies – 3 months of DAPT followed by long-term P2Y12 inhibitor monotherapy (mainly with clopidogrel) or prolonged DAPT for 12 months or longer – in 2,993 patients who had undergone PCI with a drug-eluting stent. Results at 12 months showed a similar rate of ischemic events with both strategies but a lower rate of bleeding in the group that received shortened DAPT.

The SMART-CHOICE investigators now report the 3-year results showing similar outcomes.

At 3 years, the primary endpoint, a composite of all-cause death, myocardial infarction, or stroke, had occurred in 6.3% of the shortened DAPT group and 6.1% in the prolonged DAPT group, giving a hazard ratio of 1.06 (95% confidence interval, 0.79-1.44).

But in the shortened DAPT group, the risk of bleeding was reduced. Bleeding Academic Research Consortium (BARC) types 2-5 bleeding had occurred in 3.2% of the shortened DAPT group and in 8.2% of the prolonged DAPT group (hazard ratio, 0.39; 95% CI, 0.28-0.55). Major bleeding, BARC types 3-5, occurred in 1.2% of the shortened DAPT group and in 2.4% of the prolonged DAPT group (HR, 0.56; 95% CI 0.31-0.99).

The landmark analyses between 3 months and 3 years and per-protocol analyses showed consistent results.

The researchers point out that this is the first trial to report on the long-term safety and efficacy of P2Y12-inhibitor monotherapy as long-term maintenance therapy for stable patients treated with PCI.

“Especially considering that extended DAPT significantly reduced the risks of ischemic events compared with aspirin monotherapy in a couple of trials, comparison between P2Y12-inhibitor monotherapy and prolonged DAPT for recurrent ischemic events over a longer period beyond 1 year is of great importance,” they say.

They cite two other trials – HOST-EXAM and GLOBAL LEADERS – which have shown P2Y12-inhibitor monotherapy to be superior to aspirin monotherapy in preventing both ischemic and bleeding events during the long-term maintenance period after PCI.

“Combining the results of the current study, HOST-EXAM trial, and landmark analysis of the GLOBAL LEADERS trial, long-term P2Y12-inhibitor monotherapy after a minimum period of DAPT might be the most reliable option from among aspirin monotherapy, P2Y12 monotherapy, and extended DAPT for maintenance therapy after stabilizing patients who have undergone PCI with a current-generation DES,” they conclude.

They note that the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guidelines for coronary artery revascularization newly recommends a shorter course of DAPT followed by P2Y12 monotherapy as a class IIa indication. The recommendation is based on results of five large, randomized clinical trials, including SMART-CHOICE, TWILIGHT, STOPDAPT-2, TICO, and GLOBAL LEADERS.

“The current results of extended follow-up from the SMART-CHOICE trial support evidence of aspirin-dropping strategy with indefinite use of P2Y12 inhibitor after minimum use of DAPT in patients who underwent PCI,” they say.

They point out that two further trials, A-CLOSE in high-risk patients and SMART-CHOICE III, will be helpful to confirm these findings.
 

P2Y12-inhibitor monotherapy ‘attractive concept’

In an accompanying editor’s note, Ajay Kirtane, MD, Columbia University Irving Medical Center/New York–Presbyterian Hospital, New York, and Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai and the Cardiovascular Research Foundation, New York, note that current guidelines recommend 3-6 months of DAPT following PCI with current-generation drug-eluting stents in stable patients and 6-12 months or longer for those with acute coronary syndromes. For patients at higher risk of bleeding, even shorter DAPT durations can be considered on a case-by-case basis.

Historically, the component of DAPT subject to discontinuation decisions was the P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), but more recent trials have further explored whether discontinuation of the aspirin component of DAPT can mitigate bleeding while preserving anti-ischemic efficacy.

The editorialists explain that the concept of P2Y1-inhibitor monotherapy is attractive because it may optimize antiplatelet effects through a single agent that can avoid the gastrointestinal toxicity of aspirin as well as the increased bleeding that comes with combing multiple antithrombotic agents.

They suggest that the long-term results from the SMART-CHOICE trial “should lead clinicians to consider a strategy of monotherapy after a short period of DAPT as a viable one to mitigate bleeding risk,” although they also point out that SMART-CHOICE was underpowered to rigorously assess ischemic differences, so caution is warranted.

“For patients at greatest risk for recurrent ischemic events, the role of continued DAPT is always an option, but these data (and other consistent trials) give clinicians more options to pursue individualized treatment decisions,” they write.

“To some, the continually moving field of post-PCI antiplatelet therapy has provided too many choices, which can at times be dizzying. To us, every patient is different, and thoughtful evidence-based consideration is increasingly possible for many of our treatment decisions,” they conclude.

The SMART-CHOICE study was supported by unrestricted grants from the Korean Society of Interventional Cardiology, Abbott Vascular, Biotronik, and Boston Scientific.

A version of this article first appeared on Medscape.com.

Shortening the duration of dual-antiplatelet therapy (DAPT) and continuing with a P2Y12 inhibitor alone after percutaneous coronary intervention (PCI) was associated with a similar rate of ischemic events but with less bleeding than prolonged DAPT after 3 years of follow-up in the SMART-CHOICE trial.

“The current results of extended follow-up from the SMART-CHOICE trial support evidence of an aspirin dropping strategy with indefinite use of P2Y12 inhibitor after minimum use of DAPT in patients who underwent PCI,” the investigators, with lead author Ki Hong Choi, MD, division of cardiology, department of medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, conclude.

The 3-year results from the study were published online in JAMA Cardiology.

The authors explain that although dual therapy with aspirin and a P2Y12 inhibitor after PCI with a drug-eluting stent (DES) is crucial to reduce the risk of ischemic events, it raises concerns about increased risk of bleeding, and the antiplatelet strategy after PCI is currently shifting to reduce the duration of DAPT.

Several recent randomized studies have consistently shown that a short duration of DAPT (1-3 months) followed by P2Y12 inhibitor monotherapy had ischemia protection effects comparable with that of DAPT of longer duration, and it was associated with a significantly reduced risk of bleeding events in patients who underwent PCI, they note. However, these studies have so far reported only 1-year outcomes, and long-term results are not yet available.

The SMART-CHOICE trial compared two antiplatelet strategies – 3 months of DAPT followed by long-term P2Y12 inhibitor monotherapy (mainly with clopidogrel) or prolonged DAPT for 12 months or longer – in 2,993 patients who had undergone PCI with a drug-eluting stent. Results at 12 months showed a similar rate of ischemic events with both strategies but a lower rate of bleeding in the group that received shortened DAPT.

The SMART-CHOICE investigators now report the 3-year results showing similar outcomes.

At 3 years, the primary endpoint, a composite of all-cause death, myocardial infarction, or stroke, had occurred in 6.3% of the shortened DAPT group and 6.1% in the prolonged DAPT group, giving a hazard ratio of 1.06 (95% confidence interval, 0.79-1.44).

But in the shortened DAPT group, the risk of bleeding was reduced. Bleeding Academic Research Consortium (BARC) types 2-5 bleeding had occurred in 3.2% of the shortened DAPT group and in 8.2% of the prolonged DAPT group (hazard ratio, 0.39; 95% CI, 0.28-0.55). Major bleeding, BARC types 3-5, occurred in 1.2% of the shortened DAPT group and in 2.4% of the prolonged DAPT group (HR, 0.56; 95% CI 0.31-0.99).

The landmark analyses between 3 months and 3 years and per-protocol analyses showed consistent results.

The researchers point out that this is the first trial to report on the long-term safety and efficacy of P2Y12-inhibitor monotherapy as long-term maintenance therapy for stable patients treated with PCI.

“Especially considering that extended DAPT significantly reduced the risks of ischemic events compared with aspirin monotherapy in a couple of trials, comparison between P2Y12-inhibitor monotherapy and prolonged DAPT for recurrent ischemic events over a longer period beyond 1 year is of great importance,” they say.

They cite two other trials – HOST-EXAM and GLOBAL LEADERS – which have shown P2Y12-inhibitor monotherapy to be superior to aspirin monotherapy in preventing both ischemic and bleeding events during the long-term maintenance period after PCI.

“Combining the results of the current study, HOST-EXAM trial, and landmark analysis of the GLOBAL LEADERS trial, long-term P2Y12-inhibitor monotherapy after a minimum period of DAPT might be the most reliable option from among aspirin monotherapy, P2Y12 monotherapy, and extended DAPT for maintenance therapy after stabilizing patients who have undergone PCI with a current-generation DES,” they conclude.

They note that the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guidelines for coronary artery revascularization newly recommends a shorter course of DAPT followed by P2Y12 monotherapy as a class IIa indication. The recommendation is based on results of five large, randomized clinical trials, including SMART-CHOICE, TWILIGHT, STOPDAPT-2, TICO, and GLOBAL LEADERS.

“The current results of extended follow-up from the SMART-CHOICE trial support evidence of aspirin-dropping strategy with indefinite use of P2Y12 inhibitor after minimum use of DAPT in patients who underwent PCI,” they say.

They point out that two further trials, A-CLOSE in high-risk patients and SMART-CHOICE III, will be helpful to confirm these findings.
 

P2Y12-inhibitor monotherapy ‘attractive concept’

In an accompanying editor’s note, Ajay Kirtane, MD, Columbia University Irving Medical Center/New York–Presbyterian Hospital, New York, and Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai and the Cardiovascular Research Foundation, New York, note that current guidelines recommend 3-6 months of DAPT following PCI with current-generation drug-eluting stents in stable patients and 6-12 months or longer for those with acute coronary syndromes. For patients at higher risk of bleeding, even shorter DAPT durations can be considered on a case-by-case basis.

Historically, the component of DAPT subject to discontinuation decisions was the P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), but more recent trials have further explored whether discontinuation of the aspirin component of DAPT can mitigate bleeding while preserving anti-ischemic efficacy.

The editorialists explain that the concept of P2Y1-inhibitor monotherapy is attractive because it may optimize antiplatelet effects through a single agent that can avoid the gastrointestinal toxicity of aspirin as well as the increased bleeding that comes with combing multiple antithrombotic agents.

They suggest that the long-term results from the SMART-CHOICE trial “should lead clinicians to consider a strategy of monotherapy after a short period of DAPT as a viable one to mitigate bleeding risk,” although they also point out that SMART-CHOICE was underpowered to rigorously assess ischemic differences, so caution is warranted.

“For patients at greatest risk for recurrent ischemic events, the role of continued DAPT is always an option, but these data (and other consistent trials) give clinicians more options to pursue individualized treatment decisions,” they write.

“To some, the continually moving field of post-PCI antiplatelet therapy has provided too many choices, which can at times be dizzying. To us, every patient is different, and thoughtful evidence-based consideration is increasingly possible for many of our treatment decisions,” they conclude.

The SMART-CHOICE study was supported by unrestricted grants from the Korean Society of Interventional Cardiology, Abbott Vascular, Biotronik, and Boston Scientific.

A version of this article first appeared on Medscape.com.

STOCKHOLM – Recent study results confirm that two agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class can significantly cut the incidence of adverse cardiovascular events in patients with heart failure with reduced ejection fraction (HFpEF), a disease especially common in people with type 2 diabetes, obesity, or both.

And findings from secondary analyses of the studies – including one reported at the annual meeting of the European Association for the Study of Diabetes – show that these SGLT2 inhibitors work as well for cutting incident adverse events (cardiovascular death or worsening heart failure) in patients with HFpEF and diabetes as they do for people with normal blood glucose levels.

But delivering treatment with these proven agents, dapagliflozin (Farxiga) and empagliflozin (Jardiance), first requires diagnosis of HFpEF, a task that clinicians have historically fallen short in accomplishing.

When in 2021, results from the EMPEROR-Preserved trial with empagliflozin and when in September 2022 results from the DELIVER trial with dapagliflozin established the efficacy of these two SGLT2 inhibitors as the first treatments proven to benefit patients with HFpEF, they also raised the stakes for clinicians to be much more diligent and systematic in evaluating people at high risk for developing HFpEF because of having type 2 diabetes or obesity, two of the most potent risk factors for this form of heart failure.
 

‘Vigilance ... needs to increase’

“Vigilance for HFpEF needs to increase because we can now help these patients,” declared Lars H. Lund, MD, PhD, speaking at the meeting. “Type 2 diabetes dramatically increases the incidence of HFpEF,” and the mechanisms by which it does this are “especially amenable to treatment with SGLT2 inhibitors,” said Dr. Lund, a cardiologist and heart failure specialist at the Karolinska Institute, Stockholm.

HFpEF has a history of going undetected in people with type 2 diabetes, an ironic situation given its high incidence as well as the elevated rate of adverse cardiovascular events when heart failure occurs in patients with type 2 diabetes compared with patients who do not have diabetes.

The key, say experts, is for clinicians to maintain a high index of suspicion for signs and symptoms of heart failure in people with type 2 diabetes and to regularly assess them, starting with just a few simple questions that probe for the presence of dyspnea, exertional fatigue, or both, an approach not widely employed up to now.

Clinicians who care for people with type 2 diabetes must become “alert to thinking about heart failure and alert to asking questions about signs and symptoms” that flag the presence of HFpEF, advised Naveed Sattar, MBChB, PhD, a professor of metabolic medicine at the University of Glasgow.

Soon, medical groups will issue guidelines for appropriate assessment for the presence of HFpEF in people with type 2 diabetes, Dr. Sattar predicted in an interview.
 

A need to probe

“You can’t simply ask patients with type 2 diabetes whether they have shortness of breath or exertional fatigue and stop there,” because often their first response will be no.

“Commonly, patients will initially say they have no dyspnea, but when you probe further, you find symptoms,” noted Mikhail N. Kosiborod, MD, codirector of Saint Luke’s Cardiometabolic Center of Excellence in Kansas City, Mo.

These people are often sedentary, so they frequently don’t experience shortness of breath at baseline, Dr. Kosiborod said in an interview. In some cases, they may limit their activity because of their exertional intolerance.

Once a person’s suggestive symptoms become known, the next step is to measure the serum level of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker considered to be a generally reliable signal of existing heart failure when elevated.

Any value above 125 pg/mL is suggestive of prevalent heart failure and should lead to the next diagnostic step of echocardiography, Dr. Sattar said.

Elevated NT-proBNP has such good positive predictive value for identifying heart failure that it is tempting to use it broadly in people with type 2 diabetes. A 2022 consensus report from the American Diabetes Association says that “measurement of a natriuretic peptide [such as NT-proBNP] or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest HF [heart failure] stages and implement strategies to prevent transition to symptomatic HF.”
 

Test costs require targeting

But because of the relatively high current price for an NT-proBNP test, the cost-benefit ratio for widespread annual testing of all people with type 2 diabetes would be poor, some experts caution.

“Screening everyone may not be the right answer. Hundreds of millions of people worldwide” have type 2 diabetes. “You first need to target evaluation to people with symptoms,” advised Dr. Kosiborod.

He also warned that a low NT-proBNP level does not always rule out HFpEF, especially among people with type 2 diabetes who also have overweight or obesity, because NT-proBNP levels can be “artificially low” in people with obesity.

Other potential aids to diagnosis are assessment scores that researchers have developed, such as the H2FPEF score, which relies on variables that include age, obesity, and the presence of atrial fibrillation and hypertension.

However, this score also requires an echocardiography examination, another test that would have a questionable cost-benefit ratio if performed widely for patients with type 2 diabetes without targeting, Dr. Kosiborod said.
 

SGLT2 inhibitors benefit HFpEF regardless of glucose levels

A prespecified analysis of the DELIVER results that divided the study cohort on the basis of their glycemic status proved the efficacy of the SGLT2 inhibitor dapagliflozin for patients with HFpEF regardless of whether or not they had type 2 diabetes, prediabetes, or were normoglycemic at entry into the study, Silvio E. Inzucchi, MD, reported at the EASD meeting.

Mitchel L. Zoler/MDedge News

Treatment with dapagliflozin cut the incidence of the trial’s primary outcome of cardiovascular death or worsening heart failure by a significant 18% relative to placebo among all enrolled patients.

The new analysis reported by Dr. Inzucchi showed that treatment was associated with a 23% relative risk reduction among those with normoglycemia, a 13% reduction among those with prediabetes, and a 19% reduction among those with type 2 diabetes, with no signal of a significant difference among the three subgroups.

“There was no statistical interaction between categorical glycemic subgrouping and dapagliflozin’s treatment effect,” concluded Dr. Inzucchi, director of the Yale Medicine Diabetes Center, New Haven, Conn.

He also reported that, among the 6,259 people in the trial with HFpEF, 50% had diabetes, 31% had prediabetes, and a scant 19% had normoglycemia. The finding highlights once again the high prevalence of dysglycemia among people with HFpEF.

Previously, a prespecified secondary analysis of data from the EMPEROR-Preserved trial yielded similar findings for empagliflozin that showed the agent’s efficacy for people with HFpEF across the range of glucose levels.

The DELIVER trial was funded by AstraZeneca, the company that markets dapagliflozin (Farxiga). The EMPEROR-Preserved trial was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that jointly market empagliflozin (Jardiance). Dr. Lund has been a consultant to AstraZeneca and Boehringer Ingelheim and to numerous other companies, and he is a stockholder in AnaCardio. Dr. Sattar has been a consultant to and has received research support from AstraZeneca and Boehringer Ingelheim, and he has been a consultant with numerous companies. Dr. Kosiborod has been a consultant to and has received research funding from AstraZeneca and Boehringer Ingelheim and has been a consultant to Eli Lilly and numerous other companies. Dr. Inzucchi has been a consultant to, given talks on behalf of, or served on trial committees for Abbott, AstraZeneca, Boehringer Ingelheim, Esperion, Lexicon, Merck, Novo Nordisk, Pfizer, and vTv Therapetics.

A version of this article first appeared on Medscape.com.

STOCKHOLM – Recent study results confirm that two agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class can significantly cut the incidence of adverse cardiovascular events in patients with heart failure with reduced ejection fraction (HFpEF), a disease especially common in people with type 2 diabetes, obesity, or both.

And findings from secondary analyses of the studies – including one reported at the annual meeting of the European Association for the Study of Diabetes – show that these SGLT2 inhibitors work as well for cutting incident adverse events (cardiovascular death or worsening heart failure) in patients with HFpEF and diabetes as they do for people with normal blood glucose levels.

But delivering treatment with these proven agents, dapagliflozin (Farxiga) and empagliflozin (Jardiance), first requires diagnosis of HFpEF, a task that clinicians have historically fallen short in accomplishing.

When in 2021, results from the EMPEROR-Preserved trial with empagliflozin and when in September 2022 results from the DELIVER trial with dapagliflozin established the efficacy of these two SGLT2 inhibitors as the first treatments proven to benefit patients with HFpEF, they also raised the stakes for clinicians to be much more diligent and systematic in evaluating people at high risk for developing HFpEF because of having type 2 diabetes or obesity, two of the most potent risk factors for this form of heart failure.
 

‘Vigilance ... needs to increase’

“Vigilance for HFpEF needs to increase because we can now help these patients,” declared Lars H. Lund, MD, PhD, speaking at the meeting. “Type 2 diabetes dramatically increases the incidence of HFpEF,” and the mechanisms by which it does this are “especially amenable to treatment with SGLT2 inhibitors,” said Dr. Lund, a cardiologist and heart failure specialist at the Karolinska Institute, Stockholm.

HFpEF has a history of going undetected in people with type 2 diabetes, an ironic situation given its high incidence as well as the elevated rate of adverse cardiovascular events when heart failure occurs in patients with type 2 diabetes compared with patients who do not have diabetes.

The key, say experts, is for clinicians to maintain a high index of suspicion for signs and symptoms of heart failure in people with type 2 diabetes and to regularly assess them, starting with just a few simple questions that probe for the presence of dyspnea, exertional fatigue, or both, an approach not widely employed up to now.

Clinicians who care for people with type 2 diabetes must become “alert to thinking about heart failure and alert to asking questions about signs and symptoms” that flag the presence of HFpEF, advised Naveed Sattar, MBChB, PhD, a professor of metabolic medicine at the University of Glasgow.

Soon, medical groups will issue guidelines for appropriate assessment for the presence of HFpEF in people with type 2 diabetes, Dr. Sattar predicted in an interview.
 

A need to probe

“You can’t simply ask patients with type 2 diabetes whether they have shortness of breath or exertional fatigue and stop there,” because often their first response will be no.

“Commonly, patients will initially say they have no dyspnea, but when you probe further, you find symptoms,” noted Mikhail N. Kosiborod, MD, codirector of Saint Luke’s Cardiometabolic Center of Excellence in Kansas City, Mo.

These people are often sedentary, so they frequently don’t experience shortness of breath at baseline, Dr. Kosiborod said in an interview. In some cases, they may limit their activity because of their exertional intolerance.

Once a person’s suggestive symptoms become known, the next step is to measure the serum level of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker considered to be a generally reliable signal of existing heart failure when elevated.

Any value above 125 pg/mL is suggestive of prevalent heart failure and should lead to the next diagnostic step of echocardiography, Dr. Sattar said.

Elevated NT-proBNP has such good positive predictive value for identifying heart failure that it is tempting to use it broadly in people with type 2 diabetes. A 2022 consensus report from the American Diabetes Association says that “measurement of a natriuretic peptide [such as NT-proBNP] or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest HF [heart failure] stages and implement strategies to prevent transition to symptomatic HF.”
 

Test costs require targeting

But because of the relatively high current price for an NT-proBNP test, the cost-benefit ratio for widespread annual testing of all people with type 2 diabetes would be poor, some experts caution.

“Screening everyone may not be the right answer. Hundreds of millions of people worldwide” have type 2 diabetes. “You first need to target evaluation to people with symptoms,” advised Dr. Kosiborod.

He also warned that a low NT-proBNP level does not always rule out HFpEF, especially among people with type 2 diabetes who also have overweight or obesity, because NT-proBNP levels can be “artificially low” in people with obesity.

Other potential aids to diagnosis are assessment scores that researchers have developed, such as the H2FPEF score, which relies on variables that include age, obesity, and the presence of atrial fibrillation and hypertension.

However, this score also requires an echocardiography examination, another test that would have a questionable cost-benefit ratio if performed widely for patients with type 2 diabetes without targeting, Dr. Kosiborod said.
 

SGLT2 inhibitors benefit HFpEF regardless of glucose levels

A prespecified analysis of the DELIVER results that divided the study cohort on the basis of their glycemic status proved the efficacy of the SGLT2 inhibitor dapagliflozin for patients with HFpEF regardless of whether or not they had type 2 diabetes, prediabetes, or were normoglycemic at entry into the study, Silvio E. Inzucchi, MD, reported at the EASD meeting.

Mitchel L. Zoler/MDedge News

Treatment with dapagliflozin cut the incidence of the trial’s primary outcome of cardiovascular death or worsening heart failure by a significant 18% relative to placebo among all enrolled patients.

The new analysis reported by Dr. Inzucchi showed that treatment was associated with a 23% relative risk reduction among those with normoglycemia, a 13% reduction among those with prediabetes, and a 19% reduction among those with type 2 diabetes, with no signal of a significant difference among the three subgroups.

“There was no statistical interaction between categorical glycemic subgrouping and dapagliflozin’s treatment effect,” concluded Dr. Inzucchi, director of the Yale Medicine Diabetes Center, New Haven, Conn.

He also reported that, among the 6,259 people in the trial with HFpEF, 50% had diabetes, 31% had prediabetes, and a scant 19% had normoglycemia. The finding highlights once again the high prevalence of dysglycemia among people with HFpEF.

Previously, a prespecified secondary analysis of data from the EMPEROR-Preserved trial yielded similar findings for empagliflozin that showed the agent’s efficacy for people with HFpEF across the range of glucose levels.

The DELIVER trial was funded by AstraZeneca, the company that markets dapagliflozin (Farxiga). The EMPEROR-Preserved trial was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that jointly market empagliflozin (Jardiance). Dr. Lund has been a consultant to AstraZeneca and Boehringer Ingelheim and to numerous other companies, and he is a stockholder in AnaCardio. Dr. Sattar has been a consultant to and has received research support from AstraZeneca and Boehringer Ingelheim, and he has been a consultant with numerous companies. Dr. Kosiborod has been a consultant to and has received research funding from AstraZeneca and Boehringer Ingelheim and has been a consultant to Eli Lilly and numerous other companies. Dr. Inzucchi has been a consultant to, given talks on behalf of, or served on trial committees for Abbott, AstraZeneca, Boehringer Ingelheim, Esperion, Lexicon, Merck, Novo Nordisk, Pfizer, and vTv Therapetics.

A version of this article first appeared on Medscape.com.

STOCKHOLM – Recent study results confirm that two agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class can significantly cut the incidence of adverse cardiovascular events in patients with heart failure with reduced ejection fraction (HFpEF), a disease especially common in people with type 2 diabetes, obesity, or both.

And findings from secondary analyses of the studies – including one reported at the annual meeting of the European Association for the Study of Diabetes – show that these SGLT2 inhibitors work as well for cutting incident adverse events (cardiovascular death or worsening heart failure) in patients with HFpEF and diabetes as they do for people with normal blood glucose levels.

But delivering treatment with these proven agents, dapagliflozin (Farxiga) and empagliflozin (Jardiance), first requires diagnosis of HFpEF, a task that clinicians have historically fallen short in accomplishing.

When in 2021, results from the EMPEROR-Preserved trial with empagliflozin and when in September 2022 results from the DELIVER trial with dapagliflozin established the efficacy of these two SGLT2 inhibitors as the first treatments proven to benefit patients with HFpEF, they also raised the stakes for clinicians to be much more diligent and systematic in evaluating people at high risk for developing HFpEF because of having type 2 diabetes or obesity, two of the most potent risk factors for this form of heart failure.
 

‘Vigilance ... needs to increase’

“Vigilance for HFpEF needs to increase because we can now help these patients,” declared Lars H. Lund, MD, PhD, speaking at the meeting. “Type 2 diabetes dramatically increases the incidence of HFpEF,” and the mechanisms by which it does this are “especially amenable to treatment with SGLT2 inhibitors,” said Dr. Lund, a cardiologist and heart failure specialist at the Karolinska Institute, Stockholm.

HFpEF has a history of going undetected in people with type 2 diabetes, an ironic situation given its high incidence as well as the elevated rate of adverse cardiovascular events when heart failure occurs in patients with type 2 diabetes compared with patients who do not have diabetes.

The key, say experts, is for clinicians to maintain a high index of suspicion for signs and symptoms of heart failure in people with type 2 diabetes and to regularly assess them, starting with just a few simple questions that probe for the presence of dyspnea, exertional fatigue, or both, an approach not widely employed up to now.

Clinicians who care for people with type 2 diabetes must become “alert to thinking about heart failure and alert to asking questions about signs and symptoms” that flag the presence of HFpEF, advised Naveed Sattar, MBChB, PhD, a professor of metabolic medicine at the University of Glasgow.

Soon, medical groups will issue guidelines for appropriate assessment for the presence of HFpEF in people with type 2 diabetes, Dr. Sattar predicted in an interview.
 

A need to probe

“You can’t simply ask patients with type 2 diabetes whether they have shortness of breath or exertional fatigue and stop there,” because often their first response will be no.

“Commonly, patients will initially say they have no dyspnea, but when you probe further, you find symptoms,” noted Mikhail N. Kosiborod, MD, codirector of Saint Luke’s Cardiometabolic Center of Excellence in Kansas City, Mo.

These people are often sedentary, so they frequently don’t experience shortness of breath at baseline, Dr. Kosiborod said in an interview. In some cases, they may limit their activity because of their exertional intolerance.

Once a person’s suggestive symptoms become known, the next step is to measure the serum level of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker considered to be a generally reliable signal of existing heart failure when elevated.

Any value above 125 pg/mL is suggestive of prevalent heart failure and should lead to the next diagnostic step of echocardiography, Dr. Sattar said.

Elevated NT-proBNP has such good positive predictive value for identifying heart failure that it is tempting to use it broadly in people with type 2 diabetes. A 2022 consensus report from the American Diabetes Association says that “measurement of a natriuretic peptide [such as NT-proBNP] or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest HF [heart failure] stages and implement strategies to prevent transition to symptomatic HF.”
 

Test costs require targeting

But because of the relatively high current price for an NT-proBNP test, the cost-benefit ratio for widespread annual testing of all people with type 2 diabetes would be poor, some experts caution.

“Screening everyone may not be the right answer. Hundreds of millions of people worldwide” have type 2 diabetes. “You first need to target evaluation to people with symptoms,” advised Dr. Kosiborod.

He also warned that a low NT-proBNP level does not always rule out HFpEF, especially among people with type 2 diabetes who also have overweight or obesity, because NT-proBNP levels can be “artificially low” in people with obesity.

Other potential aids to diagnosis are assessment scores that researchers have developed, such as the H2FPEF score, which relies on variables that include age, obesity, and the presence of atrial fibrillation and hypertension.

However, this score also requires an echocardiography examination, another test that would have a questionable cost-benefit ratio if performed widely for patients with type 2 diabetes without targeting, Dr. Kosiborod said.
 

SGLT2 inhibitors benefit HFpEF regardless of glucose levels

A prespecified analysis of the DELIVER results that divided the study cohort on the basis of their glycemic status proved the efficacy of the SGLT2 inhibitor dapagliflozin for patients with HFpEF regardless of whether or not they had type 2 diabetes, prediabetes, or were normoglycemic at entry into the study, Silvio E. Inzucchi, MD, reported at the EASD meeting.

Mitchel L. Zoler/MDedge News

Treatment with dapagliflozin cut the incidence of the trial’s primary outcome of cardiovascular death or worsening heart failure by a significant 18% relative to placebo among all enrolled patients.

The new analysis reported by Dr. Inzucchi showed that treatment was associated with a 23% relative risk reduction among those with normoglycemia, a 13% reduction among those with prediabetes, and a 19% reduction among those with type 2 diabetes, with no signal of a significant difference among the three subgroups.

“There was no statistical interaction between categorical glycemic subgrouping and dapagliflozin’s treatment effect,” concluded Dr. Inzucchi, director of the Yale Medicine Diabetes Center, New Haven, Conn.

He also reported that, among the 6,259 people in the trial with HFpEF, 50% had diabetes, 31% had prediabetes, and a scant 19% had normoglycemia. The finding highlights once again the high prevalence of dysglycemia among people with HFpEF.

Previously, a prespecified secondary analysis of data from the EMPEROR-Preserved trial yielded similar findings for empagliflozin that showed the agent’s efficacy for people with HFpEF across the range of glucose levels.

The DELIVER trial was funded by AstraZeneca, the company that markets dapagliflozin (Farxiga). The EMPEROR-Preserved trial was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that jointly market empagliflozin (Jardiance). Dr. Lund has been a consultant to AstraZeneca and Boehringer Ingelheim and to numerous other companies, and he is a stockholder in AnaCardio. Dr. Sattar has been a consultant to and has received research support from AstraZeneca and Boehringer Ingelheim, and he has been a consultant with numerous companies. Dr. Kosiborod has been a consultant to and has received research funding from AstraZeneca and Boehringer Ingelheim and has been a consultant to Eli Lilly and numerous other companies. Dr. Inzucchi has been a consultant to, given talks on behalf of, or served on trial committees for Abbott, AstraZeneca, Boehringer Ingelheim, Esperion, Lexicon, Merck, Novo Nordisk, Pfizer, and vTv Therapetics.

A version of this article first appeared on Medscape.com.

In 2002, two landmark trials found that targeted temperature management (TTM) after out-of-hospital cardiac arrest led to improvements in neurologic outcomes. The larger of the two trials found a reduction in mortality. Such treatment benefits are hard to come by in critical care in general and in out-of-hospital cardiac arrest in particular. With the therapeutic overconfidence typical of our profession, my institution embraced TTM quickly and completely soon after these trials were published. Remember, this was “back in the day” when sepsis management included drotrecogin alfa, Cortrosyn stim tests, tight glucose control (90-120 mg/dL), and horrible over-resuscitation via the early goal-directed therapy paradigm.

If you’ve been practicing critical care medicine for more than a few years, you already know where I’m going. Most of the interventions in the preceding paragraph were adopted but discarded before 2010. Though TTM has managed to stand the test of time, our confidence in its benefit has waned since 2002. Hypothermia – temperature management with a goal of 32-36° C – has been struggling to stay relevant ever since the publication of the TTM randomized controlled trial (RCT) in 2013. Then came the HYPERION trial, which brought the 32-36° C target back from the dead (pun definitely intended) in 2019. This is critical care medicine: Today’s life-saving intervention proves harmful tomorrow, but withholding it may constitute malpractice a few months down the road.

So where are we now? Good question. I’ve had seasoned neurointensivists insist that 33° C remains the standard of care and others who’ve endorsed normothermia. So much for finding an answer via my more specialized colleagues.

Let’s go to the guidelines then. Prompted largely by HYPERION, a temperature target of 32-36° C was endorsed in 2020 and 2021. Then came publication of the TTM2 trial, the largest temperature management RCT to date, which found no benefit to targeting 33° C. A network meta-analysis published in 2021 reached a similar conclusion. A recently released update by the same international guideline group now recommends targeting normothermia (< 37.7° C) and avoiding fever, and it specifically says that there is insufficient evidence to support a 32-36° C target. Okay, everyone tracking all that?

Lest I sound overly catty and nihilistic, I see all this in a positive light. Huge credit goes to the critical care medicine academic community for putting together so many RCTs. The scientific reality is that it takes “a lotta” sample size to clarify the effects of an intervention. Throw in the inevitable bevy of confounders (in- vs. out-of-hospital cardiac arrest, resuscitation time, initial rhythm, and so on), and you get a feel for the work required to understand a treatment’s true effects.

Advances in guideline science and the hard, often unpaid work of panels are also important. The guideline panel I’ve been citing came out for aggressive temperature control (32-36° C) a few months before the TTM2 RCT was published. In the past, they updated their recommendations every 5 years, but this time, they were out with a new manuscript that incorporated TTM2 in less than a year. If you’ve been involved at any level with producing guidelines, you can appreciate this achievement. Assuming that aggressive hypothermia is truly harmful, waiting 5 years to incorporate TTM2 could have led to significant morbidity.

I do take issue with you early adopters, though. Given the litany of failed therapies that have shown initial promise, and the well-documented human tendency to underestimate the impact of sample size, your rapid implementation of major interventions is puzzling. One might think you’d learned your lessons after seeing drotrecogin alfa, Cortrosyn stim tests, tight glucose control, early goal-directed therapy, and aggressive TTM come and go. Your recent enthusiasm for vitamin C after publication of a single before-after study suggests that you haven’t.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center, Bethesda, Md. He has received a research grant from Fisher-Paykel.

A version of this article first appeared on Medscape.com.

In 2002, two landmark trials found that targeted temperature management (TTM) after out-of-hospital cardiac arrest led to improvements in neurologic outcomes. The larger of the two trials found a reduction in mortality. Such treatment benefits are hard to come by in critical care in general and in out-of-hospital cardiac arrest in particular. With the therapeutic overconfidence typical of our profession, my institution embraced TTM quickly and completely soon after these trials were published. Remember, this was “back in the day” when sepsis management included drotrecogin alfa, Cortrosyn stim tests, tight glucose control (90-120 mg/dL), and horrible over-resuscitation via the early goal-directed therapy paradigm.

If you’ve been practicing critical care medicine for more than a few years, you already know where I’m going. Most of the interventions in the preceding paragraph were adopted but discarded before 2010. Though TTM has managed to stand the test of time, our confidence in its benefit has waned since 2002. Hypothermia – temperature management with a goal of 32-36° C – has been struggling to stay relevant ever since the publication of the TTM randomized controlled trial (RCT) in 2013. Then came the HYPERION trial, which brought the 32-36° C target back from the dead (pun definitely intended) in 2019. This is critical care medicine: Today’s life-saving intervention proves harmful tomorrow, but withholding it may constitute malpractice a few months down the road.

So where are we now? Good question. I’ve had seasoned neurointensivists insist that 33° C remains the standard of care and others who’ve endorsed normothermia. So much for finding an answer via my more specialized colleagues.

Let’s go to the guidelines then. Prompted largely by HYPERION, a temperature target of 32-36° C was endorsed in 2020 and 2021. Then came publication of the TTM2 trial, the largest temperature management RCT to date, which found no benefit to targeting 33° C. A network meta-analysis published in 2021 reached a similar conclusion. A recently released update by the same international guideline group now recommends targeting normothermia (< 37.7° C) and avoiding fever, and it specifically says that there is insufficient evidence to support a 32-36° C target. Okay, everyone tracking all that?

Lest I sound overly catty and nihilistic, I see all this in a positive light. Huge credit goes to the critical care medicine academic community for putting together so many RCTs. The scientific reality is that it takes “a lotta” sample size to clarify the effects of an intervention. Throw in the inevitable bevy of confounders (in- vs. out-of-hospital cardiac arrest, resuscitation time, initial rhythm, and so on), and you get a feel for the work required to understand a treatment’s true effects.

Advances in guideline science and the hard, often unpaid work of panels are also important. The guideline panel I’ve been citing came out for aggressive temperature control (32-36° C) a few months before the TTM2 RCT was published. In the past, they updated their recommendations every 5 years, but this time, they were out with a new manuscript that incorporated TTM2 in less than a year. If you’ve been involved at any level with producing guidelines, you can appreciate this achievement. Assuming that aggressive hypothermia is truly harmful, waiting 5 years to incorporate TTM2 could have led to significant morbidity.

I do take issue with you early adopters, though. Given the litany of failed therapies that have shown initial promise, and the well-documented human tendency to underestimate the impact of sample size, your rapid implementation of major interventions is puzzling. One might think you’d learned your lessons after seeing drotrecogin alfa, Cortrosyn stim tests, tight glucose control, early goal-directed therapy, and aggressive TTM come and go. Your recent enthusiasm for vitamin C after publication of a single before-after study suggests that you haven’t.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center, Bethesda, Md. He has received a research grant from Fisher-Paykel.

A version of this article first appeared on Medscape.com.

In 2002, two landmark trials found that targeted temperature management (TTM) after out-of-hospital cardiac arrest led to improvements in neurologic outcomes. The larger of the two trials found a reduction in mortality. Such treatment benefits are hard to come by in critical care in general and in out-of-hospital cardiac arrest in particular. With the therapeutic overconfidence typical of our profession, my institution embraced TTM quickly and completely soon after these trials were published. Remember, this was “back in the day” when sepsis management included drotrecogin alfa, Cortrosyn stim tests, tight glucose control (90-120 mg/dL), and horrible over-resuscitation via the early goal-directed therapy paradigm.

If you’ve been practicing critical care medicine for more than a few years, you already know where I’m going. Most of the interventions in the preceding paragraph were adopted but discarded before 2010. Though TTM has managed to stand the test of time, our confidence in its benefit has waned since 2002. Hypothermia – temperature management with a goal of 32-36° C – has been struggling to stay relevant ever since the publication of the TTM randomized controlled trial (RCT) in 2013. Then came the HYPERION trial, which brought the 32-36° C target back from the dead (pun definitely intended) in 2019. This is critical care medicine: Today’s life-saving intervention proves harmful tomorrow, but withholding it may constitute malpractice a few months down the road.

So where are we now? Good question. I’ve had seasoned neurointensivists insist that 33° C remains the standard of care and others who’ve endorsed normothermia. So much for finding an answer via my more specialized colleagues.

Let’s go to the guidelines then. Prompted largely by HYPERION, a temperature target of 32-36° C was endorsed in 2020 and 2021. Then came publication of the TTM2 trial, the largest temperature management RCT to date, which found no benefit to targeting 33° C. A network meta-analysis published in 2021 reached a similar conclusion. A recently released update by the same international guideline group now recommends targeting normothermia (< 37.7° C) and avoiding fever, and it specifically says that there is insufficient evidence to support a 32-36° C target. Okay, everyone tracking all that?

Lest I sound overly catty and nihilistic, I see all this in a positive light. Huge credit goes to the critical care medicine academic community for putting together so many RCTs. The scientific reality is that it takes “a lotta” sample size to clarify the effects of an intervention. Throw in the inevitable bevy of confounders (in- vs. out-of-hospital cardiac arrest, resuscitation time, initial rhythm, and so on), and you get a feel for the work required to understand a treatment’s true effects.

Advances in guideline science and the hard, often unpaid work of panels are also important. The guideline panel I’ve been citing came out for aggressive temperature control (32-36° C) a few months before the TTM2 RCT was published. In the past, they updated their recommendations every 5 years, but this time, they were out with a new manuscript that incorporated TTM2 in less than a year. If you’ve been involved at any level with producing guidelines, you can appreciate this achievement. Assuming that aggressive hypothermia is truly harmful, waiting 5 years to incorporate TTM2 could have led to significant morbidity.

I do take issue with you early adopters, though. Given the litany of failed therapies that have shown initial promise, and the well-documented human tendency to underestimate the impact of sample size, your rapid implementation of major interventions is puzzling. One might think you’d learned your lessons after seeing drotrecogin alfa, Cortrosyn stim tests, tight glucose control, early goal-directed therapy, and aggressive TTM come and go. Your recent enthusiasm for vitamin C after publication of a single before-after study suggests that you haven’t.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center, Bethesda, Md. He has received a research grant from Fisher-Paykel.

A version of this article first appeared on Medscape.com.

STOCKHOLM – The investigational once-weekly insulin icodec (Novo Nordisk) significantly reduces A1c without increasing hypoglycemia in people with type 2 diabetes, the first phase 3 data of such an insulin formulation suggest. The data are from one of six trials in the company’s ONWARDS program.

“Once-weekly insulin may redefine diabetes management,” enthused Athena Philis-Tsimikas, MD, who presented the findings at a session during the European Association for the Study of Diabetes (EASD) 2022 Annual Meeting, which also included a summary of previously reported top-line data from other ONWARDS trials as well as phase 2 data for Lilly›s investigational once-weekly Basal Insulin Fc (BIF).

Phase 2 data for icodec were published in 2020 in the New England Journal of Medicine and in 2021 in Diabetes Care, as reported by this news organization.

The capacity for reducing the number of basal insulin injections from at least 365 to just 52 per year means that once-weekly insulin “has the potential to facilitate insulin initiation and improve treatment adherence and persistence in diabetes,” noted Dr. Philis-Tsimikas, corporate vice president of Scripps Whittier Diabetes Institute, San Diego.

Asked to comment, independent diabetes industry consultant Charles Alexander, MD, told this news organization that the new data from ONWARDS 2 of patients switching from daily to once-weekly basal insulin were reassuring with regard to hypoglycemia, at least for people with type 2 diabetes.

“For type 2, I think there’s enough data now to feel comfortable that it’s going to be good, especially for people who are on once-weekly [glucagon-like peptide-1 (GLP-1) agonists].”

However, for type 1 diabetes, the company reported top-line ONWARDS 6 data earlier this year, in which icodec was associated with significantly increased rates of hypoglycemia compared with daily degludec. “In type 1, even the basal needs are [often] changing. That kind of person would want to stay away from once-weekly insulin,” Dr. Alexander said.

And he noted, for any patient who adjusts their insulin dose frequently, “obviously, you’re not going to be able to do that with a once-weekly.”
 

Similar A1c reduction as daily basal without increased hypoglycemia

In ONWARDS 2, 526 adults with type 2 diabetes were randomized to switch from their current once- or twice-daily basal insulin to either once-weekly icodec or once-daily insulin degludec (Tresiba) for 26 weeks. The study was open-label, with a treat-to-glucose target of 80-130 mg/dL design.

Participants had A1c levels of 7.0%-10.0% and were also taking stable doses of other noninsulin glucose-lowering medications. Over 80% were taking metformin, a third were taking an SGLT2 inhibitor, and about a quarter each were taking a GLP-1 agonist or DPP-4 inhibitor. Those medications were continued, but sulfonylureas were discontinued in the 22% taking those at baseline.

The basal insulin used at baseline was glargine U100 for 42%, degludec for 28%, and glargine U300 for 16%, “so, a very typical presentation of patients we see in our practices today,” Dr. Philis-Tsimikas noted.

The primary endpoint, change in A1c from baseline to week 26, dropped from 8.17% to 7.20% with icodec and from 8.10% to 7.42% with degludec. The estimated treatment difference of –0.22 percentage points met the margins for both noninferiority (P < .0001) and superiority (P = .0028). Those taking icodec were significantly more likely to achieve an A1c under 7% compared with degludec, at 40.3% versus 26.5% (P = .0019).

Continuous glucose monitoring parameters during weeks 22-26 showed time in glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) was 63.1% for icodec and 59.5% for degludec, which was not significantly different, Dr. Philis-Tsimikas reported.

Body weight increased by 1.4 kg (3 lb) with icodec but dropped slightly by 0.30 kg with degludec, which was significantly different (P < .001).

When asked about the body weight results, Dr. Alexander said: “It’s really hard to say. We know that insulin generally causes weight gain. A 1.4-kg weight gain over 6 months isn’t really surprising. Why there wasn’t with degludec, I don’t know.”

There was just one episode of severe hypoglycemia (requiring assistance) in the trial in the degludec group. Rates of combined severe or clinically significant hypoglycemic events (glucose < 54 mg/dL / < 3.0 mmol/L) per patient-year exposed were 0.73 for icodec versus 0.27 for degludec, which was not significantly different (P = .0782). Similar findings were seen for nocturnal hypoglycemia.

Significantly more patients achieved an A1c under 7% without significant hypoglycemia with icodec than degludec, at 36.7% versus 26.8% (P = .0223). Other adverse events were equivalent between the two groups, Dr. Philis-Tsimikas reported.

Scores on the diabetes treatment satisfaction questionnaire, which addresses convenience, flexibility, satisfaction, and willingness to recommend treatment to others, were significantly higher for icodec than degludec, at 4.22 versus 2.96 (P = .0036).

“For me, this is one of the most important outcomes,” she commented.  
 

Benefit in type 2 diabetes, potential concern in type 1 diabetes

Top-line results from ONWARDS 1, a phase 3a 78-week trial in 984 drug-naive people with type 2 diabetes and ONWARDS 6, a 52-week trial in 583 people with type 1 diabetes, were presented earlier this year at the American Diabetes Association 81st Scientific Sessions.

In ONWARDS 1, icodec achieved noninferiority to daily insulin glargine, reducing A1c by 1.55 versus 1.35 percentage points, with superior time in range and no significant differences in hypoglycemia rates.

However, in ONWARDS 6, while noninferiority in A1c lowering compared with daily degludec was achieved, with reductions of 0.47 versus 0.51 percentage points from a baseline A1c of 7.6%, there was a significantly greater rate of severe or clinically significant hypoglycemia with icodec, at 19.93 versus 10.37 events per patient-year with degludec.

Dr. Philis-Tsimikas has reported performing research and serving as an advisor on behalf of her employer for Abbott, Bayer, Dexcom, Eli Lilly, Medtronic, Merck, Novo Nordisk, and Sanofi. All reimbursements go to her employer. Dr. Alexander has reported being a nonpaid advisor for diaTribe and a consultant for Kinexum.

A version of this article first appeared on Medscape.com.

STOCKHOLM – The investigational once-weekly insulin icodec (Novo Nordisk) significantly reduces A1c without increasing hypoglycemia in people with type 2 diabetes, the first phase 3 data of such an insulin formulation suggest. The data are from one of six trials in the company’s ONWARDS program.

“Once-weekly insulin may redefine diabetes management,” enthused Athena Philis-Tsimikas, MD, who presented the findings at a session during the European Association for the Study of Diabetes (EASD) 2022 Annual Meeting, which also included a summary of previously reported top-line data from other ONWARDS trials as well as phase 2 data for Lilly›s investigational once-weekly Basal Insulin Fc (BIF).

Phase 2 data for icodec were published in 2020 in the New England Journal of Medicine and in 2021 in Diabetes Care, as reported by this news organization.

The capacity for reducing the number of basal insulin injections from at least 365 to just 52 per year means that once-weekly insulin “has the potential to facilitate insulin initiation and improve treatment adherence and persistence in diabetes,” noted Dr. Philis-Tsimikas, corporate vice president of Scripps Whittier Diabetes Institute, San Diego.

Asked to comment, independent diabetes industry consultant Charles Alexander, MD, told this news organization that the new data from ONWARDS 2 of patients switching from daily to once-weekly basal insulin were reassuring with regard to hypoglycemia, at least for people with type 2 diabetes.

“For type 2, I think there’s enough data now to feel comfortable that it’s going to be good, especially for people who are on once-weekly [glucagon-like peptide-1 (GLP-1) agonists].”

However, for type 1 diabetes, the company reported top-line ONWARDS 6 data earlier this year, in which icodec was associated with significantly increased rates of hypoglycemia compared with daily degludec. “In type 1, even the basal needs are [often] changing. That kind of person would want to stay away from once-weekly insulin,” Dr. Alexander said.

And he noted, for any patient who adjusts their insulin dose frequently, “obviously, you’re not going to be able to do that with a once-weekly.”
 

Similar A1c reduction as daily basal without increased hypoglycemia

In ONWARDS 2, 526 adults with type 2 diabetes were randomized to switch from their current once- or twice-daily basal insulin to either once-weekly icodec or once-daily insulin degludec (Tresiba) for 26 weeks. The study was open-label, with a treat-to-glucose target of 80-130 mg/dL design.

Participants had A1c levels of 7.0%-10.0% and were also taking stable doses of other noninsulin glucose-lowering medications. Over 80% were taking metformin, a third were taking an SGLT2 inhibitor, and about a quarter each were taking a GLP-1 agonist or DPP-4 inhibitor. Those medications were continued, but sulfonylureas were discontinued in the 22% taking those at baseline.

The basal insulin used at baseline was glargine U100 for 42%, degludec for 28%, and glargine U300 for 16%, “so, a very typical presentation of patients we see in our practices today,” Dr. Philis-Tsimikas noted.

The primary endpoint, change in A1c from baseline to week 26, dropped from 8.17% to 7.20% with icodec and from 8.10% to 7.42% with degludec. The estimated treatment difference of –0.22 percentage points met the margins for both noninferiority (P < .0001) and superiority (P = .0028). Those taking icodec were significantly more likely to achieve an A1c under 7% compared with degludec, at 40.3% versus 26.5% (P = .0019).

Continuous glucose monitoring parameters during weeks 22-26 showed time in glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) was 63.1% for icodec and 59.5% for degludec, which was not significantly different, Dr. Philis-Tsimikas reported.

Body weight increased by 1.4 kg (3 lb) with icodec but dropped slightly by 0.30 kg with degludec, which was significantly different (P < .001).

When asked about the body weight results, Dr. Alexander said: “It’s really hard to say. We know that insulin generally causes weight gain. A 1.4-kg weight gain over 6 months isn’t really surprising. Why there wasn’t with degludec, I don’t know.”

There was just one episode of severe hypoglycemia (requiring assistance) in the trial in the degludec group. Rates of combined severe or clinically significant hypoglycemic events (glucose < 54 mg/dL / < 3.0 mmol/L) per patient-year exposed were 0.73 for icodec versus 0.27 for degludec, which was not significantly different (P = .0782). Similar findings were seen for nocturnal hypoglycemia.

Significantly more patients achieved an A1c under 7% without significant hypoglycemia with icodec than degludec, at 36.7% versus 26.8% (P = .0223). Other adverse events were equivalent between the two groups, Dr. Philis-Tsimikas reported.

Scores on the diabetes treatment satisfaction questionnaire, which addresses convenience, flexibility, satisfaction, and willingness to recommend treatment to others, were significantly higher for icodec than degludec, at 4.22 versus 2.96 (P = .0036).

“For me, this is one of the most important outcomes,” she commented.  
 

Benefit in type 2 diabetes, potential concern in type 1 diabetes

Top-line results from ONWARDS 1, a phase 3a 78-week trial in 984 drug-naive people with type 2 diabetes and ONWARDS 6, a 52-week trial in 583 people with type 1 diabetes, were presented earlier this year at the American Diabetes Association 81st Scientific Sessions.

In ONWARDS 1, icodec achieved noninferiority to daily insulin glargine, reducing A1c by 1.55 versus 1.35 percentage points, with superior time in range and no significant differences in hypoglycemia rates.

However, in ONWARDS 6, while noninferiority in A1c lowering compared with daily degludec was achieved, with reductions of 0.47 versus 0.51 percentage points from a baseline A1c of 7.6%, there was a significantly greater rate of severe or clinically significant hypoglycemia with icodec, at 19.93 versus 10.37 events per patient-year with degludec.

Dr. Philis-Tsimikas has reported performing research and serving as an advisor on behalf of her employer for Abbott, Bayer, Dexcom, Eli Lilly, Medtronic, Merck, Novo Nordisk, and Sanofi. All reimbursements go to her employer. Dr. Alexander has reported being a nonpaid advisor for diaTribe and a consultant for Kinexum.

A version of this article first appeared on Medscape.com.

STOCKHOLM – The investigational once-weekly insulin icodec (Novo Nordisk) significantly reduces A1c without increasing hypoglycemia in people with type 2 diabetes, the first phase 3 data of such an insulin formulation suggest. The data are from one of six trials in the company’s ONWARDS program.

“Once-weekly insulin may redefine diabetes management,” enthused Athena Philis-Tsimikas, MD, who presented the findings at a session during the European Association for the Study of Diabetes (EASD) 2022 Annual Meeting, which also included a summary of previously reported top-line data from other ONWARDS trials as well as phase 2 data for Lilly›s investigational once-weekly Basal Insulin Fc (BIF).

Phase 2 data for icodec were published in 2020 in the New England Journal of Medicine and in 2021 in Diabetes Care, as reported by this news organization.

The capacity for reducing the number of basal insulin injections from at least 365 to just 52 per year means that once-weekly insulin “has the potential to facilitate insulin initiation and improve treatment adherence and persistence in diabetes,” noted Dr. Philis-Tsimikas, corporate vice president of Scripps Whittier Diabetes Institute, San Diego.

Asked to comment, independent diabetes industry consultant Charles Alexander, MD, told this news organization that the new data from ONWARDS 2 of patients switching from daily to once-weekly basal insulin were reassuring with regard to hypoglycemia, at least for people with type 2 diabetes.

“For type 2, I think there’s enough data now to feel comfortable that it’s going to be good, especially for people who are on once-weekly [glucagon-like peptide-1 (GLP-1) agonists].”

However, for type 1 diabetes, the company reported top-line ONWARDS 6 data earlier this year, in which icodec was associated with significantly increased rates of hypoglycemia compared with daily degludec. “In type 1, even the basal needs are [often] changing. That kind of person would want to stay away from once-weekly insulin,” Dr. Alexander said.

And he noted, for any patient who adjusts their insulin dose frequently, “obviously, you’re not going to be able to do that with a once-weekly.”
 

Similar A1c reduction as daily basal without increased hypoglycemia

In ONWARDS 2, 526 adults with type 2 diabetes were randomized to switch from their current once- or twice-daily basal insulin to either once-weekly icodec or once-daily insulin degludec (Tresiba) for 26 weeks. The study was open-label, with a treat-to-glucose target of 80-130 mg/dL design.

Participants had A1c levels of 7.0%-10.0% and were also taking stable doses of other noninsulin glucose-lowering medications. Over 80% were taking metformin, a third were taking an SGLT2 inhibitor, and about a quarter each were taking a GLP-1 agonist or DPP-4 inhibitor. Those medications were continued, but sulfonylureas were discontinued in the 22% taking those at baseline.

The basal insulin used at baseline was glargine U100 for 42%, degludec for 28%, and glargine U300 for 16%, “so, a very typical presentation of patients we see in our practices today,” Dr. Philis-Tsimikas noted.

The primary endpoint, change in A1c from baseline to week 26, dropped from 8.17% to 7.20% with icodec and from 8.10% to 7.42% with degludec. The estimated treatment difference of –0.22 percentage points met the margins for both noninferiority (P < .0001) and superiority (P = .0028). Those taking icodec were significantly more likely to achieve an A1c under 7% compared with degludec, at 40.3% versus 26.5% (P = .0019).

Continuous glucose monitoring parameters during weeks 22-26 showed time in glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) was 63.1% for icodec and 59.5% for degludec, which was not significantly different, Dr. Philis-Tsimikas reported.

Body weight increased by 1.4 kg (3 lb) with icodec but dropped slightly by 0.30 kg with degludec, which was significantly different (P < .001).

When asked about the body weight results, Dr. Alexander said: “It’s really hard to say. We know that insulin generally causes weight gain. A 1.4-kg weight gain over 6 months isn’t really surprising. Why there wasn’t with degludec, I don’t know.”

There was just one episode of severe hypoglycemia (requiring assistance) in the trial in the degludec group. Rates of combined severe or clinically significant hypoglycemic events (glucose < 54 mg/dL / < 3.0 mmol/L) per patient-year exposed were 0.73 for icodec versus 0.27 for degludec, which was not significantly different (P = .0782). Similar findings were seen for nocturnal hypoglycemia.

Significantly more patients achieved an A1c under 7% without significant hypoglycemia with icodec than degludec, at 36.7% versus 26.8% (P = .0223). Other adverse events were equivalent between the two groups, Dr. Philis-Tsimikas reported.

Scores on the diabetes treatment satisfaction questionnaire, which addresses convenience, flexibility, satisfaction, and willingness to recommend treatment to others, were significantly higher for icodec than degludec, at 4.22 versus 2.96 (P = .0036).

“For me, this is one of the most important outcomes,” she commented.  
 

Benefit in type 2 diabetes, potential concern in type 1 diabetes

Top-line results from ONWARDS 1, a phase 3a 78-week trial in 984 drug-naive people with type 2 diabetes and ONWARDS 6, a 52-week trial in 583 people with type 1 diabetes, were presented earlier this year at the American Diabetes Association 81st Scientific Sessions.

In ONWARDS 1, icodec achieved noninferiority to daily insulin glargine, reducing A1c by 1.55 versus 1.35 percentage points, with superior time in range and no significant differences in hypoglycemia rates.

However, in ONWARDS 6, while noninferiority in A1c lowering compared with daily degludec was achieved, with reductions of 0.47 versus 0.51 percentage points from a baseline A1c of 7.6%, there was a significantly greater rate of severe or clinically significant hypoglycemia with icodec, at 19.93 versus 10.37 events per patient-year with degludec.

Dr. Philis-Tsimikas has reported performing research and serving as an advisor on behalf of her employer for Abbott, Bayer, Dexcom, Eli Lilly, Medtronic, Merck, Novo Nordisk, and Sanofi. All reimbursements go to her employer. Dr. Alexander has reported being a nonpaid advisor for diaTribe and a consultant for Kinexum.

A version of this article first appeared on Medscape.com.

Ezetimibe given in combination with rosuvastatin has a beneficial effect on liver fat in people with nonalcoholic fatty liver disease (NAFLD), according results of a randomized, active-controlled trial.

The findings, which come from the investigator-initiated ESSENTIAL trial, are likely to add to the debate over whether or not the lipid-lowering combination could be of benefit beyond its effects in the blood.

Dr_Microbe/Getty Images

“We used magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF], which is highly reliable method of assessing hepatic steatosis,” Youngjoon Kim, PhD, one of the study investigators, said at the annual meeting of the European Association for the Study of Diabetes in Barcelona.

“It enables accurate, repeatable and reproducible quantitative assessment of liver fat over the entire liver,” observed Dr. Kim, who works at Severance Hospital, part of Yonsei University in Seoul.

He reported that there was a significant 5.8% decrease in liver fat following 24 weeks’ treatment with ezetimibe and rosuvastatin comparing baseline with end of treatment MRI-PDFF values; a drop that was significant (18.2% vs. 12.3%, P < .001).

Rosuvastatin monotherapy also reduced liver fat from 15.0% at baseline to 12.4% after 24 weeks; this drop of 2.6% was also significant (P = .003).

This gave an absolute mean difference between the two study arms of 3.2% (P = .02).
 

Rationale for the ESSENTIAL study

Dr. Kim observed during his presentation that NAFLD is burgeoning problem around the world. Ezetimibe plus rosuvastatin was a combination treatment already used widely in clinical practice, and there had been some suggestion that ezetimibe might have an effect on liver fat.

“Although the effect of ezetimibe on hepatic steatosis is still controversial, ezetimibe has been reported to reduce visceral fat and improve insulin resistance in several studies” Dr. Kim said.

“Recently, our group reported that the use of ezetimibe affects autophagy of hepatocytes and the NLRP3 [NOD-like receptors containing pyrin domain 3] inflammasome,” he said.

Moreover, he added, “ezetimibe improved NASH [nonalcoholic steatohepatitis] in an animal model. However, the effects of ezetimibe have not been clearly shown in a human study.”

Dr. Kim also acknowledged a prior randomized control trial that had looked at the role of ezetimibe in 50 patients with NASH, but had not shown a benefit for the drug over placebo in terms of liver fat reduction.
 

Addressing the Hawthorne effect

“The size of the effect by that might actually be more modest due to the Hawthorne effect,” said session chair Onno Holleboom, MD, PhD, of Amsterdam UMC in the Netherlands.

“What we observe in the large clinical trials is an enormous Hawthorne effect – participating in a NAFLD trial makes people live healthier because they have health checks,” he said.

“That’s a major problem for showing efficacy for the intervention arm,” he added, but of course the open design meant that the trial only had intervention arms; “there was no placebo arm.”
 

A randomized, active-controlled, clinician-initiated trial

The main objective of the ESSENTIAL trial was therefore to take another look at the potential effect of ezetimibe on hepatic steatosis and doing so in the setting of statin therapy.

In all, 70 patients with NAFLD that had been confirmed via ultrasound were recruited into the prospective, single center, phase 4 trial. Participants were randomized 1:1 to received either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.

Change in liver fat was measured via MRI-PDFF, taking the average values in each of nine liver segments. Magnetic resonance elastography (MRE) was also used to measure liver fibrosis, although results did not show any differences either from baseline to end of treatment values in either group or when the two treatment groups were compared.

Dr. Kim reported that both treatment with the ezetimibe-rosuvastatin combination and rosuvastatin monotherapy reduced parameters that might be associated with a negative outcome in NAFLD, such as body mass index and waist circumference, triglycerides, and LDL cholesterol. There was also a reduction in C-reactive protein levels in the blood, and interleulin-18. There was no change in liver enzymes.

Several subgroup analyses were performed indicating that “individuals with higher BMI, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to ezetimibe treatment,” Dr. Kim said.

“These data indicate that ezetimibe plus rosuvastatin is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia,” he concluded.

The results of the ESSENTIAL study have been published in BMC Medicine.

The study was funded by the Yuhan Corporation. Dr. Kim had no conflicts of interest to report. Dr. Holleboom was not involved in the study and had no conflicts of interest.

Ezetimibe given in combination with rosuvastatin has a beneficial effect on liver fat in people with nonalcoholic fatty liver disease (NAFLD), according results of a randomized, active-controlled trial.

The findings, which come from the investigator-initiated ESSENTIAL trial, are likely to add to the debate over whether or not the lipid-lowering combination could be of benefit beyond its effects in the blood.

Dr_Microbe/Getty Images

“We used magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF], which is highly reliable method of assessing hepatic steatosis,” Youngjoon Kim, PhD, one of the study investigators, said at the annual meeting of the European Association for the Study of Diabetes in Barcelona.

“It enables accurate, repeatable and reproducible quantitative assessment of liver fat over the entire liver,” observed Dr. Kim, who works at Severance Hospital, part of Yonsei University in Seoul.

He reported that there was a significant 5.8% decrease in liver fat following 24 weeks’ treatment with ezetimibe and rosuvastatin comparing baseline with end of treatment MRI-PDFF values; a drop that was significant (18.2% vs. 12.3%, P < .001).

Rosuvastatin monotherapy also reduced liver fat from 15.0% at baseline to 12.4% after 24 weeks; this drop of 2.6% was also significant (P = .003).

This gave an absolute mean difference between the two study arms of 3.2% (P = .02).
 

Rationale for the ESSENTIAL study

Dr. Kim observed during his presentation that NAFLD is burgeoning problem around the world. Ezetimibe plus rosuvastatin was a combination treatment already used widely in clinical practice, and there had been some suggestion that ezetimibe might have an effect on liver fat.

“Although the effect of ezetimibe on hepatic steatosis is still controversial, ezetimibe has been reported to reduce visceral fat and improve insulin resistance in several studies” Dr. Kim said.

“Recently, our group reported that the use of ezetimibe affects autophagy of hepatocytes and the NLRP3 [NOD-like receptors containing pyrin domain 3] inflammasome,” he said.

Moreover, he added, “ezetimibe improved NASH [nonalcoholic steatohepatitis] in an animal model. However, the effects of ezetimibe have not been clearly shown in a human study.”

Dr. Kim also acknowledged a prior randomized control trial that had looked at the role of ezetimibe in 50 patients with NASH, but had not shown a benefit for the drug over placebo in terms of liver fat reduction.
 

Addressing the Hawthorne effect

“The size of the effect by that might actually be more modest due to the Hawthorne effect,” said session chair Onno Holleboom, MD, PhD, of Amsterdam UMC in the Netherlands.

“What we observe in the large clinical trials is an enormous Hawthorne effect – participating in a NAFLD trial makes people live healthier because they have health checks,” he said.

“That’s a major problem for showing efficacy for the intervention arm,” he added, but of course the open design meant that the trial only had intervention arms; “there was no placebo arm.”
 

A randomized, active-controlled, clinician-initiated trial

The main objective of the ESSENTIAL trial was therefore to take another look at the potential effect of ezetimibe on hepatic steatosis and doing so in the setting of statin therapy.

In all, 70 patients with NAFLD that had been confirmed via ultrasound were recruited into the prospective, single center, phase 4 trial. Participants were randomized 1:1 to received either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.

Change in liver fat was measured via MRI-PDFF, taking the average values in each of nine liver segments. Magnetic resonance elastography (MRE) was also used to measure liver fibrosis, although results did not show any differences either from baseline to end of treatment values in either group or when the two treatment groups were compared.

Dr. Kim reported that both treatment with the ezetimibe-rosuvastatin combination and rosuvastatin monotherapy reduced parameters that might be associated with a negative outcome in NAFLD, such as body mass index and waist circumference, triglycerides, and LDL cholesterol. There was also a reduction in C-reactive protein levels in the blood, and interleulin-18. There was no change in liver enzymes.

Several subgroup analyses were performed indicating that “individuals with higher BMI, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to ezetimibe treatment,” Dr. Kim said.

“These data indicate that ezetimibe plus rosuvastatin is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia,” he concluded.

The results of the ESSENTIAL study have been published in BMC Medicine.

The study was funded by the Yuhan Corporation. Dr. Kim had no conflicts of interest to report. Dr. Holleboom was not involved in the study and had no conflicts of interest.

Ezetimibe given in combination with rosuvastatin has a beneficial effect on liver fat in people with nonalcoholic fatty liver disease (NAFLD), according results of a randomized, active-controlled trial.

The findings, which come from the investigator-initiated ESSENTIAL trial, are likely to add to the debate over whether or not the lipid-lowering combination could be of benefit beyond its effects in the blood.

Dr_Microbe/Getty Images

“We used magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF], which is highly reliable method of assessing hepatic steatosis,” Youngjoon Kim, PhD, one of the study investigators, said at the annual meeting of the European Association for the Study of Diabetes in Barcelona.

“It enables accurate, repeatable and reproducible quantitative assessment of liver fat over the entire liver,” observed Dr. Kim, who works at Severance Hospital, part of Yonsei University in Seoul.

He reported that there was a significant 5.8% decrease in liver fat following 24 weeks’ treatment with ezetimibe and rosuvastatin comparing baseline with end of treatment MRI-PDFF values; a drop that was significant (18.2% vs. 12.3%, P < .001).

Rosuvastatin monotherapy also reduced liver fat from 15.0% at baseline to 12.4% after 24 weeks; this drop of 2.6% was also significant (P = .003).

This gave an absolute mean difference between the two study arms of 3.2% (P = .02).
 

Rationale for the ESSENTIAL study

Dr. Kim observed during his presentation that NAFLD is burgeoning problem around the world. Ezetimibe plus rosuvastatin was a combination treatment already used widely in clinical practice, and there had been some suggestion that ezetimibe might have an effect on liver fat.

“Although the effect of ezetimibe on hepatic steatosis is still controversial, ezetimibe has been reported to reduce visceral fat and improve insulin resistance in several studies” Dr. Kim said.

“Recently, our group reported that the use of ezetimibe affects autophagy of hepatocytes and the NLRP3 [NOD-like receptors containing pyrin domain 3] inflammasome,” he said.

Moreover, he added, “ezetimibe improved NASH [nonalcoholic steatohepatitis] in an animal model. However, the effects of ezetimibe have not been clearly shown in a human study.”

Dr. Kim also acknowledged a prior randomized control trial that had looked at the role of ezetimibe in 50 patients with NASH, but had not shown a benefit for the drug over placebo in terms of liver fat reduction.
 

Addressing the Hawthorne effect

“The size of the effect by that might actually be more modest due to the Hawthorne effect,” said session chair Onno Holleboom, MD, PhD, of Amsterdam UMC in the Netherlands.

“What we observe in the large clinical trials is an enormous Hawthorne effect – participating in a NAFLD trial makes people live healthier because they have health checks,” he said.

“That’s a major problem for showing efficacy for the intervention arm,” he added, but of course the open design meant that the trial only had intervention arms; “there was no placebo arm.”
 

A randomized, active-controlled, clinician-initiated trial

The main objective of the ESSENTIAL trial was therefore to take another look at the potential effect of ezetimibe on hepatic steatosis and doing so in the setting of statin therapy.

In all, 70 patients with NAFLD that had been confirmed via ultrasound were recruited into the prospective, single center, phase 4 trial. Participants were randomized 1:1 to received either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.

Change in liver fat was measured via MRI-PDFF, taking the average values in each of nine liver segments. Magnetic resonance elastography (MRE) was also used to measure liver fibrosis, although results did not show any differences either from baseline to end of treatment values in either group or when the two treatment groups were compared.

Dr. Kim reported that both treatment with the ezetimibe-rosuvastatin combination and rosuvastatin monotherapy reduced parameters that might be associated with a negative outcome in NAFLD, such as body mass index and waist circumference, triglycerides, and LDL cholesterol. There was also a reduction in C-reactive protein levels in the blood, and interleulin-18. There was no change in liver enzymes.

Several subgroup analyses were performed indicating that “individuals with higher BMI, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to ezetimibe treatment,” Dr. Kim said.

“These data indicate that ezetimibe plus rosuvastatin is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia,” he concluded.

The results of the ESSENTIAL study have been published in BMC Medicine.

The study was funded by the Yuhan Corporation. Dr. Kim had no conflicts of interest to report. Dr. Holleboom was not involved in the study and had no conflicts of interest.

STOCKHOLM – It remains inconclusive whether SARS-CoV-2 infection predisposes children and adolescents to a higher risk of type 1 diabetes. Data from two new studies and a recently published research letter add to the growing body of knowledge on the subject, but still can’t draw any definitive conclusions.

The latest results from a Norwegian and a Scottish study both examine incidence of type 1 diabetes in young people with a history of SARS-CoV-2 infection and were reported at the annual meeting of the European Association for the Study of Diabetes.

A 60% increased risk for type 1 diabetes at least 31 days after SARS-CoV-2 infection (adjusted hazard ratio, 1.63) was found in the Norwegian study, while in contrast, the Scottish study only found an increased risk in the first few months of the pandemic, in 2020, but importantly, no association over a much longer time period (March 2020–November 2021).

In a comment on Twitter on the two studies presented at EASD, session moderator Kamlesh Khunti, MD, professor of primary care diabetes and vascular medicine at the University of Leicester, (England), said: “In summary, two studies showing no or weak association of type 1 diabetes with COVID.”

But new data in the research letter published in JAMA Network Open, based on U.S. figures, also found an almost doubling of type 1 diabetes in children in the first few months after COVID-19 infection relative to infection with other respiratory viruses.

Lead author of the Scottish study, Helen Colhoun, PhD, honorary public health consultant at Public Health Scotland, commented: “Data in children are variable year on year, which emphasizes the need to be cautious over taking a tiny snapshot.”

Nevertheless, this is “a hugely important question and we must not drop the ball. [We must] keep looking at it and maintain scientific equipoise. ... [This] reinforces the need to carry on this analysis into the future to obtain an unequivocal picture,” she emphasized.
 

Norwegian study: If there is an association, the risk is small

German Tapia, PhD, from the Norwegian Institute of Public Health, Oslo, presented the results of a study of SARS-CoV-2 infection and subsequent risk of type 1 diabetes in 1.2 million children in Norway.

Of these, 424,354 children had been infected with SARS-CoV-2, and there were 990 incident cases of type 1 diabetes.

“What we do know about COVID-19 in children is that the symptoms are mild and only a small proportion are hospitalized with more serious symptoms. But we do not know the long-term effects of COVID-19 infection because this requires a longer follow-up period,” remarked Dr. Tapia, adding that other viral infections are thought to be linked to the development of type 1 diabetes, in particular, respiratory infections.

The data were sourced from the Norwegian Emergency Preparedness Register for COVID-19, which gathers daily data updates including infections (positive and negative results for free-of-charge testing), diagnoses (primary and secondary care), vaccinations (also free of charge), prescribed medications, and basic demographics.

“We link these data using the personal identification number that every Norwegian citizen has,” explained Dr. Tapia.

He presented results from two cohorts: firstly, results in children only, including those tested for SARS-CoV-2 infection, and secondly, a full national Norwegian population cohort.

Regarding the first cohort, those under 18 years who tested positive for SARS-CoV-2 infection, from March 2020 to March 2022, had a significantly increased risk of type 1 diabetes at least 31 days after infection, with an adjusted hazard ratio of 1.63 (95% confidence interval, 1.08-2.47; P = .02). Adjustments were made for age, sex, non-Nordic country of origin, geographic area, and socioeconomic factors.

For children who developed type 1 diabetes within 30 days of a SARS-CoV-2 infection, the HR was 1.26 (95% CI, 0.72-2.19; P = .42), which did not reach statistical significance.

“The fact that fewer people developed type 1 diabetes within 30 days is not surprising because we know that type 1 diabetes develops over a long period of time,” Dr. Tapia said.

“For this reason, we would not expect to find new cases of those people who develop type 1 diabetes within 30 days of COVID-19 infection,” he explained. In these cases, “it is most likely that they already had [type 1 diabetes], and the infection probably triggered clinical symptoms, so their type 1 diabetes was discovered.”

Turning to the full population cohort and diagnoses of type 1 diabetes over 30 days after SARS-CoV-2 infection, the Norwegian researchers found an association, with an HR of 1.57 (95% CI, 1.06-2.33; P = .03), while diagnosis of type 1 diabetes at 30 days or less generated a hazard ratio of 1.22 (95% CI, 0.72-2.19; P = .42).

“So very similar results were found, and after adjustment for confounders, results were still similar,” reported Dr. Tapia.

He also conducted a similar analysis with vaccination as an exposure but found no association between vaccination against SARS-CoV-2 and diagnosis of type 1 diabetes.

“From these results, we conclude that this suggests an increase in diagnosis of type 1 diabetes after SARS-CoV-2 infection, but it must be noted that the absolute risk of developing type 1 diabetes after infection in children is low, with most children not developing the disease,” he emphasized. “There are nearly half a million children who have been infected with SARS-CoV-2 in Norway, but only a very small proportion develop type 1 diabetes.”
 

Scottish study: No association found over longer term

Dr. Colhoun and colleagues looked at the relationship between incident type 1 diabetes and SARS-CoV-2 infection in children in Scotland using e-health record linkage.

The study involved 1.8 million people under 35 years of age and found very weak, if any, evidence of an association between incident type 1 diabetes and SARS-CoV-2.

Examining data between March 2020 and November 2021, Dr. Colhoun and colleagues identified 365,080 individuals up to age 35 with at least one detected SARS-CoV-2 infection during follow-up and 1,074 who developed type 1 diabetes.

“In children under 16 years, suspected cases of type 1 diabetes are admitted to hospital, and 97% of diagnosis dates are recorded in the Scottish Care Information – Diabetes Collaboration register [SCI-Diabetes] prior to or within 2 days of the first hospital admission for type 1 diabetes,” Dr. Colhoun said, stressing the timeliness of the data.

“We found the incidence of type 1 diabetes diagnosis increased 1.2-fold in those aged 0-14 years, but we did not find any association at an individual level of COVID-19 infection over 30 days prior to a type 1 diabetes diagnosis, in this particular dataset,” she reported. In young people aged 15-34, there was a linear increase in incident type 1 diabetes from 2015 to 2021 with no pandemic increase.

Referring to the 1.2-fold increase soon after the pandemic started, she explained that, in 0- to 14-year-olds, the increase followed a drop in the preceding months prepandemic in 2019. They also found that the seasonal pattern of type 1 diabetes diagnoses remained roughly the same across the pandemic months, with typical peaks in February and September.

In the cohort of under 35s, researchers also found a rate ratio of 2.62 (95% CI, 1.81-3.78) within a 30-day window of SARS-CoV-2 infection, but beyond 30 days, no evidence was seen of an association, with a RR of 0.86 (95% CI, 0.62-1.21; P = .40), she reported.

She explained her reasons for not considering diagnoses within 30 days of COVID-19 as causative. Echoing Dr. Tapia, Dr. Colhoun said the median time from symptom onset to diagnosis of type 1 diabetes is 25 days. “This suggests that 50% have had symptoms for over 25 days at diagnosis.”

She also stressed that when they compared the timing of SARS-CoV-2 testing with diagnosis, they found a much higher rate of COVID-19 testing around diagnosis. “This was not least because everyone admitted to hospital had to have a COVID-19 test.”
 

Latest U.S. data point to a link

Meanwhile, for the new data reported in JAMA Network Open, medical student Ellen K. Kendall of Case Western Reserve University, Cleveland, matched 571,256 pediatric patients: 285,628 with COVID-19 and 285,628 with non–COVID-19 respiratory infections.

By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of type 1 diabetes, but only 72 (0.025%) were diagnosed with type 1 diabetes within 6 months after non–COVID-19 respiratory infection.

At 1, 3, and 6 months after infection, risk of diagnosis of type 1 diabetes was greater among those infected with SARS-CoV-2, compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96; 3 months: HR, 2.10; and 6 months: HR, 1.83), and in subgroups of patients aged 0-9 years, a group unlikely to develop type 2 diabetes.

“In this study, new type 1 diabetes diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems),” noted Ms. Kendall and coauthors. “Respiratory infections have previously been associated with onset of type 1 diabetes, but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths.”

“The increased risk of new-onset type 1 diabetes after COVID-19 adds an important consideration for risk–benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations,” they concluded.

A study from the Centers for Disease Control and Prevention published in January 2022, also concluded there was a link between COVID-19 and diabetes in children, but not with other acute respiratory infections. Children were 2.5 times more likely to be diagnosed with diabetes following a SARS-CoV-2 infection, it found.

However, the study has been criticized because it pooled all types of diabetes together and did not account for other health conditions, medications that can increase blood glucose levels, race, obesity, and other social determinants of health that might influence a child’s risk of acquiring COVID-19 or diabetes.

“I’ve no doubt that the CDC data were incorrect because the incidence rate for ... diabetes, even in those never exposed to COVID-19 infection, was 10 times the rate ever reported in the U.S.,” Dr. Colhoun said. “There’s no way these data are correct. I believe there was a confusion between incidence and prevalence of diabetes.”

“This paper caused a great deal of panic, especially among those who have a child with type 1diabetes, so we need to be very careful not to cause undue alarm until we have more definitive evidence in this arena,” she stressed.

However, she also acknowledged that the new Norwegian study was well conducted, and she has no methodological concerns about it, so “I think we just have to wait and see.”

Given the inconclusiveness on the issue, there is an ongoing CoviDiab registry collecting data on this very subject.

Dr. Tapia presented on behalf of lead author Dr. Gulseth, who has reported no relevant financial relationships. Dr. Colhoun also reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

STOCKHOLM – It remains inconclusive whether SARS-CoV-2 infection predisposes children and adolescents to a higher risk of type 1 diabetes. Data from two new studies and a recently published research letter add to the growing body of knowledge on the subject, but still can’t draw any definitive conclusions.

The latest results from a Norwegian and a Scottish study both examine incidence of type 1 diabetes in young people with a history of SARS-CoV-2 infection and were reported at the annual meeting of the European Association for the Study of Diabetes.

A 60% increased risk for type 1 diabetes at least 31 days after SARS-CoV-2 infection (adjusted hazard ratio, 1.63) was found in the Norwegian study, while in contrast, the Scottish study only found an increased risk in the first few months of the pandemic, in 2020, but importantly, no association over a much longer time period (March 2020–November 2021).

In a comment on Twitter on the two studies presented at EASD, session moderator Kamlesh Khunti, MD, professor of primary care diabetes and vascular medicine at the University of Leicester, (England), said: “In summary, two studies showing no or weak association of type 1 diabetes with COVID.”

But new data in the research letter published in JAMA Network Open, based on U.S. figures, also found an almost doubling of type 1 diabetes in children in the first few months after COVID-19 infection relative to infection with other respiratory viruses.

Lead author of the Scottish study, Helen Colhoun, PhD, honorary public health consultant at Public Health Scotland, commented: “Data in children are variable year on year, which emphasizes the need to be cautious over taking a tiny snapshot.”

Nevertheless, this is “a hugely important question and we must not drop the ball. [We must] keep looking at it and maintain scientific equipoise. ... [This] reinforces the need to carry on this analysis into the future to obtain an unequivocal picture,” she emphasized.
 

Norwegian study: If there is an association, the risk is small

German Tapia, PhD, from the Norwegian Institute of Public Health, Oslo, presented the results of a study of SARS-CoV-2 infection and subsequent risk of type 1 diabetes in 1.2 million children in Norway.

Of these, 424,354 children had been infected with SARS-CoV-2, and there were 990 incident cases of type 1 diabetes.

“What we do know about COVID-19 in children is that the symptoms are mild and only a small proportion are hospitalized with more serious symptoms. But we do not know the long-term effects of COVID-19 infection because this requires a longer follow-up period,” remarked Dr. Tapia, adding that other viral infections are thought to be linked to the development of type 1 diabetes, in particular, respiratory infections.

The data were sourced from the Norwegian Emergency Preparedness Register for COVID-19, which gathers daily data updates including infections (positive and negative results for free-of-charge testing), diagnoses (primary and secondary care), vaccinations (also free of charge), prescribed medications, and basic demographics.

“We link these data using the personal identification number that every Norwegian citizen has,” explained Dr. Tapia.

He presented results from two cohorts: firstly, results in children only, including those tested for SARS-CoV-2 infection, and secondly, a full national Norwegian population cohort.

Regarding the first cohort, those under 18 years who tested positive for SARS-CoV-2 infection, from March 2020 to March 2022, had a significantly increased risk of type 1 diabetes at least 31 days after infection, with an adjusted hazard ratio of 1.63 (95% confidence interval, 1.08-2.47; P = .02). Adjustments were made for age, sex, non-Nordic country of origin, geographic area, and socioeconomic factors.

For children who developed type 1 diabetes within 30 days of a SARS-CoV-2 infection, the HR was 1.26 (95% CI, 0.72-2.19; P = .42), which did not reach statistical significance.

“The fact that fewer people developed type 1 diabetes within 30 days is not surprising because we know that type 1 diabetes develops over a long period of time,” Dr. Tapia said.

“For this reason, we would not expect to find new cases of those people who develop type 1 diabetes within 30 days of COVID-19 infection,” he explained. In these cases, “it is most likely that they already had [type 1 diabetes], and the infection probably triggered clinical symptoms, so their type 1 diabetes was discovered.”

Turning to the full population cohort and diagnoses of type 1 diabetes over 30 days after SARS-CoV-2 infection, the Norwegian researchers found an association, with an HR of 1.57 (95% CI, 1.06-2.33; P = .03), while diagnosis of type 1 diabetes at 30 days or less generated a hazard ratio of 1.22 (95% CI, 0.72-2.19; P = .42).

“So very similar results were found, and after adjustment for confounders, results were still similar,” reported Dr. Tapia.

He also conducted a similar analysis with vaccination as an exposure but found no association between vaccination against SARS-CoV-2 and diagnosis of type 1 diabetes.

“From these results, we conclude that this suggests an increase in diagnosis of type 1 diabetes after SARS-CoV-2 infection, but it must be noted that the absolute risk of developing type 1 diabetes after infection in children is low, with most children not developing the disease,” he emphasized. “There are nearly half a million children who have been infected with SARS-CoV-2 in Norway, but only a very small proportion develop type 1 diabetes.”
 

Scottish study: No association found over longer term

Dr. Colhoun and colleagues looked at the relationship between incident type 1 diabetes and SARS-CoV-2 infection in children in Scotland using e-health record linkage.

The study involved 1.8 million people under 35 years of age and found very weak, if any, evidence of an association between incident type 1 diabetes and SARS-CoV-2.

Examining data between March 2020 and November 2021, Dr. Colhoun and colleagues identified 365,080 individuals up to age 35 with at least one detected SARS-CoV-2 infection during follow-up and 1,074 who developed type 1 diabetes.

“In children under 16 years, suspected cases of type 1 diabetes are admitted to hospital, and 97% of diagnosis dates are recorded in the Scottish Care Information – Diabetes Collaboration register [SCI-Diabetes] prior to or within 2 days of the first hospital admission for type 1 diabetes,” Dr. Colhoun said, stressing the timeliness of the data.

“We found the incidence of type 1 diabetes diagnosis increased 1.2-fold in those aged 0-14 years, but we did not find any association at an individual level of COVID-19 infection over 30 days prior to a type 1 diabetes diagnosis, in this particular dataset,” she reported. In young people aged 15-34, there was a linear increase in incident type 1 diabetes from 2015 to 2021 with no pandemic increase.

Referring to the 1.2-fold increase soon after the pandemic started, she explained that, in 0- to 14-year-olds, the increase followed a drop in the preceding months prepandemic in 2019. They also found that the seasonal pattern of type 1 diabetes diagnoses remained roughly the same across the pandemic months, with typical peaks in February and September.

In the cohort of under 35s, researchers also found a rate ratio of 2.62 (95% CI, 1.81-3.78) within a 30-day window of SARS-CoV-2 infection, but beyond 30 days, no evidence was seen of an association, with a RR of 0.86 (95% CI, 0.62-1.21; P = .40), she reported.

She explained her reasons for not considering diagnoses within 30 days of COVID-19 as causative. Echoing Dr. Tapia, Dr. Colhoun said the median time from symptom onset to diagnosis of type 1 diabetes is 25 days. “This suggests that 50% have had symptoms for over 25 days at diagnosis.”

She also stressed that when they compared the timing of SARS-CoV-2 testing with diagnosis, they found a much higher rate of COVID-19 testing around diagnosis. “This was not least because everyone admitted to hospital had to have a COVID-19 test.”
 

Latest U.S. data point to a link

Meanwhile, for the new data reported in JAMA Network Open, medical student Ellen K. Kendall of Case Western Reserve University, Cleveland, matched 571,256 pediatric patients: 285,628 with COVID-19 and 285,628 with non–COVID-19 respiratory infections.

By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of type 1 diabetes, but only 72 (0.025%) were diagnosed with type 1 diabetes within 6 months after non–COVID-19 respiratory infection.

At 1, 3, and 6 months after infection, risk of diagnosis of type 1 diabetes was greater among those infected with SARS-CoV-2, compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96; 3 months: HR, 2.10; and 6 months: HR, 1.83), and in subgroups of patients aged 0-9 years, a group unlikely to develop type 2 diabetes.

“In this study, new type 1 diabetes diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems),” noted Ms. Kendall and coauthors. “Respiratory infections have previously been associated with onset of type 1 diabetes, but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths.”

“The increased risk of new-onset type 1 diabetes after COVID-19 adds an important consideration for risk–benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations,” they concluded.

A study from the Centers for Disease Control and Prevention published in January 2022, also concluded there was a link between COVID-19 and diabetes in children, but not with other acute respiratory infections. Children were 2.5 times more likely to be diagnosed with diabetes following a SARS-CoV-2 infection, it found.

However, the study has been criticized because it pooled all types of diabetes together and did not account for other health conditions, medications that can increase blood glucose levels, race, obesity, and other social determinants of health that might influence a child’s risk of acquiring COVID-19 or diabetes.

“I’ve no doubt that the CDC data were incorrect because the incidence rate for ... diabetes, even in those never exposed to COVID-19 infection, was 10 times the rate ever reported in the U.S.,” Dr. Colhoun said. “There’s no way these data are correct. I believe there was a confusion between incidence and prevalence of diabetes.”

“This paper caused a great deal of panic, especially among those who have a child with type 1diabetes, so we need to be very careful not to cause undue alarm until we have more definitive evidence in this arena,” she stressed.

However, she also acknowledged that the new Norwegian study was well conducted, and she has no methodological concerns about it, so “I think we just have to wait and see.”

Given the inconclusiveness on the issue, there is an ongoing CoviDiab registry collecting data on this very subject.

Dr. Tapia presented on behalf of lead author Dr. Gulseth, who has reported no relevant financial relationships. Dr. Colhoun also reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

STOCKHOLM – It remains inconclusive whether SARS-CoV-2 infection predisposes children and adolescents to a higher risk of type 1 diabetes. Data from two new studies and a recently published research letter add to the growing body of knowledge on the subject, but still can’t draw any definitive conclusions.

The latest results from a Norwegian and a Scottish study both examine incidence of type 1 diabetes in young people with a history of SARS-CoV-2 infection and were reported at the annual meeting of the European Association for the Study of Diabetes.

A 60% increased risk for type 1 diabetes at least 31 days after SARS-CoV-2 infection (adjusted hazard ratio, 1.63) was found in the Norwegian study, while in contrast, the Scottish study only found an increased risk in the first few months of the pandemic, in 2020, but importantly, no association over a much longer time period (March 2020–November 2021).

In a comment on Twitter on the two studies presented at EASD, session moderator Kamlesh Khunti, MD, professor of primary care diabetes and vascular medicine at the University of Leicester, (England), said: “In summary, two studies showing no or weak association of type 1 diabetes with COVID.”

But new data in the research letter published in JAMA Network Open, based on U.S. figures, also found an almost doubling of type 1 diabetes in children in the first few months after COVID-19 infection relative to infection with other respiratory viruses.

Lead author of the Scottish study, Helen Colhoun, PhD, honorary public health consultant at Public Health Scotland, commented: “Data in children are variable year on year, which emphasizes the need to be cautious over taking a tiny snapshot.”

Nevertheless, this is “a hugely important question and we must not drop the ball. [We must] keep looking at it and maintain scientific equipoise. ... [This] reinforces the need to carry on this analysis into the future to obtain an unequivocal picture,” she emphasized.
 

Norwegian study: If there is an association, the risk is small

German Tapia, PhD, from the Norwegian Institute of Public Health, Oslo, presented the results of a study of SARS-CoV-2 infection and subsequent risk of type 1 diabetes in 1.2 million children in Norway.

Of these, 424,354 children had been infected with SARS-CoV-2, and there were 990 incident cases of type 1 diabetes.

“What we do know about COVID-19 in children is that the symptoms are mild and only a small proportion are hospitalized with more serious symptoms. But we do not know the long-term effects of COVID-19 infection because this requires a longer follow-up period,” remarked Dr. Tapia, adding that other viral infections are thought to be linked to the development of type 1 diabetes, in particular, respiratory infections.

The data were sourced from the Norwegian Emergency Preparedness Register for COVID-19, which gathers daily data updates including infections (positive and negative results for free-of-charge testing), diagnoses (primary and secondary care), vaccinations (also free of charge), prescribed medications, and basic demographics.

“We link these data using the personal identification number that every Norwegian citizen has,” explained Dr. Tapia.

He presented results from two cohorts: firstly, results in children only, including those tested for SARS-CoV-2 infection, and secondly, a full national Norwegian population cohort.

Regarding the first cohort, those under 18 years who tested positive for SARS-CoV-2 infection, from March 2020 to March 2022, had a significantly increased risk of type 1 diabetes at least 31 days after infection, with an adjusted hazard ratio of 1.63 (95% confidence interval, 1.08-2.47; P = .02). Adjustments were made for age, sex, non-Nordic country of origin, geographic area, and socioeconomic factors.

For children who developed type 1 diabetes within 30 days of a SARS-CoV-2 infection, the HR was 1.26 (95% CI, 0.72-2.19; P = .42), which did not reach statistical significance.

“The fact that fewer people developed type 1 diabetes within 30 days is not surprising because we know that type 1 diabetes develops over a long period of time,” Dr. Tapia said.

“For this reason, we would not expect to find new cases of those people who develop type 1 diabetes within 30 days of COVID-19 infection,” he explained. In these cases, “it is most likely that they already had [type 1 diabetes], and the infection probably triggered clinical symptoms, so their type 1 diabetes was discovered.”

Turning to the full population cohort and diagnoses of type 1 diabetes over 30 days after SARS-CoV-2 infection, the Norwegian researchers found an association, with an HR of 1.57 (95% CI, 1.06-2.33; P = .03), while diagnosis of type 1 diabetes at 30 days or less generated a hazard ratio of 1.22 (95% CI, 0.72-2.19; P = .42).

“So very similar results were found, and after adjustment for confounders, results were still similar,” reported Dr. Tapia.

He also conducted a similar analysis with vaccination as an exposure but found no association between vaccination against SARS-CoV-2 and diagnosis of type 1 diabetes.

“From these results, we conclude that this suggests an increase in diagnosis of type 1 diabetes after SARS-CoV-2 infection, but it must be noted that the absolute risk of developing type 1 diabetes after infection in children is low, with most children not developing the disease,” he emphasized. “There are nearly half a million children who have been infected with SARS-CoV-2 in Norway, but only a very small proportion develop type 1 diabetes.”
 

Scottish study: No association found over longer term

Dr. Colhoun and colleagues looked at the relationship between incident type 1 diabetes and SARS-CoV-2 infection in children in Scotland using e-health record linkage.

The study involved 1.8 million people under 35 years of age and found very weak, if any, evidence of an association between incident type 1 diabetes and SARS-CoV-2.

Examining data between March 2020 and November 2021, Dr. Colhoun and colleagues identified 365,080 individuals up to age 35 with at least one detected SARS-CoV-2 infection during follow-up and 1,074 who developed type 1 diabetes.

“In children under 16 years, suspected cases of type 1 diabetes are admitted to hospital, and 97% of diagnosis dates are recorded in the Scottish Care Information – Diabetes Collaboration register [SCI-Diabetes] prior to or within 2 days of the first hospital admission for type 1 diabetes,” Dr. Colhoun said, stressing the timeliness of the data.

“We found the incidence of type 1 diabetes diagnosis increased 1.2-fold in those aged 0-14 years, but we did not find any association at an individual level of COVID-19 infection over 30 days prior to a type 1 diabetes diagnosis, in this particular dataset,” she reported. In young people aged 15-34, there was a linear increase in incident type 1 diabetes from 2015 to 2021 with no pandemic increase.

Referring to the 1.2-fold increase soon after the pandemic started, she explained that, in 0- to 14-year-olds, the increase followed a drop in the preceding months prepandemic in 2019. They also found that the seasonal pattern of type 1 diabetes diagnoses remained roughly the same across the pandemic months, with typical peaks in February and September.

In the cohort of under 35s, researchers also found a rate ratio of 2.62 (95% CI, 1.81-3.78) within a 30-day window of SARS-CoV-2 infection, but beyond 30 days, no evidence was seen of an association, with a RR of 0.86 (95% CI, 0.62-1.21; P = .40), she reported.

She explained her reasons for not considering diagnoses within 30 days of COVID-19 as causative. Echoing Dr. Tapia, Dr. Colhoun said the median time from symptom onset to diagnosis of type 1 diabetes is 25 days. “This suggests that 50% have had symptoms for over 25 days at diagnosis.”

She also stressed that when they compared the timing of SARS-CoV-2 testing with diagnosis, they found a much higher rate of COVID-19 testing around diagnosis. “This was not least because everyone admitted to hospital had to have a COVID-19 test.”
 

Latest U.S. data point to a link

Meanwhile, for the new data reported in JAMA Network Open, medical student Ellen K. Kendall of Case Western Reserve University, Cleveland, matched 571,256 pediatric patients: 285,628 with COVID-19 and 285,628 with non–COVID-19 respiratory infections.

By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of type 1 diabetes, but only 72 (0.025%) were diagnosed with type 1 diabetes within 6 months after non–COVID-19 respiratory infection.

At 1, 3, and 6 months after infection, risk of diagnosis of type 1 diabetes was greater among those infected with SARS-CoV-2, compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96; 3 months: HR, 2.10; and 6 months: HR, 1.83), and in subgroups of patients aged 0-9 years, a group unlikely to develop type 2 diabetes.

“In this study, new type 1 diabetes diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems),” noted Ms. Kendall and coauthors. “Respiratory infections have previously been associated with onset of type 1 diabetes, but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths.”

“The increased risk of new-onset type 1 diabetes after COVID-19 adds an important consideration for risk–benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations,” they concluded.

A study from the Centers for Disease Control and Prevention published in January 2022, also concluded there was a link between COVID-19 and diabetes in children, but not with other acute respiratory infections. Children were 2.5 times more likely to be diagnosed with diabetes following a SARS-CoV-2 infection, it found.

However, the study has been criticized because it pooled all types of diabetes together and did not account for other health conditions, medications that can increase blood glucose levels, race, obesity, and other social determinants of health that might influence a child’s risk of acquiring COVID-19 or diabetes.

“I’ve no doubt that the CDC data were incorrect because the incidence rate for ... diabetes, even in those never exposed to COVID-19 infection, was 10 times the rate ever reported in the U.S.,” Dr. Colhoun said. “There’s no way these data are correct. I believe there was a confusion between incidence and prevalence of diabetes.”

“This paper caused a great deal of panic, especially among those who have a child with type 1diabetes, so we need to be very careful not to cause undue alarm until we have more definitive evidence in this arena,” she stressed.

However, she also acknowledged that the new Norwegian study was well conducted, and she has no methodological concerns about it, so “I think we just have to wait and see.”

Given the inconclusiveness on the issue, there is an ongoing CoviDiab registry collecting data on this very subject.

Dr. Tapia presented on behalf of lead author Dr. Gulseth, who has reported no relevant financial relationships. Dr. Colhoun also reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Aspirin may be of specific benefit for the primary prevention of cardiovascular disease in individuals with raised Lp(a) levels, a new study has suggested.

The study analyzed data from the ASPREE (ASPirin in Reducing Events in the Elderly) trial, which randomized 19,000 individuals aged 70 years or older without a history of cardiovascular disease to aspirin (100 mg/day) or placebo. While the main results, reported previously, showed no net benefit of aspirin in the overall population, the current analysis suggests there may be a benefit in individuals with raised Lp(a) levels.

jimdeli/Fotolia

Similar findings in the Women’s Health Study

Dr. Lacaze and colleagues point out that similar results have also been seen in another large aspirin primary prevention study – the Women’s Health Study (WHS).

The WHS compared aspirin 100 mg every other day with placebo in initially healthy younger women. Previously reported results showed that women carrying the rs3798220-C variant, associated with highly elevated Lp(a) levels, had a twofold higher risk of cardiovascular events than noncarrier women in the placebo group, but this risk was reduced in the aspirin group. And there was no increased risk of bleeding in women with elevated Lp(a).

“These results, in the absence of any other randomized controlled trial evidence or approved therapy for treating Lp(a)-associated risk, have been used by some physicians as justification for prescribing aspirin in patients with elevated Lp(a),” Dr. Lacaze and colleagues note.

“In the present study of the ASPREE trial population, our results were consistent with the WHS analysis, despite randomizing older individuals (both men and women),” they add.

They say this validation of the WHS result provides evidence that a very high-risk subgroup of individuals with highly elevated Lp(a) – those carrying the rs3798220-C allele – may benefit from low-dose aspirin for the primary prevention of cardiovascular events. Further, the benefits in this subgroup specifically may outweigh any bleeding risk.

But they point out that rs3798220-C carriers comprise only a small portion of all individuals with elevated Lp(a) in the general population, while the polygenic LPA-GRS explains about 60% of the variation in directly measured plasma Lp(a) levels and has the potential advantage of being able to identify a larger group of individuals at increased risk.

The researchers note, however, that it is not clear to what extent the LPA-GRS results add further evidence to suggest that individuals with elevated Lp(a), beyond rs3798220-C carriers, may be more likely to benefit from aspirin.

“If the benefit of aspirin extends beyond very high-risk rs3798220-C carriers alone, to the broader 20%-30% of individuals with elevated Lp(a), the potential utility of aspirin for the primary prevention of cardiovascular events would increase substantially,” they say.
 

‘Very high clinical relevance’

In an accompanying editorial, Ana Devesa, MD, Borja Ibanez, MD, PhD, and Valentin Fuster, MD, PhD, The National Center for Cardiovascular Research, Madrid, say that: “[Dr.] Lacaze et al. are to be congratulated for a study of very high clinical relevance that represents a first indication for primary prevention for patients at high cardiovascular risk.”

They explain that the pathogenic mechanism of Lp(a) is believed to be a combination of prothrombotic and proatherogenic effects, and the current findings support the hypothesis that the prothrombotic mechanism of Lp(a) is mediated by platelet aggregation. 

This would explain the occurrence of thrombotic events in the presence of atherosclerosis in that elevated Lp(a) levels may induce platelet adhesion and aggregation to the activated atherosclerotic plaque, thus enhancing the atherothrombotic process. Moreover, activated platelets release several mediators that result in cell adhesion and attraction of chemokines and proinflammatory cytokines, driving an inflammatory response and mediating atherosclerosis progression, they add.

The editorialists highlight the limitations of the study already acknowledged by the authors: The analysis used genotypes rather than elevated Lp(a) levels and included only those of European ancestry, meaning the results are difficult to extrapolate to other populations.

“The next steps in clinical practice should be defined, and there are still questions to be answered,” they conclude. “Will every patient benefit from antithrombotic therapies? Should all patients who have elevated Lp(a) levels be treated with aspirin?”

The ASPREE Biobank is supported by grants from the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne, National Institutes of Health, National Health and Medical Research Council of Australia, and the Victorian Cancer Agency. Dr. Lacaze is supported by a National Heart Foundation Future Leader Fellowship.

A version of this article first appeared on Medscape.com.

Aspirin may be of specific benefit for the primary prevention of cardiovascular disease in individuals with raised Lp(a) levels, a new study has suggested.

The study analyzed data from the ASPREE (ASPirin in Reducing Events in the Elderly) trial, which randomized 19,000 individuals aged 70 years or older without a history of cardiovascular disease to aspirin (100 mg/day) or placebo. While the main results, reported previously, showed no net benefit of aspirin in the overall population, the current analysis suggests there may be a benefit in individuals with raised Lp(a) levels.

jimdeli/Fotolia

Similar findings in the Women’s Health Study

Dr. Lacaze and colleagues point out that similar results have also been seen in another large aspirin primary prevention study – the Women’s Health Study (WHS).

The WHS compared aspirin 100 mg every other day with placebo in initially healthy younger women. Previously reported results showed that women carrying the rs3798220-C variant, associated with highly elevated Lp(a) levels, had a twofold higher risk of cardiovascular events than noncarrier women in the placebo group, but this risk was reduced in the aspirin group. And there was no increased risk of bleeding in women with elevated Lp(a).

“These results, in the absence of any other randomized controlled trial evidence or approved therapy for treating Lp(a)-associated risk, have been used by some physicians as justification for prescribing aspirin in patients with elevated Lp(a),” Dr. Lacaze and colleagues note.

“In the present study of the ASPREE trial population, our results were consistent with the WHS analysis, despite randomizing older individuals (both men and women),” they add.

They say this validation of the WHS result provides evidence that a very high-risk subgroup of individuals with highly elevated Lp(a) – those carrying the rs3798220-C allele – may benefit from low-dose aspirin for the primary prevention of cardiovascular events. Further, the benefits in this subgroup specifically may outweigh any bleeding risk.

But they point out that rs3798220-C carriers comprise only a small portion of all individuals with elevated Lp(a) in the general population, while the polygenic LPA-GRS explains about 60% of the variation in directly measured plasma Lp(a) levels and has the potential advantage of being able to identify a larger group of individuals at increased risk.

The researchers note, however, that it is not clear to what extent the LPA-GRS results add further evidence to suggest that individuals with elevated Lp(a), beyond rs3798220-C carriers, may be more likely to benefit from aspirin.

“If the benefit of aspirin extends beyond very high-risk rs3798220-C carriers alone, to the broader 20%-30% of individuals with elevated Lp(a), the potential utility of aspirin for the primary prevention of cardiovascular events would increase substantially,” they say.
 

‘Very high clinical relevance’

In an accompanying editorial, Ana Devesa, MD, Borja Ibanez, MD, PhD, and Valentin Fuster, MD, PhD, The National Center for Cardiovascular Research, Madrid, say that: “[Dr.] Lacaze et al. are to be congratulated for a study of very high clinical relevance that represents a first indication for primary prevention for patients at high cardiovascular risk.”

They explain that the pathogenic mechanism of Lp(a) is believed to be a combination of prothrombotic and proatherogenic effects, and the current findings support the hypothesis that the prothrombotic mechanism of Lp(a) is mediated by platelet aggregation. 

This would explain the occurrence of thrombotic events in the presence of atherosclerosis in that elevated Lp(a) levels may induce platelet adhesion and aggregation to the activated atherosclerotic plaque, thus enhancing the atherothrombotic process. Moreover, activated platelets release several mediators that result in cell adhesion and attraction of chemokines and proinflammatory cytokines, driving an inflammatory response and mediating atherosclerosis progression, they add.

The editorialists highlight the limitations of the study already acknowledged by the authors: The analysis used genotypes rather than elevated Lp(a) levels and included only those of European ancestry, meaning the results are difficult to extrapolate to other populations.

“The next steps in clinical practice should be defined, and there are still questions to be answered,” they conclude. “Will every patient benefit from antithrombotic therapies? Should all patients who have elevated Lp(a) levels be treated with aspirin?”

The ASPREE Biobank is supported by grants from the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne, National Institutes of Health, National Health and Medical Research Council of Australia, and the Victorian Cancer Agency. Dr. Lacaze is supported by a National Heart Foundation Future Leader Fellowship.

A version of this article first appeared on Medscape.com.

Aspirin may be of specific benefit for the primary prevention of cardiovascular disease in individuals with raised Lp(a) levels, a new study has suggested.

The study analyzed data from the ASPREE (ASPirin in Reducing Events in the Elderly) trial, which randomized 19,000 individuals aged 70 years or older without a history of cardiovascular disease to aspirin (100 mg/day) or placebo. While the main results, reported previously, showed no net benefit of aspirin in the overall population, the current analysis suggests there may be a benefit in individuals with raised Lp(a) levels.

jimdeli/Fotolia

Similar findings in the Women’s Health Study

Dr. Lacaze and colleagues point out that similar results have also been seen in another large aspirin primary prevention study – the Women’s Health Study (WHS).

The WHS compared aspirin 100 mg every other day with placebo in initially healthy younger women. Previously reported results showed that women carrying the rs3798220-C variant, associated with highly elevated Lp(a) levels, had a twofold higher risk of cardiovascular events than noncarrier women in the placebo group, but this risk was reduced in the aspirin group. And there was no increased risk of bleeding in women with elevated Lp(a).

“These results, in the absence of any other randomized controlled trial evidence or approved therapy for treating Lp(a)-associated risk, have been used by some physicians as justification for prescribing aspirin in patients with elevated Lp(a),” Dr. Lacaze and colleagues note.

“In the present study of the ASPREE trial population, our results were consistent with the WHS analysis, despite randomizing older individuals (both men and women),” they add.

They say this validation of the WHS result provides evidence that a very high-risk subgroup of individuals with highly elevated Lp(a) – those carrying the rs3798220-C allele – may benefit from low-dose aspirin for the primary prevention of cardiovascular events. Further, the benefits in this subgroup specifically may outweigh any bleeding risk.

But they point out that rs3798220-C carriers comprise only a small portion of all individuals with elevated Lp(a) in the general population, while the polygenic LPA-GRS explains about 60% of the variation in directly measured plasma Lp(a) levels and has the potential advantage of being able to identify a larger group of individuals at increased risk.

The researchers note, however, that it is not clear to what extent the LPA-GRS results add further evidence to suggest that individuals with elevated Lp(a), beyond rs3798220-C carriers, may be more likely to benefit from aspirin.

“If the benefit of aspirin extends beyond very high-risk rs3798220-C carriers alone, to the broader 20%-30% of individuals with elevated Lp(a), the potential utility of aspirin for the primary prevention of cardiovascular events would increase substantially,” they say.
 

‘Very high clinical relevance’

In an accompanying editorial, Ana Devesa, MD, Borja Ibanez, MD, PhD, and Valentin Fuster, MD, PhD, The National Center for Cardiovascular Research, Madrid, say that: “[Dr.] Lacaze et al. are to be congratulated for a study of very high clinical relevance that represents a first indication for primary prevention for patients at high cardiovascular risk.”

They explain that the pathogenic mechanism of Lp(a) is believed to be a combination of prothrombotic and proatherogenic effects, and the current findings support the hypothesis that the prothrombotic mechanism of Lp(a) is mediated by platelet aggregation. 

This would explain the occurrence of thrombotic events in the presence of atherosclerosis in that elevated Lp(a) levels may induce platelet adhesion and aggregation to the activated atherosclerotic plaque, thus enhancing the atherothrombotic process. Moreover, activated platelets release several mediators that result in cell adhesion and attraction of chemokines and proinflammatory cytokines, driving an inflammatory response and mediating atherosclerosis progression, they add.

The editorialists highlight the limitations of the study already acknowledged by the authors: The analysis used genotypes rather than elevated Lp(a) levels and included only those of European ancestry, meaning the results are difficult to extrapolate to other populations.

“The next steps in clinical practice should be defined, and there are still questions to be answered,” they conclude. “Will every patient benefit from antithrombotic therapies? Should all patients who have elevated Lp(a) levels be treated with aspirin?”

The ASPREE Biobank is supported by grants from the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne, National Institutes of Health, National Health and Medical Research Council of Australia, and the Victorian Cancer Agency. Dr. Lacaze is supported by a National Heart Foundation Future Leader Fellowship.

A version of this article first appeared on Medscape.com.

In a new scientific statement, the American Heart Association highlights the unique drivers of burnout in academic cardiovascular medicine physicians and proposes system-level and personal interventions to support individual wellness in this setting.

“The future cardiovascular health of Americans relies on a well-trained and experienced physician workforce created by rigorous academic medical training,” the writing group says in Circulation.

“Cardiovascular physicians pursuing careers in academic medicine are critical to continuing this mission, which includes providing clinical care for common and increasingly complex disease, educating and training the next generation of physicians/health care workers, and pursuing scientific discovery and innovation to treat and cure disease,” write Elisa Bradley, Penn State Health Heart and Vascular Institute, Hershey, Pa., and coauthors.

Given the multitasking nature of academic medicine, exhaustion and burnout uniquely threaten future and early career academic physicians, they say.

Drivers of burnout in this setting include productivity-driven compensation models that force competition for time between clinical care and academics; the requirement for promotion in systems that have not evolved to consider combined clinical and academic expectations; and distinct expectations based on faculty pathway, such as grant funding and publications.

In addition, at the early career and fellow-in-training level, drivers of burnout also include significant changes in personal and family life, coupled with long hours and high clinical and research demands, as well as financial strain and educational debt.

Many of the drivers of burnout in academic medicine are external and beyond the control of a single individual. Therefore, proposed solutions must be largely at the level of organizations, institutions, and government, the writing group says.

These solutions include appropriate mentorship, goal planning, efficiency in the workplace, time management and time “protection,” and manageable schedules.

Professional satisfaction “should be a shared responsibility between the clinician and the institution. Each must adapt their values to find a middle ground that meets the needs of both, recognizing that health care is both personal and a business,” the writing group says.

“Interventions to support efficiency of practice and a culture of wellness span normalizing and supporting flexible work environments to enhancing clinical support,” they add.

To enhance flexible clinical environments, organizations should consider “float teams” to provide care to bridge gaps when a physician is not available, job sharing and flexible hours, and telemedicine, the writing group says.

At the individual level, academic cardiovascular professionals should build individualized strategies to combat fatigue and to promote wellness, focusing on self-care and healthy habits (adequate sleep, healthy nutrition, exercise, outside interests, meaningful social relationships), they advise.

With help, “young academicians can look forward to a fulfilling and long career in academic cardiovascular medicine,” they conclude.

This research had no commercial funding. Members of the writing group reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In a new scientific statement, the American Heart Association highlights the unique drivers of burnout in academic cardiovascular medicine physicians and proposes system-level and personal interventions to support individual wellness in this setting.

“The future cardiovascular health of Americans relies on a well-trained and experienced physician workforce created by rigorous academic medical training,” the writing group says in Circulation.

“Cardiovascular physicians pursuing careers in academic medicine are critical to continuing this mission, which includes providing clinical care for common and increasingly complex disease, educating and training the next generation of physicians/health care workers, and pursuing scientific discovery and innovation to treat and cure disease,” write Elisa Bradley, Penn State Health Heart and Vascular Institute, Hershey, Pa., and coauthors.

Given the multitasking nature of academic medicine, exhaustion and burnout uniquely threaten future and early career academic physicians, they say.

Drivers of burnout in this setting include productivity-driven compensation models that force competition for time between clinical care and academics; the requirement for promotion in systems that have not evolved to consider combined clinical and academic expectations; and distinct expectations based on faculty pathway, such as grant funding and publications.

In addition, at the early career and fellow-in-training level, drivers of burnout also include significant changes in personal and family life, coupled with long hours and high clinical and research demands, as well as financial strain and educational debt.

Many of the drivers of burnout in academic medicine are external and beyond the control of a single individual. Therefore, proposed solutions must be largely at the level of organizations, institutions, and government, the writing group says.

These solutions include appropriate mentorship, goal planning, efficiency in the workplace, time management and time “protection,” and manageable schedules.

Professional satisfaction “should be a shared responsibility between the clinician and the institution. Each must adapt their values to find a middle ground that meets the needs of both, recognizing that health care is both personal and a business,” the writing group says.

“Interventions to support efficiency of practice and a culture of wellness span normalizing and supporting flexible work environments to enhancing clinical support,” they add.

To enhance flexible clinical environments, organizations should consider “float teams” to provide care to bridge gaps when a physician is not available, job sharing and flexible hours, and telemedicine, the writing group says.

At the individual level, academic cardiovascular professionals should build individualized strategies to combat fatigue and to promote wellness, focusing on self-care and healthy habits (adequate sleep, healthy nutrition, exercise, outside interests, meaningful social relationships), they advise.

With help, “young academicians can look forward to a fulfilling and long career in academic cardiovascular medicine,” they conclude.

This research had no commercial funding. Members of the writing group reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In a new scientific statement, the American Heart Association highlights the unique drivers of burnout in academic cardiovascular medicine physicians and proposes system-level and personal interventions to support individual wellness in this setting.

“The future cardiovascular health of Americans relies on a well-trained and experienced physician workforce created by rigorous academic medical training,” the writing group says in Circulation.

“Cardiovascular physicians pursuing careers in academic medicine are critical to continuing this mission, which includes providing clinical care for common and increasingly complex disease, educating and training the next generation of physicians/health care workers, and pursuing scientific discovery and innovation to treat and cure disease,” write Elisa Bradley, Penn State Health Heart and Vascular Institute, Hershey, Pa., and coauthors.

Given the multitasking nature of academic medicine, exhaustion and burnout uniquely threaten future and early career academic physicians, they say.

Drivers of burnout in this setting include productivity-driven compensation models that force competition for time between clinical care and academics; the requirement for promotion in systems that have not evolved to consider combined clinical and academic expectations; and distinct expectations based on faculty pathway, such as grant funding and publications.

In addition, at the early career and fellow-in-training level, drivers of burnout also include significant changes in personal and family life, coupled with long hours and high clinical and research demands, as well as financial strain and educational debt.

Many of the drivers of burnout in academic medicine are external and beyond the control of a single individual. Therefore, proposed solutions must be largely at the level of organizations, institutions, and government, the writing group says.

These solutions include appropriate mentorship, goal planning, efficiency in the workplace, time management and time “protection,” and manageable schedules.

Professional satisfaction “should be a shared responsibility between the clinician and the institution. Each must adapt their values to find a middle ground that meets the needs of both, recognizing that health care is both personal and a business,” the writing group says.

“Interventions to support efficiency of practice and a culture of wellness span normalizing and supporting flexible work environments to enhancing clinical support,” they add.

To enhance flexible clinical environments, organizations should consider “float teams” to provide care to bridge gaps when a physician is not available, job sharing and flexible hours, and telemedicine, the writing group says.

At the individual level, academic cardiovascular professionals should build individualized strategies to combat fatigue and to promote wellness, focusing on self-care and healthy habits (adequate sleep, healthy nutrition, exercise, outside interests, meaningful social relationships), they advise.

With help, “young academicians can look forward to a fulfilling and long career in academic cardiovascular medicine,” they conclude.

This research had no commercial funding. Members of the writing group reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This transcript of Impact Factor with F. Perry Wilson has been edited for clarity.

It was 100 years ago when Leonard Thompson, age 13, received a reprieve from a death sentence. Young master Thompson had type 1 diabetes, a disease that was uniformly fatal within months of diagnosis. But he received a new treatment, insulin, from a canine pancreas. He would live 13 more years before dying at age 26 of pneumonia.

The history of type 1 diabetes since that time has been a battle on two fronts: First, the search for a cause of and cure for the disease; second, the effort to make the administration of insulin safer, more reliable, and easier.

The past 2 decades have seen a technological revolution in type 1 diabetes care, with continuous glucose monitors decreasing the need for painful finger sticks, and insulin pumps allowing for more precise titration of doses.

The dream, of course, has been to combine those two technologies, continuous glucose monitoring and insulin pumps, to create so-called closed-loop systems – basically an artificial pancreas – that would obviate the need for any intervention on the part of the patient, save the occasional refilling of an insulin reservoir.

We aren’t there yet, but we are closer than ever.

Closed-loop systems for insulin delivery, like the Tandem Control IQ system, are a marvel of technology, but they are not exactly hands-free. Users need to dial in settings for their insulin usage, count carbohydrates at meals, and inform the system that they are about to eat those meals to allow the algorithm to administer an appropriate insulin dose.

The perceived complexity of these systems may be responsible for why there are substantial disparities in the prescription of closed-loop systems. Kids of lower socioeconomic status are dramatically less likely to receive these advanced technologies. Providers may feel that patients with lower health literacy or social supports are not “ideal” for these technologies, even though they lead to demonstrably better outcomes.

That means that easier might be better. And a “bionic pancreas,” as reported in an article from The New England Journal of Medicine, is exactly that.

Broadly, it’s another closed-loop system. The bionic pancreas integrates with a continuous glucose monitor and administers insulin when needed. But the algorithm appears to be a bit smarter than what we have in existing devices. For example, patients do not need to provide any information about their usual insulin doses – just their body weight. They don’t need to count carbohydrates at meals – just to inform the device when they are eating, and whether the meal is the usual amount they eat, more, or less. The algorithm learns and adapts as it is used. Easy.

And in this randomized trial, easy does it.

A total of 219 participants were randomized in a 2:1 ratio to the bionic pancreas or usual diabetes care, though it was required that control participants use a continuous glucose monitor. Participants were as young as 6 years old and up to 79 years old; the majority were White and had a relatively high household income. The mean A1c was around 7.8% at baseline.

By the end of the study, the A1c was significantly improved in the bionic pancreas group, with a mean of 7.3% vs. 7.7% in the usual-care group.

This effect was most pronounced in those with a higher A1c at baseline.

People randomized to the bionic pancreas also spent more time in the target glucose range of 70-180 mg/dL.

All in all, the technology that makes it easy to manage your blood sugar, well, made it easy to manage your blood sugar.

But new technology is never without its hiccups. Those randomized to the bionic pancreas had a markedly higher rate of adverse events (244 events in 126 people compared with 10 events in 8 people in the usual-care group.)

This is actually a little misleading, though. The vast majority of these events were hyperglycemic episodes due to infusion set failures, which were reportable only in the bionic pancreas group. In other words, the patients in the control group who had an infusion set failure (assuming they were using an insulin pump at all) would have just called their regular doctor to get things sorted and not reported it to the study team.

Nevertheless, these adverse events – not serious, but common – highlight the fact that good software is not the only key to solving the closed-loop problem. We need good hardware too, hardware that can withstand the very active lives that children with type 1 diabetes deserve to live.

In short, the dream of a functional cure to type 1 diabetes, a true artificial pancreas, is closer than ever, but it’s still just a dream. With iterative advances like this, though, the reality may be here before you know it.

Dr. Wilson is associate professor of medicine and director of Yale University’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. A version of this article first appeared on Medscape.com.

This transcript of Impact Factor with F. Perry Wilson has been edited for clarity.

It was 100 years ago when Leonard Thompson, age 13, received a reprieve from a death sentence. Young master Thompson had type 1 diabetes, a disease that was uniformly fatal within months of diagnosis. But he received a new treatment, insulin, from a canine pancreas. He would live 13 more years before dying at age 26 of pneumonia.

The history of type 1 diabetes since that time has been a battle on two fronts: First, the search for a cause of and cure for the disease; second, the effort to make the administration of insulin safer, more reliable, and easier.

The past 2 decades have seen a technological revolution in type 1 diabetes care, with continuous glucose monitors decreasing the need for painful finger sticks, and insulin pumps allowing for more precise titration of doses.

The dream, of course, has been to combine those two technologies, continuous glucose monitoring and insulin pumps, to create so-called closed-loop systems – basically an artificial pancreas – that would obviate the need for any intervention on the part of the patient, save the occasional refilling of an insulin reservoir.

We aren’t there yet, but we are closer than ever.

Closed-loop systems for insulin delivery, like the Tandem Control IQ system, are a marvel of technology, but they are not exactly hands-free. Users need to dial in settings for their insulin usage, count carbohydrates at meals, and inform the system that they are about to eat those meals to allow the algorithm to administer an appropriate insulin dose.

The perceived complexity of these systems may be responsible for why there are substantial disparities in the prescription of closed-loop systems. Kids of lower socioeconomic status are dramatically less likely to receive these advanced technologies. Providers may feel that patients with lower health literacy or social supports are not “ideal” for these technologies, even though they lead to demonstrably better outcomes.

That means that easier might be better. And a “bionic pancreas,” as reported in an article from The New England Journal of Medicine, is exactly that.

Broadly, it’s another closed-loop system. The bionic pancreas integrates with a continuous glucose monitor and administers insulin when needed. But the algorithm appears to be a bit smarter than what we have in existing devices. For example, patients do not need to provide any information about their usual insulin doses – just their body weight. They don’t need to count carbohydrates at meals – just to inform the device when they are eating, and whether the meal is the usual amount they eat, more, or less. The algorithm learns and adapts as it is used. Easy.

And in this randomized trial, easy does it.

A total of 219 participants were randomized in a 2:1 ratio to the bionic pancreas or usual diabetes care, though it was required that control participants use a continuous glucose monitor. Participants were as young as 6 years old and up to 79 years old; the majority were White and had a relatively high household income. The mean A1c was around 7.8% at baseline.

By the end of the study, the A1c was significantly improved in the bionic pancreas group, with a mean of 7.3% vs. 7.7% in the usual-care group.

This effect was most pronounced in those with a higher A1c at baseline.

People randomized to the bionic pancreas also spent more time in the target glucose range of 70-180 mg/dL.

All in all, the technology that makes it easy to manage your blood sugar, well, made it easy to manage your blood sugar.

But new technology is never without its hiccups. Those randomized to the bionic pancreas had a markedly higher rate of adverse events (244 events in 126 people compared with 10 events in 8 people in the usual-care group.)

This is actually a little misleading, though. The vast majority of these events were hyperglycemic episodes due to infusion set failures, which were reportable only in the bionic pancreas group. In other words, the patients in the control group who had an infusion set failure (assuming they were using an insulin pump at all) would have just called their regular doctor to get things sorted and not reported it to the study team.

Nevertheless, these adverse events – not serious, but common – highlight the fact that good software is not the only key to solving the closed-loop problem. We need good hardware too, hardware that can withstand the very active lives that children with type 1 diabetes deserve to live.

In short, the dream of a functional cure to type 1 diabetes, a true artificial pancreas, is closer than ever, but it’s still just a dream. With iterative advances like this, though, the reality may be here before you know it.

Dr. Wilson is associate professor of medicine and director of Yale University’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. A version of this article first appeared on Medscape.com.

This transcript of Impact Factor with F. Perry Wilson has been edited for clarity.

It was 100 years ago when Leonard Thompson, age 13, received a reprieve from a death sentence. Young master Thompson had type 1 diabetes, a disease that was uniformly fatal within months of diagnosis. But he received a new treatment, insulin, from a canine pancreas. He would live 13 more years before dying at age 26 of pneumonia.

The history of type 1 diabetes since that time has been a battle on two fronts: First, the search for a cause of and cure for the disease; second, the effort to make the administration of insulin safer, more reliable, and easier.

The past 2 decades have seen a technological revolution in type 1 diabetes care, with continuous glucose monitors decreasing the need for painful finger sticks, and insulin pumps allowing for more precise titration of doses.

The dream, of course, has been to combine those two technologies, continuous glucose monitoring and insulin pumps, to create so-called closed-loop systems – basically an artificial pancreas – that would obviate the need for any intervention on the part of the patient, save the occasional refilling of an insulin reservoir.

We aren’t there yet, but we are closer than ever.

Closed-loop systems for insulin delivery, like the Tandem Control IQ system, are a marvel of technology, but they are not exactly hands-free. Users need to dial in settings for their insulin usage, count carbohydrates at meals, and inform the system that they are about to eat those meals to allow the algorithm to administer an appropriate insulin dose.

The perceived complexity of these systems may be responsible for why there are substantial disparities in the prescription of closed-loop systems. Kids of lower socioeconomic status are dramatically less likely to receive these advanced technologies. Providers may feel that patients with lower health literacy or social supports are not “ideal” for these technologies, even though they lead to demonstrably better outcomes.

That means that easier might be better. And a “bionic pancreas,” as reported in an article from The New England Journal of Medicine, is exactly that.

Broadly, it’s another closed-loop system. The bionic pancreas integrates with a continuous glucose monitor and administers insulin when needed. But the algorithm appears to be a bit smarter than what we have in existing devices. For example, patients do not need to provide any information about their usual insulin doses – just their body weight. They don’t need to count carbohydrates at meals – just to inform the device when they are eating, and whether the meal is the usual amount they eat, more, or less. The algorithm learns and adapts as it is used. Easy.

And in this randomized trial, easy does it.

A total of 219 participants were randomized in a 2:1 ratio to the bionic pancreas or usual diabetes care, though it was required that control participants use a continuous glucose monitor. Participants were as young as 6 years old and up to 79 years old; the majority were White and had a relatively high household income. The mean A1c was around 7.8% at baseline.

By the end of the study, the A1c was significantly improved in the bionic pancreas group, with a mean of 7.3% vs. 7.7% in the usual-care group.

This effect was most pronounced in those with a higher A1c at baseline.

People randomized to the bionic pancreas also spent more time in the target glucose range of 70-180 mg/dL.

All in all, the technology that makes it easy to manage your blood sugar, well, made it easy to manage your blood sugar.

But new technology is never without its hiccups. Those randomized to the bionic pancreas had a markedly higher rate of adverse events (244 events in 126 people compared with 10 events in 8 people in the usual-care group.)

This is actually a little misleading, though. The vast majority of these events were hyperglycemic episodes due to infusion set failures, which were reportable only in the bionic pancreas group. In other words, the patients in the control group who had an infusion set failure (assuming they were using an insulin pump at all) would have just called their regular doctor to get things sorted and not reported it to the study team.

Nevertheless, these adverse events – not serious, but common – highlight the fact that good software is not the only key to solving the closed-loop problem. We need good hardware too, hardware that can withstand the very active lives that children with type 1 diabetes deserve to live.

In short, the dream of a functional cure to type 1 diabetes, a true artificial pancreas, is closer than ever, but it’s still just a dream. With iterative advances like this, though, the reality may be here before you know it.

Dr. Wilson is associate professor of medicine and director of Yale University’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. A version of this article first appeared on Medscape.com.

Long COVID is likely to cost the U.S. economy trillions of dollars and will almost certainly affect multiple industries, from restaurants struggling to replace low-wage workers, to airlines scrambling to replace crew, to overwhelmed hospitals, experts are predicting.

“There’s a lot we need to do to understand what it takes to enable disabled people to participate more in the economy,” said Katie Bach, a senior fellow with Brookings Institution and the author of a study looking into long COVID’s impact on the labor market.

Data from June 2022 from the Centers for Disease Control and Prevention shows that, of the 40% of American adults who contracted COVID-19, nearly one in five still have long COVID symptoms. That works out to 1 in 13, or 7.5%, of the overall U.S. adult population.

Drawing from the CDC data, Ms. Bach estimates in her August 2022 report that as many as 4 million working-age Americans are too sick with long COVID to perform their jobs. That works out to as much as $230 billion in lost wages, or almost 1% of the U.S. GDP.

“This is a big deal,” she said. “We’re talking potentially hundreds of billions of dollars a year and that this is big enough to have a measurable impact on the labor market.”

Other sources have suggested lower figures, but the conclusions are the same: Long COVID is an urgent issue that will cost tens of billions of dollars a year in lost wages alone, Ms. Bach said. But it’s not just lost income for workers. There is a cost for businesses and the public.

Throughout the pandemic, COVID-19’s crippling force could be felt across multiple industries. While business has picked up again, staffing shortages remain a challenge. At some airports this summer, air passengers spent hours in security lines; were stranded for days as flights were canceled, rebooked, and canceled again on short notice; and waited weeks for lost luggage. Restaurants have had to cut back their hours. Those seeking medical care had longer than usual wait times in EDs and urgent care clinics. Some EDs temporarily closed.

These challenges have been attributed in part to the “great resignation” and in part because so many infected workers were out, especially during the Omicron waves. But increasingly, economists and health care professionals alike worry about long COVID’s impact on employers and the broader economy.

David Cutler, PhD, a professor of economics at Harvard University, Cambridge, Mass., believes the total economic loss could be as high as $3.7 trillion, when factoring in the lost quality of life, the cost in lost earnings, and the cost of higher spending on medical care. His estimate is more than a trillion dollars higher than a previous projection he and fellow economist Lawrence Summers, PhD, made in 2020. The reason? Long COVID.

“The higher estimate is largely a result of the greater prevalence of long COVID than we had guessed at the time,” Dr. Cutler wrote in a paper released in July.

“There are about 10 times the number of people with long COVID as have died of COVID. Because long COVID is so new, there is uncertainty about all of the numbers involved in the calculations. Still, the costs here are conservative, based on only cases to date.”

In Ms. Bach’s Brookings report, she projected that, if recovery from long COVID does not pick up and the population of Americans with long COVID were to grow by 10% a year, the annual cost of lost wages alone could reach half a trillion dollars in a decade.

Meanwhile, a working paper by the National Bureau of Economic Research found that workers who missed an entire week of work because of probable COVID-19 illnesses were roughly 7 percentage points less likely to be working a year later, compared with those who did not miss work for health reasons.

“It’s not just individuals with long COVID who are suffering from this. It impacts their families, their livelihoods, and the economy on a global scale. So, we have to raise awareness about those ripple effects,” said Linda Geng, MD, a clinical assistant professor of medicine with Stanford (Calif.) University’s Primary Care and Population Health. 

“I think it’s hard for the public to grasp ... and understand the scale of this public health crisis.”
 

Debilitating fatigue

Long COVID is roughly defined; the CDC defines it as symptoms that linger 3 or more months after a patient first catches the virus.

The symptoms vary and include profound fatigue and brain issues.

“It’s a new degree of extreme and debilitating fatigue and exhaustion, to the point where you can’t do your daily tasks,” said Dr. Geng, who is also the codirector of Stanford’s Post-Acute COVID-19 Syndrome Clinic.

“People can be so debilitated, they can’t even do basic things, like the activities of daily living, let alone do their job, particularly if it’s physically or mentally demanding.”

Patients can also have postexertional malaise, where they feel especially bad and symptoms worsen when they exert themselves physically or mentally, Dr. Geng said. Compounding the issue for many long COVID patients is their trouble getting restful sleep. Those with brain fog have issues with memory, processing information, focused concentration, confusion, making mistakes, and multitasking. Pain is another debilitating symptom that can disrupt daily life and ability to work.

Even people with relatively mild infections can end up with long COVID, Dr. Geng said, noting that many of the patients at the Stanford clinic were never hospitalized with their initial infections. While existing research and Dr. Geng’s clinical experience show that long COVID can hit any age, she most commonly sees patients from ages 20 to their 60s, with an average age in the 40s – people in their prime working ages.

Jason Furman, PhD, a former White House economic adviser who is now a professor at Harvard University, noted in August that the labor force participation rate was far below what could be explained by standard demographic changes like an aging population, with the decline evident across all age groups. Dr. Furman does not speculate about why, but others have.

“We are pessimistic: Both the aging of the population and the impact of long COVID imply that the participation rate will be slow to return to its prepandemic level,” Anna Wong, Yelena Shulyatyeva, Andrew Husby, and Eliza Winger, economists with Bloomberg Economics, wrote in a research note. 
 

Supportive policies 

There is some evidence that vaccination reduces the risk of long COVID, but not completely, and it is too early to know if repeat infections increase long COVID risks. There is also no definitive data on how fast or how many people are recovering. Economists often assume that those with long COVID will recover at some point, Ms. Bach noted, but she is careful not to make assumptions.

“If people aren’t recovering, then this group keeps getting bigger,” she said. “We’re still adding, and if people aren’t coming out of that group, this becomes a bigger and bigger problem.”

For now, the number of new people being diagnosed with long COVID appears to have slowed, Ms. Bach said, but it remains to be seen whether the trend can be sustained.

“If people are impaired longer than we think and if the impairment turns out to be severe, then we can have a lot of people who need services like disability insurance,” Dr. Cutler said.

“That could put a really big strain on public sector programs and our ability to meet those needs.”

Policies that support the research and clinical work necessary to prevent and treat long COVID are essential, experts say.

“To me, that is the biggest economic imperative, to say nothing of human suffering,” said Ms. Bach. 

Employers also have a role, and experts say there are a number of accommodations businesses should consider. What happens when an employee has long COVID? Can accommodations be made that allow them to continue working productively? If they spend a great deal of time commuting, can they work from home? What can employers do so that family members do not have to drop out of the workforce to take care of loved ones with long COVID? 
 

Disability insurance

To be sure, there is one piece of the puzzle that does not quite fit, according to Dr. Cutler and Ms. Bach. There is no sign yet of a large increase in federal disability insurance applications, and no one quite knows why. Publicly available government data shows that online applications actually dipped by about 4% each year between 2019 and 2021. Applications in 2022 appear on track to remain slightly below prepandemic levels. 

To qualify for Social Security Disability Insurance (SSDI), people need to have a disability that lasts at least a year. 

“If you’re disabled with long COVID, who knows, right? You don’t know,” said Ms. Bach. “Two of the most dominant symptoms of long COVID are fatigue and brain fog. So, I’ve heard from people that the process of going through an SSDI application is really hard.”

Some long COVID patients told Ms. Bach they simply assumed they would not get SSDI and did not even bother applying. She stressed that working Americans with debilitating long COVID should be aware that their condition is protected by the Americans with Disabilities Act. But the challenge, based on guidance issued by the government, is that not all cases of long COVID qualify as a disability and that individual assessments are necessary.

While more long COVID data are needed, Ms. Bach believes there is enough information for decisionmakers to go after the issue more aggressively. She pointed to the $1.15 billion in funding that Congress earmarked for the National Institutes of Health over the course of 4 years in support of research into the long-term health effects of COVID-19.

“Now, $250 million a year sounds like a lot of money until you start talking about the cost of lost wages – just lost wages,” Ms. Bach said. “That’s not lost productivity. That’s not the cost of people whose family members are sick. Who have to reduce their own labor force participation. That’s not medical costs. Suddenly, $250 million doesn’t really sound like that much.”

A version of this article first appeared on WebMD.com.

Long COVID is likely to cost the U.S. economy trillions of dollars and will almost certainly affect multiple industries, from restaurants struggling to replace low-wage workers, to airlines scrambling to replace crew, to overwhelmed hospitals, experts are predicting.

“There’s a lot we need to do to understand what it takes to enable disabled people to participate more in the economy,” said Katie Bach, a senior fellow with Brookings Institution and the author of a study looking into long COVID’s impact on the labor market.

Data from June 2022 from the Centers for Disease Control and Prevention shows that, of the 40% of American adults who contracted COVID-19, nearly one in five still have long COVID symptoms. That works out to 1 in 13, or 7.5%, of the overall U.S. adult population.

Drawing from the CDC data, Ms. Bach estimates in her August 2022 report that as many as 4 million working-age Americans are too sick with long COVID to perform their jobs. That works out to as much as $230 billion in lost wages, or almost 1% of the U.S. GDP.

“This is a big deal,” she said. “We’re talking potentially hundreds of billions of dollars a year and that this is big enough to have a measurable impact on the labor market.”

Other sources have suggested lower figures, but the conclusions are the same: Long COVID is an urgent issue that will cost tens of billions of dollars a year in lost wages alone, Ms. Bach said. But it’s not just lost income for workers. There is a cost for businesses and the public.

Throughout the pandemic, COVID-19’s crippling force could be felt across multiple industries. While business has picked up again, staffing shortages remain a challenge. At some airports this summer, air passengers spent hours in security lines; were stranded for days as flights were canceled, rebooked, and canceled again on short notice; and waited weeks for lost luggage. Restaurants have had to cut back their hours. Those seeking medical care had longer than usual wait times in EDs and urgent care clinics. Some EDs temporarily closed.

These challenges have been attributed in part to the “great resignation” and in part because so many infected workers were out, especially during the Omicron waves. But increasingly, economists and health care professionals alike worry about long COVID’s impact on employers and the broader economy.

David Cutler, PhD, a professor of economics at Harvard University, Cambridge, Mass., believes the total economic loss could be as high as $3.7 trillion, when factoring in the lost quality of life, the cost in lost earnings, and the cost of higher spending on medical care. His estimate is more than a trillion dollars higher than a previous projection he and fellow economist Lawrence Summers, PhD, made in 2020. The reason? Long COVID.

“The higher estimate is largely a result of the greater prevalence of long COVID than we had guessed at the time,” Dr. Cutler wrote in a paper released in July.

“There are about 10 times the number of people with long COVID as have died of COVID. Because long COVID is so new, there is uncertainty about all of the numbers involved in the calculations. Still, the costs here are conservative, based on only cases to date.”

In Ms. Bach’s Brookings report, she projected that, if recovery from long COVID does not pick up and the population of Americans with long COVID were to grow by 10% a year, the annual cost of lost wages alone could reach half a trillion dollars in a decade.

Meanwhile, a working paper by the National Bureau of Economic Research found that workers who missed an entire week of work because of probable COVID-19 illnesses were roughly 7 percentage points less likely to be working a year later, compared with those who did not miss work for health reasons.

“It’s not just individuals with long COVID who are suffering from this. It impacts their families, their livelihoods, and the economy on a global scale. So, we have to raise awareness about those ripple effects,” said Linda Geng, MD, a clinical assistant professor of medicine with Stanford (Calif.) University’s Primary Care and Population Health. 

“I think it’s hard for the public to grasp ... and understand the scale of this public health crisis.”
 

Debilitating fatigue

Long COVID is roughly defined; the CDC defines it as symptoms that linger 3 or more months after a patient first catches the virus.

The symptoms vary and include profound fatigue and brain issues.

“It’s a new degree of extreme and debilitating fatigue and exhaustion, to the point where you can’t do your daily tasks,” said Dr. Geng, who is also the codirector of Stanford’s Post-Acute COVID-19 Syndrome Clinic.

“People can be so debilitated, they can’t even do basic things, like the activities of daily living, let alone do their job, particularly if it’s physically or mentally demanding.”

Patients can also have postexertional malaise, where they feel especially bad and symptoms worsen when they exert themselves physically or mentally, Dr. Geng said. Compounding the issue for many long COVID patients is their trouble getting restful sleep. Those with brain fog have issues with memory, processing information, focused concentration, confusion, making mistakes, and multitasking. Pain is another debilitating symptom that can disrupt daily life and ability to work.

Even people with relatively mild infections can end up with long COVID, Dr. Geng said, noting that many of the patients at the Stanford clinic were never hospitalized with their initial infections. While existing research and Dr. Geng’s clinical experience show that long COVID can hit any age, she most commonly sees patients from ages 20 to their 60s, with an average age in the 40s – people in their prime working ages.

Jason Furman, PhD, a former White House economic adviser who is now a professor at Harvard University, noted in August that the labor force participation rate was far below what could be explained by standard demographic changes like an aging population, with the decline evident across all age groups. Dr. Furman does not speculate about why, but others have.

“We are pessimistic: Both the aging of the population and the impact of long COVID imply that the participation rate will be slow to return to its prepandemic level,” Anna Wong, Yelena Shulyatyeva, Andrew Husby, and Eliza Winger, economists with Bloomberg Economics, wrote in a research note. 
 

Supportive policies 

There is some evidence that vaccination reduces the risk of long COVID, but not completely, and it is too early to know if repeat infections increase long COVID risks. There is also no definitive data on how fast or how many people are recovering. Economists often assume that those with long COVID will recover at some point, Ms. Bach noted, but she is careful not to make assumptions.

“If people aren’t recovering, then this group keeps getting bigger,” she said. “We’re still adding, and if people aren’t coming out of that group, this becomes a bigger and bigger problem.”

For now, the number of new people being diagnosed with long COVID appears to have slowed, Ms. Bach said, but it remains to be seen whether the trend can be sustained.

“If people are impaired longer than we think and if the impairment turns out to be severe, then we can have a lot of people who need services like disability insurance,” Dr. Cutler said.

“That could put a really big strain on public sector programs and our ability to meet those needs.”

Policies that support the research and clinical work necessary to prevent and treat long COVID are essential, experts say.

“To me, that is the biggest economic imperative, to say nothing of human suffering,” said Ms. Bach. 

Employers also have a role, and experts say there are a number of accommodations businesses should consider. What happens when an employee has long COVID? Can accommodations be made that allow them to continue working productively? If they spend a great deal of time commuting, can they work from home? What can employers do so that family members do not have to drop out of the workforce to take care of loved ones with long COVID? 
 

Disability insurance

To be sure, there is one piece of the puzzle that does not quite fit, according to Dr. Cutler and Ms. Bach. There is no sign yet of a large increase in federal disability insurance applications, and no one quite knows why. Publicly available government data shows that online applications actually dipped by about 4% each year between 2019 and 2021. Applications in 2022 appear on track to remain slightly below prepandemic levels. 

To qualify for Social Security Disability Insurance (SSDI), people need to have a disability that lasts at least a year. 

“If you’re disabled with long COVID, who knows, right? You don’t know,” said Ms. Bach. “Two of the most dominant symptoms of long COVID are fatigue and brain fog. So, I’ve heard from people that the process of going through an SSDI application is really hard.”

Some long COVID patients told Ms. Bach they simply assumed they would not get SSDI and did not even bother applying. She stressed that working Americans with debilitating long COVID should be aware that their condition is protected by the Americans with Disabilities Act. But the challenge, based on guidance issued by the government, is that not all cases of long COVID qualify as a disability and that individual assessments are necessary.

While more long COVID data are needed, Ms. Bach believes there is enough information for decisionmakers to go after the issue more aggressively. She pointed to the $1.15 billion in funding that Congress earmarked for the National Institutes of Health over the course of 4 years in support of research into the long-term health effects of COVID-19.

“Now, $250 million a year sounds like a lot of money until you start talking about the cost of lost wages – just lost wages,” Ms. Bach said. “That’s not lost productivity. That’s not the cost of people whose family members are sick. Who have to reduce their own labor force participation. That’s not medical costs. Suddenly, $250 million doesn’t really sound like that much.”

A version of this article first appeared on WebMD.com.

Long COVID is likely to cost the U.S. economy trillions of dollars and will almost certainly affect multiple industries, from restaurants struggling to replace low-wage workers, to airlines scrambling to replace crew, to overwhelmed hospitals, experts are predicting.

“There’s a lot we need to do to understand what it takes to enable disabled people to participate more in the economy,” said Katie Bach, a senior fellow with Brookings Institution and the author of a study looking into long COVID’s impact on the labor market.

Data from June 2022 from the Centers for Disease Control and Prevention shows that, of the 40% of American adults who contracted COVID-19, nearly one in five still have long COVID symptoms. That works out to 1 in 13, or 7.5%, of the overall U.S. adult population.

Drawing from the CDC data, Ms. Bach estimates in her August 2022 report that as many as 4 million working-age Americans are too sick with long COVID to perform their jobs. That works out to as much as $230 billion in lost wages, or almost 1% of the U.S. GDP.

“This is a big deal,” she said. “We’re talking potentially hundreds of billions of dollars a year and that this is big enough to have a measurable impact on the labor market.”

Other sources have suggested lower figures, but the conclusions are the same: Long COVID is an urgent issue that will cost tens of billions of dollars a year in lost wages alone, Ms. Bach said. But it’s not just lost income for workers. There is a cost for businesses and the public.

Throughout the pandemic, COVID-19’s crippling force could be felt across multiple industries. While business has picked up again, staffing shortages remain a challenge. At some airports this summer, air passengers spent hours in security lines; were stranded for days as flights were canceled, rebooked, and canceled again on short notice; and waited weeks for lost luggage. Restaurants have had to cut back their hours. Those seeking medical care had longer than usual wait times in EDs and urgent care clinics. Some EDs temporarily closed.

These challenges have been attributed in part to the “great resignation” and in part because so many infected workers were out, especially during the Omicron waves. But increasingly, economists and health care professionals alike worry about long COVID’s impact on employers and the broader economy.

David Cutler, PhD, a professor of economics at Harvard University, Cambridge, Mass., believes the total economic loss could be as high as $3.7 trillion, when factoring in the lost quality of life, the cost in lost earnings, and the cost of higher spending on medical care. His estimate is more than a trillion dollars higher than a previous projection he and fellow economist Lawrence Summers, PhD, made in 2020. The reason? Long COVID.

“The higher estimate is largely a result of the greater prevalence of long COVID than we had guessed at the time,” Dr. Cutler wrote in a paper released in July.

“There are about 10 times the number of people with long COVID as have died of COVID. Because long COVID is so new, there is uncertainty about all of the numbers involved in the calculations. Still, the costs here are conservative, based on only cases to date.”

In Ms. Bach’s Brookings report, she projected that, if recovery from long COVID does not pick up and the population of Americans with long COVID were to grow by 10% a year, the annual cost of lost wages alone could reach half a trillion dollars in a decade.

Meanwhile, a working paper by the National Bureau of Economic Research found that workers who missed an entire week of work because of probable COVID-19 illnesses were roughly 7 percentage points less likely to be working a year later, compared with those who did not miss work for health reasons.

“It’s not just individuals with long COVID who are suffering from this. It impacts their families, their livelihoods, and the economy on a global scale. So, we have to raise awareness about those ripple effects,” said Linda Geng, MD, a clinical assistant professor of medicine with Stanford (Calif.) University’s Primary Care and Population Health. 

“I think it’s hard for the public to grasp ... and understand the scale of this public health crisis.”
 

Debilitating fatigue

Long COVID is roughly defined; the CDC defines it as symptoms that linger 3 or more months after a patient first catches the virus.

The symptoms vary and include profound fatigue and brain issues.

“It’s a new degree of extreme and debilitating fatigue and exhaustion, to the point where you can’t do your daily tasks,” said Dr. Geng, who is also the codirector of Stanford’s Post-Acute COVID-19 Syndrome Clinic.

“People can be so debilitated, they can’t even do basic things, like the activities of daily living, let alone do their job, particularly if it’s physically or mentally demanding.”

Patients can also have postexertional malaise, where they feel especially bad and symptoms worsen when they exert themselves physically or mentally, Dr. Geng said. Compounding the issue for many long COVID patients is their trouble getting restful sleep. Those with brain fog have issues with memory, processing information, focused concentration, confusion, making mistakes, and multitasking. Pain is another debilitating symptom that can disrupt daily life and ability to work.

Even people with relatively mild infections can end up with long COVID, Dr. Geng said, noting that many of the patients at the Stanford clinic were never hospitalized with their initial infections. While existing research and Dr. Geng’s clinical experience show that long COVID can hit any age, she most commonly sees patients from ages 20 to their 60s, with an average age in the 40s – people in their prime working ages.

Jason Furman, PhD, a former White House economic adviser who is now a professor at Harvard University, noted in August that the labor force participation rate was far below what could be explained by standard demographic changes like an aging population, with the decline evident across all age groups. Dr. Furman does not speculate about why, but others have.

“We are pessimistic: Both the aging of the population and the impact of long COVID imply that the participation rate will be slow to return to its prepandemic level,” Anna Wong, Yelena Shulyatyeva, Andrew Husby, and Eliza Winger, economists with Bloomberg Economics, wrote in a research note. 
 

Supportive policies 

There is some evidence that vaccination reduces the risk of long COVID, but not completely, and it is too early to know if repeat infections increase long COVID risks. There is also no definitive data on how fast or how many people are recovering. Economists often assume that those with long COVID will recover at some point, Ms. Bach noted, but she is careful not to make assumptions.

“If people aren’t recovering, then this group keeps getting bigger,” she said. “We’re still adding, and if people aren’t coming out of that group, this becomes a bigger and bigger problem.”

For now, the number of new people being diagnosed with long COVID appears to have slowed, Ms. Bach said, but it remains to be seen whether the trend can be sustained.

“If people are impaired longer than we think and if the impairment turns out to be severe, then we can have a lot of people who need services like disability insurance,” Dr. Cutler said.

“That could put a really big strain on public sector programs and our ability to meet those needs.”

Policies that support the research and clinical work necessary to prevent and treat long COVID are essential, experts say.

“To me, that is the biggest economic imperative, to say nothing of human suffering,” said Ms. Bach. 

Employers also have a role, and experts say there are a number of accommodations businesses should consider. What happens when an employee has long COVID? Can accommodations be made that allow them to continue working productively? If they spend a great deal of time commuting, can they work from home? What can employers do so that family members do not have to drop out of the workforce to take care of loved ones with long COVID? 
 

Disability insurance

To be sure, there is one piece of the puzzle that does not quite fit, according to Dr. Cutler and Ms. Bach. There is no sign yet of a large increase in federal disability insurance applications, and no one quite knows why. Publicly available government data shows that online applications actually dipped by about 4% each year between 2019 and 2021. Applications in 2022 appear on track to remain slightly below prepandemic levels. 

To qualify for Social Security Disability Insurance (SSDI), people need to have a disability that lasts at least a year. 

“If you’re disabled with long COVID, who knows, right? You don’t know,” said Ms. Bach. “Two of the most dominant symptoms of long COVID are fatigue and brain fog. So, I’ve heard from people that the process of going through an SSDI application is really hard.”

Some long COVID patients told Ms. Bach they simply assumed they would not get SSDI and did not even bother applying. She stressed that working Americans with debilitating long COVID should be aware that their condition is protected by the Americans with Disabilities Act. But the challenge, based on guidance issued by the government, is that not all cases of long COVID qualify as a disability and that individual assessments are necessary.

While more long COVID data are needed, Ms. Bach believes there is enough information for decisionmakers to go after the issue more aggressively. She pointed to the $1.15 billion in funding that Congress earmarked for the National Institutes of Health over the course of 4 years in support of research into the long-term health effects of COVID-19.

“Now, $250 million a year sounds like a lot of money until you start talking about the cost of lost wages – just lost wages,” Ms. Bach said. “That’s not lost productivity. That’s not the cost of people whose family members are sick. Who have to reduce their own labor force participation. That’s not medical costs. Suddenly, $250 million doesn’t really sound like that much.”

A version of this article first appeared on WebMD.com.