Latent Autoimmune Diabetes in Adults (LADA): recognition and management

A recent KFF Health News article highlighted misdiagnoses of type 2 diabetes in several Black female patients who actually had latent autoimmune diabetes in adults (LADA), a slowly progressive form of type 1 diabetes. Although the article suggested that the patients’ race may have played a role in delaying their LADA diagnoses, this condition commonly goes unrecognized in primary care. According to Dr. Jeff Unger in a 2010 American Family Physician editorial, an estimated 10% of patients with a diagnosis of type 2 diabetes actually have LADA.

Unlike patients with classic type 1 diabetes, patients with LADA have initially preserved pancreatic beta cell function and thus may have a transient response to noninsulin therapy and lifestyle modifications. However, as the disease progresses, they will require insulin to maintain blood glucose control, generally within one year of diagnosis.

A feature that distinguishes LADA from type 2 diabetes is the presence of at least one autoantibody, most commonly islet call antibodies or antibodies to glutamic acid decarboxylase (GAD). While persons with type 2 diabetes have normal to high C-peptide levels, patients with LADA tend to have low levels. Dr. Unger provided other potential clues that should prompt clinicians to reconsider a type 2 diabetes diagnosis:

Suspicion of LADA should be heightened in patients with coexisting autoimmune disorders, such as hypothyroidism, who are not excessively overweight and who have deteriorating glycemic control despite intensification of oral therapies and the use of incretin mimetics. Physicians may consider GAD antibody testing to determine whether LADA is present.

A 2020 consensus statement from an international expert panel made treatment recommendations for patients with LADA. Although insulin is effective and safe, it is unclear if it should be given to patients in the early stages of LADA who may still respond to oral therapies such as metformin. The panel discouraged the use of sulfonylureas, which may accelerate loss of beta cell function. Dipeptidyl peptidase 4 inhibitors, glucagon-like peptide receptor 1 agonists, and sodium-glucose cotransporter 2 inhibitors have shown promise in small studies, but more research is required. The panel recommended that all patients with newly diagnosed type 2 diabetes be screened for LADA with a test for antibodies to GAD, followed by tests for other autoantibodies if clinical suspicion remains high.

In patients who have one or more autoantibodies and presumed LADA, the next step is C-peptide measurement. Those with C-peptide levels greater than 0.7 nmol/L can be managed similarly to patients with type 2 diabetes; those with levels lower than 0.3 nmol/L should start insulin. Patients in the “gray area” (with a C-peptide level between 0.3 and 0.7 nmol/L), should start metformin and other noninsulin agents based on blood glucose levels and cardiovascular and kidney disease risk; C-peptide levels should be rechecked every 6 months to monitor for the development of insulin deficiency.

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This post first appeared on the AFP Community Blog.

A venerable family medicine journal exits the stage

Six years ago, I was promoted to the rank of deputy editor at American Family Physician. On the whole, I continue to find translating the latest scientific evidence into continuing medical education for family physicians and trainees to be satisfying and intellectually rewarding. As I pass the likely midpoint of my career, I have achieved all of my editorial goals, save one. In pursuit of that goal, in March 2023 I applied for the position of editor-in-chief at The Journal of Family Practice, a widely respected primary care journal for nearly 50 years (AFP will celebrate its 75th anniversary in 2025) whose editor's chair had been vacated by the sudden passing of the legendary family physician educator John Hickner, MD. I began reading JFP during my residency 20 years ago, and its editorial board still included the same faculty mentor (now retired) who launched my editing career by urging me to write a clinical review article for AFP. The timing seemed favorable for me to climb the last rung of the editorial ladder.

Alas, not only was another very well-qualified candidate selected instead, but in November, JFP permanently ceased publication for financial reasons. It happened so abruptly that the journal had a backlog of accepted but unpublished articles that would need to find new homes elsewhere; I'm happy to share that a few of them will appear in future issues of AFP. In the January issue of Family Medicine, Dr. John Frey penned an eloquent "curtain call" for JFP:

A superior group of editorial board members guided publication of research on topics that still are the source of much of the literature in the discipline and philosophical and intellectual articles by some of the most important writers and researchers in the first 20 years of family medicine’s existence. That the journal continued to publish after shifting from a primary research journal to a quality review journal, and managed to survive as long as it did is a tribute to the integrity and hard work of the many distinguished academic editors over its history. ... JFP was one of the principal reasons that family physicians, who were unused to reading primary sources of clinical research, began to change both by reading and contributing to the scholarship of a new field.

Although the past half-century has seen an outpouring of scholarship on clinical questions relevant to family physicians, academic family medicine remains woefully undervalued by research funders such as the National Institutes of Health, which from 2017 to 2021 devoted a paltry 0.2 percent of its budget to grants to family medicine departments. Nonetheless, a 2019 study found that faculty in family medicine departments publish 84% of the time in non-family medicine journals, paralleling my own publication record. This statistic suggests that the exit of JFP hardly closes the door on the possibility of new family medicine journals being launched to publish a share of the discipline's future scholarly output.

Despite weak evidence, spinal cord stimulators are big business

A Cochrane for Clinicians article in the December 2023 issue of American Family Physician reviewed randomized trials assessing the effectiveness of surgically implanted spinal cord stimulation devices for the treatment of chronic low back pain. These devices come with a high price tag ($30,000) and potential complications that include electrode migration, hematoma formation, infection, spinal cord injury, and cerebrospinal fluid leak. Dr. Brian Nelson and colleagues summarized a Cochrane review of 13 placebo-controlled trials with 699 adult participants (mean age 47 to 59 years) who had low back pain for at least 12 weeks. Primary outcomes included pain intensity, physical function, and quality of life. Most studies reported outcomes at follow-up dates of one month or less; only one study reported outcomes at six months.

Overall, the body of evidence was assessed as having significant bias, including selection bias (five studies), performance and detection bias (10 studies), attrition bias, and selective reporting bias. The largest study, with 50 participants, found no statistical benefits. Three smaller trials suggested that “adding spinal cord stimulation to medical management may slightly improve function and slightly reduce opioid use in the medium term (i.e., one to less than 12 months).” Based on these findings, Dr. Nelson concluded:

The data do not support the use of spinal cord stimulation to manage low back pain outside of a clinical trial, and it is unclear if spinal cord stimulation has long-term clinical benefits to reasonably outweigh the costs and risks of surgical intervention.

In a recent commentary in JAMA Internal Medicine, two of the Cochrane review authors discussed tactics used by the spinal cord stimulator industry to dismiss the findings of their review and other independent reviews and studies that came to similar conclusions. These tactics included publishing lengthy critiques in paywalled industry-affiliated journals rather than the journal where the original study was published. They stated that “the credibility of our review team was attacked because one of the authors … had authored books on harms in health care,” equating this intellectual interest with financial conflicts held by supporters of spinal cord stimulators. Finally, critics conflated approval of spinal cord stimulators by the U.S. Food and Drug Administration (FDA) through the “substantial equivalence” 510(k) pathway with evidence of effectiveness and safety, even though this pathway does not require evidence of that kind.

In a 2022 Lown Right Care article on interventional procedures for low back pain, Drs. Alan Roth and Andy Lazris noted that “Surgery for low back pain is one of the most overused procedures in the United States, with more than 1.2 million back surgeries performed every year.” At an estimated 50,000 procedures annually, spinal cord stimulators make up a relatively small portion of these back surgeries. However, in a 2020 letter to health care providers, the FDA reported that over the preceding four-year period, it received “a total of 107,728 medical device reports related to spinal cord stimulators intended for pain, including 497 associated with a patient death [representing 428 deaths], 77,937 with patient injury, and 29,294 with device malfunction.” That seems like an unacceptably high rate of unintended effects for a device with modest benefits.

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This post first appeared on the AFP Community Blog.

What do the Air Force and family medicine have in common? AI

This year, I did a lot of reading about current and future applications of artificial intelligence (AI) in health care - for example, how it will reduce the grunt work of selecting future physicians; become a required competency in medical education; provide relief from overflowing primary care electronic in-baskets; and provide clinical decision support for treating patients with depression. I've read pessimistic commentaries about chatbots and large language models being a "Pandora's box" and more optimistic pieces arguing that generative AI can overcome the "productivity paradox" of information technology: that is, it won't take decades to see large gains in health care quality and efficiency, as we haven't seen with implementation of electronic health records. Meanwhile, regulatory authorities are still struggling to catch up to ensure the safety of AI products without discouraging technological innovation. (And while I was retrieving these articles online, Microsoft Bing's AI-enabled search engine kept trying to take over writing this blog post.) But the most interesting article that I read about AI this year had nothing to do with health care. It was about the U.S. Air Force.

"AI brings the robot wingman to aerial combat," declared the science fiction-sounding headline of this August 2023 New York Times story. It discussed the XQ-58A Valkyrie, a pilotless "collaborative combat aircraft" described as "essentially a next-generation drone." Eying a seemingly inevitable armed conflict with China over the disputed island of Taiwan, U.S. Air Force war planners hope that these robot wingmen (wingAIs?) will not only be far less expensive to produce than conventional piloted warplanes, but also spare the lives of many human pilots who would otherwise be shot down by China's vast antiaircraft apparatus. Why expect our flying servicemen and women to become casualties while performing exploits of derring-do when a fearless AI can complete the same mission at a fraction of the risk?

Military AI raises ethical dilemmas, of course. Behind every drone attack on suspected terrorists is a human being who has judged (rightly or wrongly) that the target is indeed a wartime adversary and fair game. But "the autonomous use of lethal force" - the idea that AI could be making kill decisions without any human signoff - makes many people uneasy. The Pentagon, naturally, dodged a reporter's question about whether the Valkyrie aircraft could eventually have this capability.

Similarly, I could imagine that in the next decade or two (before the end of my career) AI could be developed to perform many of the basic functions of a physician assistant in primary care: ordering recommended screening tests and vaccines, titrating medications for hypertension and diabetes, and deciding whether or not to prescribe antibiotics or antiviral drugs for patients with acute respiratory illnesses. Physician supervision would probably consist of reviewing charts and signing off on them at the end of a clinical session rather than double-checking the AI's decisions in real time. Would that mean that AI would be autonomously practicing health care? Sure it would. Would this application be easier or harder to adjust to than formations of armed Valkyries using machine algorithms to identify enemy personnel and shooting to kill?

My favorite public health and health care books of 2023

This year's annual list of my favorite reads includes two works of fiction and eight real-life narratives about cancer, the history of medicine, rural family practice, and urban street medicine. As usual, I have listed them alphabetically by title rather than in any order of preference. For more great titles, feel free to peruse my lists from 2022, 2021, and 2015-2020. Other than the occasional free book to review for Family Medicine, I don't receive anything for reading or sharing them.

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1. Chasing My Cure: A Doctor’s Race to Turn Hope into Action, by David Fajgenbaum



2. From Whispers to Shouts: The Ways We Talk About Cancer, by Elaine Schattner

3. Maladies of Empire: How Colonialism, Slavery, and War Transformed Medicine, by Jim Downs



4. The Masters of Medicine: Our Greatest Triumphs in the Race to Cure Humanity’s Deadliest Diseases, by Andrew Lam



5. Medicine and Miracles in the High Desert: My Life Among the Navajo People, by Erica Elliott



6. The Other Dr. Gilmer: Two Men, A Murder, and an Unlikely Fight for Justice, by Benjamin Gilmer



7. Rough Sleepers: Dr. Jim O’Connell’s Urgent Mission to Bring Healing to Homeless People, by Tracy Kidder



8. Take My Hand, by Dolen Perkins-Valdez

 

9. That Time I Got Cancer: A Love Story, by Jim Zervanos

 


10. 2060, by Richard Young

Will the high price of gene therapy for sickle cell disease put this cure out of reach?

On December 8, 2023, the U.S. Food and Drug Administration (FDA) approved Casgevy, the first gene therapy utilizing clustered, regularly interspaced short palindromic repeats (CRISPR) for the treatment of sickle cell disease in patients 12 years and older. Mimicking a protective mutation that causes fetal hemoglobin (HbF) to persist into adulthood, Casgevy uses the CRISPR-Cas9 enzyme to edit a patient’s own blood stem cells to intentionally disable a DNA “brake” on HbF production. The modified stem cells are transplanted back to the patient and result in the production of high levels of HbF, preventing the sickling of red blood cells and eliminating or greatly reducing future painful vaso-occlusive (VOC) crises. In an ongoing single-arm trial—initial results were published in 2020—29 out of 31 treated patients had no severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period.

The approval of Casgevy, which has a list price of $2.2 million for the single course of treatment, had been anticipated for months. However, the number of the estimated 100,000 Americans affected with sickle cell disease who will be able to afford it is unclear. Although the lifetime medical costs associated with sickle cell disease average $1.7 million, insurance companies may be unwilling to pay the exceptionally high up-front cost of this curative therapy. Compared with standard of care, one analysis found gene therapy to be an equitable strategy for U.S. patients per distributional cost-effectiveness analysis standards. Obstacles in addition to cost include needing to undergo chemotherapy and being hospitalized for months until the patient’s immune system recovers.

In Africa and India, which are home to most of the world’s population living with sickle cell disease, many patients die in childhood because of lack of access to standard-of-care treatments. For example, hydroxyurea, which reduces the frequency of VOCs and prolongs survival, was approved by the FDA in 1998 but remains unavailable to most patients. Experts recently proposed expanding the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) to provide hydroxyurea therapy for $67 per person to sickle cell patients in sub-Saharan Africa at a total cost of less than $100 million per year. That modest budget would barely begin to meet the needs of those potentially eligible for gene therapy, even if they were able to travel to one of the only three centers for bone marrow transplants in Nigeria, Tanzania, and South Africa.

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This post first appeared on the AFP Community Blog.