Newer glucose-lowering drugs also treat obesity and heart failure

Last June, the U.S. Food and Drug Administration (FDA) approved a weekly semaglutide (Wegovy) subcutaneous injection for chronic weight management in adults with obesity or overweight with at least one weight-related condition, based on randomized controlled trial (RCT) evidence that it produces substantial weight loss in persons with a body mass index of 27 or greater without diabetes. A lower dose of semaglutide (Ozempic), a glucagon-like peptide-1 (GLP-1) receptor agonist, had previously been approved by the FDA as a second-line therapy for patients with type 2 diabetes that reduced risk of major adverse cardiac events (MACE) in patients with established cardiovascular disease (CVD).

A 2021 BMJ clinical practice guideline examined the benefits and harms of GLP-1 receptor agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors and made recommendations for use of these two drug classes in persons with type 2 diabetes and different levels of CVD risk with and without chronic kidney disease, summarized in Patient-Oriented Evidence That Matters in the January issue of American Family Physician. A related editorial by Dr. Sandy Robertson discussed how evidence can inform when to recommend starting a diabetes drug from one of these two CVD risk-lowering classes:

Current data strongly support a reduction in MACE and all-cause mortality with SGLT-2 inhibitors and GLP-1 agonists in patients who have diabetes with established CVD or kidney disease. These patients should be offered one of these medications in the absence of contraindications, regardless of glucose control. Because there is no significant reduction in cardiovascular outcomes in patients who have diabetes without established CVD, patient-centered shared decision-making about adding an SGLT-2 inhibitor or a GLP-1 agonist for cardiovascular benefit is important and ... based on other established benefits such as weight control (moderate net weight loss for GLP-1 agonists and small weight loss for SGLT-2 inhibitors) against risks of genital infections (SGLT-2 inhibitors) or gastrointestinal disturbances (GLP-1 agonists).

Although GLP-1 agonists are associated with greater weight loss than SGLT-2 inhibitors, a population-based cohort study using Medicare and two U.S. commercial claims data sets found that starting a SGLT-2 inhibitor, compared to starting a GLP-1 agonist, reduced the relative risk of hospitalization for heart failure by about 30 percent in patients with and without CVD. A recent international RCT (622 centers in 23 countries) found that adding the SGLT-2 inhibitor empagliflozin (Jardiance) to usual therapy for patients with heart failure with preserved ejection fraction improved a composite outcome of CVD mortality and hospitalization, regardless of the presence of diabetes (RRR=19%, NNT=31). Similarly, a systematic review and meta-analysis of 8 earlier RCTs found that in heart failure patients without diabetes, SGLT-2 inhibitor treatment reduced the risk of this composite outcome by 20 percent.

Based on this new data, should family physicians consider adding a SGLT-2 inhibitor to the standard combination of drug therapies for their patients with heart failure? I think the evidence supports doing so, but it may take some time before generalists become comfortable with this practice change, as I explained in a Medscape news story. A qualitative study of Australian general practitioners suggested that knowledge gaps, drug adverse effects, and a preference for subspecialists to initiate SGLT-2 inhibitor therapy may be obstacles to increased prescribing of these drugs, which remain very expensive in the U.S.

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A slightly different version of this post first appeared on the AFP Community Blog.

Preventing mumps and COVID-19: don't let perfect be the enemy of good

The lower efficacy of COVID-19 vaccines against the SARS-CoV-2 Omicron variant due to viral mutations and waning immunity of the initial series has unfortunately fueled an anti-vaccination narrative that a less-than-perfectly protective vaccine has little clinical value. A comparison to a well-established childhood vaccine exposes the flaw in this argument. According to a 2020 Cochrane review, the effectiveness of measles, mumps, and rubella (MMR) vaccine in preventing mumps is 72% after one dose and 86% after two doses. After the two-dose MMR vaccine was added to the U.S. childhood immunization schedule, though, the number of reported cases of mumps fell from >150,000 in 1968 to 231 in 2003. In the past two decades, outbreaks have occasionally increased the incidence to several thousand reported cases per year.

A recent study in Pediatrics examined the epidemiology of mumps in U.S. children and adolescents from 2007 to 2019. It found that 87% of children diagnosed with mumps during this period had received at least one dose of MMR vaccine, including most of the 2% of children who required hospitalization. Also, only 2% of cases were associated with international travel. The authors concluded that "clinicians should suspect mumps in patients with parotitis or mumps complications, regardless of age, travel history, and vaccination status."

For physicians who have never seen a patient with this infection, a 2014 American Family Physician article on salivary gland disorders noted that mumps typically causes bilateral pain and edema of the parotid glands, otalgia, and trismus. Rarely, it can cause meningitis and encephalitis, as illustrated in a recent BMJ case report. Mumps spreads through airborne droplets (salivary, nasal, and urinary secretions) and is highly contagious. The diagnosis should be confirmed with reverse transcriptase-polymerase chain reaction (RT-PCR) or viral culture of a sample obtained with a buccal swab.

In fully vaccinated individuals, giving a third or "booster" dose of MMR vaccine was shown to reduce the risk of mumps during a 2015-16 U.S. college outbreak and 3 separate outbreaks in Queensland, Australia in 2017-18. Based on these studies, in 2018 the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommended that MMR-vaccinated individuals who are "part of a group or population at increased risk for acquiring mumps because of an outbreak" should receive a third dose of MMR vaccine "to improve protection against mumps disease and related complications." Sound familiar? Clinicians should continue to strongly recommend that patients receive authorized COVID-19 vaccines and booster doses and not let the perfect be the enemy of the good.

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This post first appeared on the AFP Community Blog.

Clinical prevention shorthand: Do, Don't Do, or Don't Know

Dr. Ned Calonge, the chairman of the U.S. Preventive Services Task Force (USPSTF) during my time as a medical officer at the Agency for Healthcare Research and Quality (AHRQ), liked to say that USPSTF recommendation letter grades boiled down to one of three things: Do, Don't Do, or Don't Know. Doctors like actionable guidelines. Do, or Don't Do. We don't like seeing Don't Know. When I left AHRQ at the end of 2010, about one-third of recommendation statements were rated "I," or insufficient evidence to determine the balance of benefits and harms. In other words, a whole lot of clinical prevention Don't Know.

A provision of the Affordable Care Act stipulated that the USPSTF submit an annual report to Congress identifying evidence gaps and recommending priority areas for prevention research. Its first report, which came out the year after I left, identified eleven clinical topics that had critical evidence gaps (resulting in "I" statements) "that if filled are likely to result in new recommendations." These topics were

1. Screening for coronary heart disease

2. Screening for colorectal cancer with fecal DNA testing and CT colonography

3. Screening for hepatitis C

4. Screening for hip dysplasia

5. Obesity: moderate- to low-intensity counseling

6. Interventions to prevent child abuse and neglect

7. Screening for illicit drug use

8. Screening for osteoporosis in men

9. Screening for depression in children

10. Screening and counseling for alcohol misuse in adolescents

11. Aspirin use in adults ages 80 years and older

I've bolded the four topics that, just over a decade later, are no longer "I" statements. #2, 3, and 7 are now Do's ("A" and "B" grades), and #11 is a Don't Do ("D" grade). That's 36 percent, which is something of a disappointment since the USPSTF called these "critical" evidence gaps, not evidence gaps that it felt researchers could fill at some indistinct future date. Moreover, two of these Do's, in my opinion, were highly questionable calls; no trials have shown that fecal DNA testing, CT colonography, or illicit drug use screening improve patient-oriented outcomes. Arguably, these changes were driven by changes in the composition of the Task Force, not new evidence.

A recent study examined characteristics of evidence and funding support for 11 USPSTF "I" statements that changed to a letter grade (most commonly a "B") between 2010 and 2019. The National Institutes of Health (NIH), the largest federal funder of biomedical research, supported a sizable percentage of the critical studies: 28.8%, to be exact. Were the researchers reading the USPSTF's annual reports to Congress when they wrote their grant requests? Perhaps a few did, but it seems unlikely to me. And for every completed study that filled a prevention evidence gap, many more studies were not done because NIH program officers didn't know there were other gaps that needed to be filled.

A new National Academy of Medicine report, "Closing Evidence Gaps in Clinical Prevention," aims to make it easier for the USPSTF and AHRQ to communicate research questions that need to be answered to the agencies that fund prevention research. An ad hoc committee developed a clinical prevention taxonomy and workflow designed to classify different types of evidence gaps (Foundational Issues, Analytic Framework, Dissemination and Implementation) and prioritize them into a research agenda that can be more easily shared. This is such a good idea that it's a wonder that no one thought of it before or, if they did, got decision-makers to pay attention. When 2032 rolls around, hopefully a much higher percentage of evidence gaps identified by the Task Force in its Eleventh Report to Congress (which, as a reflection of our times, involve health equity and disparities in cardiovascular disease and cancer topics) will be Do, or Don't Do, rather than Don't Know.