Diabetes in 2026: The Ominous Octet Just Got a New Member

 

NP CHRONICLES Clinical Deep Dive

Diabetes in 2026: The Ominous Octet Just Got a New Member

A CME update from Harvard's Martin Abrahamson, MD, brings the 2026 ADA algorithm, the CATALYST hypercortisolism data, and head-to-head incretin trials into one practical framework for NPs managing T2DM.

If you trained on DeFronzo's "Ominous Octet," you may want to update your mental model. A recent Pri-Med CME session led by Martin J. Abrahamson, MD (Harvard Medical School) walks through where diabetes management actually stands in 2026 — and one finding in particular deserves space on your differential the next time a patient's A1c won't budge despite reasonable adherence.

The Noxious Nine: Adrenals Join the Pathogenesis Model

DeFronzo's original 2009 framework identified eight interlocking defects driving hyperglycemia in T2DM: impaired insulin secretion, increased hepatic glucose production, decreased glucose uptake in skeletal muscle, increased lipolysis in adipose tissue, decreased incretin effect, increased glucagon secretion, increased renal glucose reabsorption, and neurotransmitter dysfunction in the brain. The updated model adds a ninth: adrenal hypercortisolism.

This isn't a theoretical addition. The CATALYST trial screened 1,055 people with difficult-to-control T2DM (A1c 7.5%–11.5%, on ≥3 antihyperglycemic drugs, insulin plus another agent, or multiple agents with vascular complications) using a 1 mg dexamethasone suppression test. The result: 24% — almost 1 in 4 — had biochemical evidence of endogenous hypercortisolism, and an adrenal abnormality was found on imaging in 34% of those screened positive.

AMBER FLAG — This Doesn't Mean Screen Everyone Tomorrow A 24% positive rate in a trial population selected specifically for treatment-resistant T2DM is not the same as a 24% prevalence in your general diabetic panel. Before this becomes a routine screen, professional society guidance needs to catch up with the data, and cost-effectiveness in unselected populations hasn't been established. Where it's worth remembering: the patient who is maximized on multiple agents, insulin, and lifestyle changes and still isn't moving — that's the CATALYST population, and it's reasonable to have hypercortisolism on your radar for that specific patient.

The mechanistic follow-up, CATALYST Part 2, tested whether treating the hypercortisolism actually helps. In a multicenter, double-blind, placebo-controlled phase IV trial, 91 patients with confirmed hypercortisolism and uncontrolled T2DM received oral mifepristone (300–900 mg daily) versus placebo for 24 weeks. The primary endpoint — change in A1c — favored mifepristone by 1.32 percentage points (95% CI, -1.81 to -0.83; p<0.001 at both week 12 and week 24), with secondary improvements in body weight and waist circumference as well.

What the 2026 ADA Standards of Care Actually Say

The updated ADA algorithm organizes pharmacologic decision-making around two simultaneous goals rather than a single A1c target: achieving glycemic control and achieving weight management, with cardiorenal risk reduction layered on top for patients who qualify.

●      Very high glucose-lowering efficacy: high-dose dulaglutide, semaglutide, tirzepatide, insulin, and combination regimens (oral or injectable combos, GLP-1 RA plus insulin).

●      Very high weight-loss efficacy: semaglutide and tirzepatide specifically — not the GLP-1 RA class as a whole.

●      For ASCVD or high-risk indicators (age ≥55 with 2+ of: obesity, hypertension, smoking, dyslipidemia, albuminuria): choose a GLP-1 RA or SGLT2i with proven cardiovascular benefit, independent of A1c.

●      For heart failure (HFrEF or HFpEF): SGLT2i with proven HF benefit in that specific population.

●      For CKD on maximally tolerated ACEi/ARB: SGLT2i with primary evidence of slowing CKD progression (can be started down to eGFR ≥20), or a GLP-1 RA with proven CKD benefit.

●      If MASLD/MASH risk needs mitigating: GLP-1 RA, dual GIP/GLP-1 RA, pioglitazone, or a GLP-1 RA-pioglitazone combination; insulin is reserved for decompensated cirrhosis.

The organizing principle worth internalizing: medication choice is now driven first by comorbidity profile (ASCVD, HF, CKD, MASLD), and only secondarily by A1c-lowering potency alone.

Case From Practice

Meet Mr. L: A1c at Goal, But Is His Regimen Actually Right? Mr. L is a 63-year-old part-time teacher, 6 years out from a T2DM diagnosis, with hypertension, hyperlipidemia, and coronary artery disease. Cardiac function is normal. BMI 29.4 kg/m², A1c 6.7%, eGFR 68 mL/min/1.73m², normal LFTs and urine microalbumin. Current regimen: metformin 2000 mg/day, glipizide 10 mg/day, atorvastatin 10 mg/day, lisinopril 40 mg/day, HCTZ 12.5 mg/day, aspirin 81 mg/day. The tempting answer is (a): he's at goal, leave it alone. That's the wrong answer — and the case is built specifically to surface why. ●      He meets ASCVD criteria (established coronary artery disease) — per the 2026 ADA algorithm, that alone is an indication for a GLP-1 RA or SGLT2i with proven cardiovascular benefit, independent of his A1c. ●      He's on a sulfonylurea (glipizide), which carries hypoglycemia risk and is weight-neutral-to-positive — exactly the profile the "newer agent" era is designed to move away from. ●      The best-supported answer is (d) or (e): add a GLP-1 RA or SGLT2i with proven CV benefit and stop or reduce the sulfonylurea, rather than simply layering a new drug on top of an agent that's actively working against the safety goals (hypoglycemia risk, weight gain). ●      Take-home for board prep and practice alike: an A1c at goal is necessary but not sufficient. Ask what class of problem you're actually treating — glycemic, cardiorenal, or weight — before deciding a regimen is "done."

Clinical Bottom Line

●      Difficult-to-control T2DM (multiple agents, insulin, or vascular complications despite treatment) now has a plausible, testable explanation in a meaningful minority of patients: endogenous hypercortisolism. A 1 mg dexamethasone suppression test is the first-line screen; confirmatory workup includes ACTH, DHEAS, and adrenal CT. ●      Medication selection in 2026 is comorbidity-first: ASCVD, heart failure, and CKD each have a specific preferred agent class with outcomes-trial backing, and that recommendation applies whether or not the patient's A1c is already at goal. ●      Semaglutide and tirzepatide currently top both the glucose-lowering and weight-loss efficacy tables among GLP-1-class agents — but "GLP-1 RA" is not a monolith; efficacy and evidence vary substantially within the class. ●      Glycemic targets should be individualized: tighter (<6.5%) for younger, healthier patients with long life expectancy; looser (7.0%–8.0%+) for older patients, those with comorbidities, hypoglycemia-prone patients, or shorter life expectancy. "Best control achievable safely" beats a flat number.

Board Prep: High-Yield Diabetes Pharmacology

A few associations worth drilling before your next exam or recert:

●      CVOTs with MACE benefit for GLP-1 RA: LEADER (liraglutide), SUSTAIN-6 (semaglutide), REWIND (dulaglutide), HARMONY OUTCOMES (albiglutide) — superior vs. placebo. EXSCEL (exenatide-ER) and PIONEER-6/SOUL (oral semaglutide) — noninferior.

●      CVOTs with MACE benefit for SGLT2i: EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin) — reduced MACE in secondary prevention specifically. DECLARE-TIMI 58 (dapagliflozin) and VERTIS-CV (ertugliflozin) were neutral for MACE but still showed heart failure and renal benefit.

●      DPP-4 inhibitors are the class with consistently neutral CVOT results (SAVOR-TIMI, EXAMINE, TECOS, CARMELINA) — useful when you need a weight-neutral, hypoglycemia-low option without a strong CV or renal indication.

●      Comparative A1c lowering (network meta-analysis): subcutaneous semaglutide and liraglutide lead (~1.4–1.5 percentage points), ahead of dulaglutide, basal insulin, and oral semaglutide; DPP-4 inhibitors are at the low end of the efficacy spectrum.

●      Comparative weight loss: semaglutide SC (-3.8 kg vs. placebo) and the newer combination/triple agonists (tirzepatide, retatrutide, CagriSema) outperform first-generation GLP-1 RAs by a wide margin; insulin and sulfonylureas trend toward weight gain.

●      Tirzepatide vs. semaglutide head-to-head (SURPASS trials): tirzepatide 15 mg produced greater A1c reduction (-2.30 vs. -1.86 percentage points) and greater weight loss (-12.4 kg vs. -6.2 kg at 40 weeks) than semaglutide 1 mg.

References

Abrahamson, M.J. "Diabetes in the Modern Era: Guidelines and Treatment Advances." Pri-Med Institute CME activity, 2026.

Buse, J.B., et al. "Prevalence of Hypercortisolism Among Patients With Difficult-to-Control Type 2 Diabetes." Diabetes Care 2025;48:1-9. https://doi.org/10.2337/dc24-2841

DeFronzo, R.A. "From the Triumvirate to the Ominous Octet." Diabetes 2009;58:773-795.

American Diabetes Association. "Standards of Care in Diabetes—2026." Diabetes Care 2026;49(Suppl. 1):S183-S215.

Frias, J., et al. "Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes." N Engl J Med 2021;385:503-515.

NP Chronicles — Clinical education for NP students and new graduates since 2012.

Peptides Are Having a Moment — Here's What NPs Need to Know Right Now

 

NP CHRONICLES Clinical Awareness Brief

Peptides Are Having a Moment — Here's What NPs Need to Know Right Now

An FDA advisory panel is reconsidering compounding rules for BPC-157 and six other peptides, even as the basic science press stays deeply skeptical of the mail-order peptide trade.

If your patients haven't asked you about peptides yet, they probably will soon. This week the FDA convened a two-day advisory panel to reconsider whether compounding pharmacies should be allowed to prepare seven specific peptides — including BPC-157, a favorite of biohacking and "research use only" marketplaces — under prescription and physician oversight. The timing lands right on top of two other useful reads: a widely circulated science-blog takedown of the mail-order peptide trade, and a comprehensive academic review of legitimate, FDA-approved peptide therapeutics. Read together, the three pieces sketch out exactly where the clinical conversation with patients needs to go.

Two Very Different Worlds Called "Peptides"

Part of what makes this topic slippery in the exam room is that "peptide" means two different things depending on who is saying it. Chemically, a peptide is simply a short chain of amino acids — a category broad enough to include everything from digestive breakdown products to insulin itself. Clinically and commercially, "Peptides" (capital P, as science writer Derek Lowe puts it) has become shorthand for a specific class of injectable, mail-order compounds marketed for muscle building, fat loss, hair regrowth, tissue repair, and anti-aging — most of them sold with little to no human trial data behind them.

There are more than 80 FDA-approved peptide drugs on the market today, spanning diabetes care (the GLP-1 receptor agonists), oncology, cardiovascular disease, and antimicrobial therapy. Those drugs went through the same design-synthesis-modification-trial pipeline as any other pharmaceutical. The peptides driving patient questions in your clinic right now — BPC-157, various growth-hormone-releasing peptides, and others sold through gray-market suppliers — have not.

 

What's Actually on the Table at the FDA This Week

The panel isn't deciding whether to approve BPC-157 or its peers as drugs. It's deciding whether compounding pharmacies can legally prepare them under a prescription, for a specific diagnosis, with physician oversight — a narrower and more clinically supervised pathway than the current gray market, but still well short of full FDA approval with its accompanying efficacy and manufacturing standards.

●      BPC-157 is marketed for tissue and injury healing. As one physician noted in a recent STAT piece, it has been studied in roughly a dozen human subjects — compare that to the six-figure trial populations behind statins or GLP-1 drugs.

●      The Biden-era FDA had already added nearly 20 peptides to the list of substances compounding pharmacies should not prepare, citing insufficient safety data.

●      Most of the current advisory panel and agency staff involved in that 2020s-era decision are no longer in their roles, and HHS Secretary Robert F. Kennedy Jr. has publicly described himself as a supporter of these unapproved therapies.

●      The outcome will not constitute FDA approval of any of these peptides as drugs — it would only change who is legally allowed to compound them and under what supervision.

Why the Science Press Is Sounding the Alarm

Lowe's post (published on his long-running chemistry blog) walks through the mechanistic case for caution, and it's worth internalizing the framework even if you never mention his name to a patient:

●      Bioactivity is not the same as a known safety profile. Short peptides can have dramatic biological effects, but the field is still discovering off-target activity even for extremely well-studied hormones like insulin.

●      Reactivating growth pathways carries a generic cancer-risk concern. Growth hormone axis peptides in particular risk recreating the physiology of acromegaly — bone overgrowth, joint pain, hypertension, and type 2 diabetes — when taken outside physiologic feedback control.

●      Sourcing is a black box. Patients ordering from unregulated suppliers have no way to verify purity, concentration, or degradation, and no regulatory body compelling the supplier to care.

●      The appeal is often ideological as much as clinical — a "do my own research," anti-regulatory framing that can lead patients to discontinue well-evidenced therapies (statins, in the STAT anecdote) in favor of a compound studied in a literal handful of people.

AMBER FLAG — Don't Let the GLP-1 Comparison Do the Wrong Work Patients will sometimes reason, "GLP-1 drugs are peptides too, and those turned out great — so why not this one?" It's worth naming that logical leap directly. Semaglutide and liraglutide reached the market only after extensive sequence modification, half-life extension, and trial programs involving well over 100,000 patients combined. A gray-market peptide with a study population in the dozens has none of that behind it. Same molecular category, entirely different evidence base.

Case From Practice

"My Trainer Said BPC-157 Would Heal My Rotator Cuff Faster" A 34-year-old patient with a partial supraspinatus tear, already referred to physical therapy, asks whether you can prescribe or approve a BPC-157 regimen he found through an online fitness coach. He has done "his own research" and read that it's "basically a natural healing peptide." This is a good opening for motivational, non-adversarial patient education rather than a flat refusal-and-move-on. Points worth hitting: ●      Validate the goal (faster, better healing) before addressing the method — the desire to heal well is reasonable even if the chosen tool isn't. ●      Name the evidence gap plainly: BPC-157 has essentially no controlled human trial data for musculoskeletal healing, and no established dosing, purity standard, or long-term safety profile. ●      Ask where he'd be sourcing it — most patients haven't considered that an unregulated supplier has no incentive to guarantee what's actually in the vial. ●      Redirect to what does have evidence for tendon/rotator cuff recovery: structured PT progression, load management, and, where appropriate, evidence-based adjuncts you can actually document and monitor. ●      Document the conversation. If the patient proceeds through a gray-market source anyway, you want a clear record that risks were discussed.

Clinical Bottom Line

●      Legitimate, FDA-approved peptide drugs (GLP-1 receptor agonists, insulin analogues, GnRH-derived agents, ziconotide, etc.) are a mature, well-evidenced drug class — don't let "peptide" become a red-flag word in your own head. ●      Gray-market "research peptides" like BPC-157 are a separate category with minimal human data, unverified sourcing, and real theoretical risk (growth-pathway activation, cancer risk, contamination). ●      The FDA's current review is about compounding access under prescription, not drug approval — expect this to change the conversation with patients even if it doesn't change the evidence base. ●      Anticipate the question before the patient asks it. A brief, non-judgmental script ("tell me what you've read, here's what we actually know") keeps patients from sourcing these compounds entirely outside medical supervision.

Board Prep: Know Your Peptide Drug Classes

Certification exams love peptide pharmacology because it cuts across endocrine, cardiovascular, GI, and oncology content. A few high-yield associations worth drilling:

●      GLP-1 receptor agonists (exenatide, liraglutide, semaglutide, dulaglutide) — T2DM and weight management; GI side effects; class-wide caution in personal/family history of medullary thyroid carcinoma.

●      GnRH agonists/antagonists (leuprolide, degarelix) — hormone-responsive prostate cancer, endometriosis, precocious puberty; agonists cause an initial testosterone flare, antagonists do not.

●      Somatostatin analogues (octreotide) — acromegaly, carcinoid symptom control, variceal bleeding adjunct.

●      GLP-2 analogue (teduglutide) — short bowel syndrome; distinguish mechanism from GLP-1 on exam distractor questions.

●      N-type calcium channel blocker (ziconotide) — intrathecal use only for severe chronic pain; derived from cone snail venom, a good "where do peptide drugs come from" trivia point.

●      Natriuretic peptide analogue (nesiritide) — acutely decompensated heart failure; limited by hypotension risk and modest specificity.

References

Lowe, D. "Peptides. Where to Begin?" In the Pipeline (Science Translational Medicine blog), April 6, 2026.

Wang, L., Wang, N., Zhang, W., et al. "Therapeutic peptides: current applications and future directions." Signal Transduction and Targeted Therapy 7, 48 (2022). https://doi.org/10.1038/s41392-022-00904-4

Breen, K., Yamaguchi, A. "FDA panel reviewing some peptides to consider loosening regulations for unapproved therapies." CBS News, July 23, 2026.

NP Chronicles — Clinical education for NP students and new graduates since 2012.

Abdominal Imaging Made Practical Choosing ultrasound, CT, or MRI in everyday primary care

 NP Chronicles · Clinical Deep Dive · Diagnostics

Abdominal Imaging Made Practical

Choosing ultrasound, CT, or MRI in everyday primary care

Adapted for NP Chronicles from a Pri-Med lecture by Masis Isikbay, MD, Assistant Professor of Radiology, Department of Emergency Radiology and Neuroradiology, UCSF

Abdominal pain is one of the most common reasons patients land in primary care, and it can come from nearly any organ in the abdomen or pelvis — esophagus, stomach, small bowel, appendix, colon, liver, biliary tree, pancreas, kidneys, bladder, or ovaries. With that many possible sources, picking the right imaging study the first time matters. Order the wrong one, and you may not be able to answer your clinical question at all.

Clinical Bottom LineUltrasound is your no-radiation, real-time, first-line tool for gallbladder, pelvic, renal, and scrotal complaints. CT is your rapid, large-field-of-view workhorse for anything acute, complicated, or unclear — and it needs radiation and, ideally, IV contrast to earn its keep. MRI is the specialist's tool: slow, sensitive, and targeted, reserved for when US and CT can't answer the question or when radiation must be avoided (pregnancy, pediatrics).

The Three Modalities, Side by Side

Modality	How it works	Strengths	Limitations
Ultrasound (US)	Sound waves; real-time imaging	No radiation, dynamic/interactive, compatible with devices, widely accessible	Small field of view, operator-dependent, blocked by bandages/gas — "flashlight in a cave" if the structure isn't found
CT (A/P)	X-rays rendered as a 3D grayscale map of tissue density	Fast, large field of view (whole abdomen/pelvis at once), multiphase capability, accessible	Radiation exposure, blocked by dense metallic hardware, no patient interaction during scan
MRI	Magnetic properties of tissue across many possible sequences	No radiation, highly sensitive for targeted questions, multiphase possible	Slow, least accessible, safety limits with implants/ferromagnetic material, artifact-prone, poor as a screening tool

Teaching Point — ContrastIV contrast on CT is worth leveraging whenever possible; skip non-contrast CT unless contrast is contraindicated. Renal stones are still reliably seen on a routine portal venous scan, so a dedicated non-contrast stone protocol usually isn't necessary. Oral contrast has largely fallen out of favor — it can obscure pathology and isn't needed to diagnose small bowel obstruction — but it's still useful when you're specifically evaluating for a bowel leak.

Matching Modality to Diagnosis

Hepatobiliary complaints

A right upper quadrant ultrasound is usually the gold standard for suspected acute cholecystitis and can often let you skip CT entirely — pain plus stones on US is cholecystitis until proven otherwise. CT is sometimes obtained instead, looking for gallbladder wall thickening, hyperemia, non-enhancement, or stones, but the gallbladder can be a fickle organ on CT and US may still be needed to clarify. MRI/MRCP is reserved for suspected biliary obstruction, not as a first-line or screening study; ERCP may be required regardless.

OB/gynecologic evaluation

Pelvic ultrasound, especially with transvaginal views, is the tool of choice for ectopic pregnancy, ovarian torsion, and uterine/ovarian pathology. Add RUQ or RLQ views as clinically indicated. For torsion specifically, there's really no reason to move beyond ultrasound — though keep in mind the ovary has dual arterial supply, so flow findings can be misleading, and once there's a large adnexal mass, torsion can become impossible to definitively rule out on imaging alone.

Appendicitis

Ultrasound is a reasonable starting point to limit radiation, particularly in pediatric and pregnant patients, though it often won't visualize the appendix. CT with contrast is a very good option when radiation isn't the overriding concern and can evaluate for other pathology simultaneously. MRI appendix protocol (typically without contrast, safe in pregnancy) is a strong option for pediatric patients when ultrasound is non-diagnostic.

Renal stones

Start with ultrasound, looking for hydronephrosis (a common incidental, non-obstructing finding). CT or MRI can follow as needed — MRI specifically if the patient is pregnant.

Bowel pathology

Free fluid and free air on CT should always raise concern for perforation. For suspected small bowel obstruction, CT abdomen/pelvis with contrast is the best option (no oral contrast required), and it's essential for identifying a closed-loop obstruction, which is a feared surgical complication. Diverticulitis is likewise a CT-with-contrast diagnosis, useful both for confirmation and for detecting complications.

Pancreatitis

Arguably, imaging isn't necessary at all if labs and pain are characteristic — a normal-appearing pancreas on CT is common, especially early in the disease course, and doesn't rule pancreatitis out. CT becomes useful specifically when there's concern for a complication: fluid collections, abscess, or vascular injury.

Pyelonephritis, cystitis, prostatitis, and GI bleeding

Imaging is often unnecessary for pyelonephritis — findings on CT are frequently absent or subtle, though CT can help identify complications like abscess. Cystitis, prostatitis, and esophagitis/gastritis/ulcer generally don't need imaging either; endoscopy is more useful than CT for the latter. For GI bleeding, endoscopy may be the better first move, but when CT is performed, a multiphase protocol adds real value by showing the evolution of a bleed.

Scrotal pathology

Scrotal ultrasound is the correct first study whenever testicular pathology is suspected. CT can partially visualize the scrotum but is not an appropriate primary modality here.

Cases From the Lecture

Case From Practice — Pediatric RLQ PainA 6-year-old boy presents with 2 days of right lower quadrant pain, mild tachycardia, and a WBC of 16. Start with ultrasound to limit radiation exposure. If the appendix isn't visualized (common), escalate to MRI appendix protocol before considering CT.

Case From Practice — Pregnant Patient, Unclear PainA 32-year-old at 7 weeks with a confirmed intrauterine pregnancy presents with abdominal pain of uncertain etiology, possibly a renal stone. Labs and vitals are normal. Ultrasound is essential — it can confirm the IUP, evaluate for ectopic, and even assess for hydronephrosis. Avoid CT: it poorly evaluates the uterus and ovaries and unnecessarily radiates the embryo.

Case From Practice — Suspected Ovarian TorsionA 26-year-old with 4 hours of intense intermittent pelvic pain, tachycardia, and a negative pregnancy test. Pelvic ultrasound is the only modality needed; there's no reason to escalate to CT or MRI. Involve OBGYN early when suspicion is high, regardless of imaging findings.

Case From Practice — Post-op SepsisA 26-year-old, post-op day 10 from oophorectomy, presents with worsening pain, tachycardia, hypotension, and a WBC of 22. CT abdomen/pelvis with contrast is the clear first choice — you're looking for a surgical reason to return to the OR, and ultrasound/MRI have little to add here, especially for a possible bowel leak.

Case From Practice — Pediatric ObstructionAn 8-year-old with a prior abdominal surgery presents with 2 days of no bowel movements, no flatus, distention, tachycardia, and a WBC of 18. CT abdomen/pelvis is the best study for suspected SBO; a KUB with oral contrast is an alternative in select cases. Always be alert for closed-loop obstruction, which requires CT to identify.

Case From Practice — Elevated LipaseA 54-year-old with acute epigastric pain since last night, mild tachycardia, and an elevated lipase. No imaging is required to diagnose pancreatitis when labs and pain are characteristic — imaging findings can be entirely absent early on and won't change the diagnosis.

Board Prep & Quick Recall

• US = no radiation, real-time, operator-dependent, limited field of view
• CT = radiation, fast, large field of view, IV contrast preferred over non-contrast or oral
• MRI = no radiation but device/ferromagnetic safety limits, slow, targeted only — not a screening tool
• RUQ US is first-line for cholecystitis; CT/MRI reserved for equivocal or complicated cases
• Pelvic (transvaginal) US is first-line for ectopic pregnancy and ovarian torsion
• CT with IV contrast is first-line for suspected SBO, diverticulitis, and appendicitis when radiation is not the limiting factor
• Pancreatitis, pyelonephritis, cystitis, and prostatitis are largely clinical/lab diagnoses — imaging is often unnecessary or non-contributory
• In pregnancy: default to ultrasound; use MRI without contrast if further evaluation is needed; avoid CT when possible

The throughline across every case: match the modality to the specific clinical question, not just the location of the pain. Ordering the wrong study rarely just wastes time — it can leave you without an answer, and without an answer, the patient waits longer for the right treatment.

Disclosures (Pri-Med Institute, original lecture): Charles Vega, MD, FAAFP (Moderator), disclosed consulting relationships with Boehringer Ingelheim, Exact Sciences, and GSK; all relationships were mitigated by Pri-Med Institute. All other individuals in control of content disclosed no relevant financial relationships. This content is adapted for educational purposes for NP Chronicles readers.

References

1. Isikbay M, Sugi MD, Bowman MS, Choi HH. Traumatic testicular rupture: Multimodality imaging with intraoperative correlate. Clin Imaging. 2021;71:13–16.
2. Shea JA, Berlin JA, Escarce JJ, et al. Revised estimates of diagnostic test sensitivity and specificity in suspected biliary tract disease. Arch Intern Med. 1994;154(22):2573–2581.
3. Lin EP, Bhatt S, Dogra VS. Diagnostic Clues to Ectopic Pregnancy. RadioGraphics. 2008;28(6):1661–1671.
4. Pimenta M, Guimarães LS. Small bowel obstruction: what to look for. Radiographics. 2009;29(2):423–439.
5. Lee EJ, Kwon HC, Joo HJ, Suh JH, Fleischer AC. Diagnosis of ovarian torsion with color Doppler sonography. J Ultrasound Med. 1998;17(2):83–89.
6. Paulson EK, Thompson WM. Review of Small-Bowel Obstruction: The Diagnosis and When to Worry. Radiology. 2015;275(2):332–342.
7. Karul M, Berliner C, Keller S, Tsui TY, Yamamura J. Imaging of appendicitis in adults. Rofo. 2014;186(6):551–558.
8. de Kok BM, et al. Correlation of CT findings with intra-operative outcome in closed-loop small bowel obstruction (CL-SBO). Eur J Radiol. 2021;142:109844.
9. Balthazar EJ, Birnbaum BA, Megibow AJ, Gordon RB, Whelan CA, Hulnick DH. Closed-loop and strangulating intestinal obstruction: CT signs. Radiology. 1992;185(3):769–775.

Tags: Abdominal ImagingUltrasoundCTMRIPrimary CareRadiologyDiagnosticsBoard Prep

The New Era of Obstructive Sleep Apnea Care

NP CHRONICLES Clinical Education for NP Students & New Grads

 

The New Era of Obstructive Sleep Apnea Care

From Underdiagnosis to an Evolving Treatment Paradigm

Why This Matters in Primary Care

An estimated 83.7 million U.S. adults have obstructive sleep apnea (OSA) — and roughly 80% of clinically significant cases go undiagnosed. That gap matters, because untreated moderate-to-severe OSA is tied to nearly double the risk of stroke, atrial fibrillation, heart failure, and coronary disease, plus impaired glucose metabolism, cognitive decline, depression, and — over 14 years of follow-up — up to a fivefold increase in cardiovascular mortality in patients not using CPAP.

The problem isn't just that OSA is common. It's that most primary care visits are still screening for the “classic” patient — a sleepy, snoring, middle-aged man with obesity — while a large share of real-world OSA presents very differently.

 

✦ CLINICAL BOTTOM LINE OSA is a major, modifiable driver of cardiometabolic and neurocognitive disease, but the majority of cases are missed because clinicians are screening for one phenotype in a condition with many.

 

The Pathophysiology Behind the Heterogeneity

OSA results from a sleep-induced imbalance between upper airway load (soft palate, tongue fat, hyoid position, retrognathia) and airway dilator muscle tone (hypoglossal motor output, noradrenergic/serotonergic drive). When load exceeds tone, the airway narrows or collapses, triggering intermittent hypoxia, arousal, and sleep fragmentation — which drive oxidative stress, sympathetic activation, and systemic inflammation.

Beyond anatomy, four non-anatomical endotypes are now recognized as contributing to OSA in most patients:

•     Low arousal threshold — waking too easily to sustain stable breathing

•     Unstable ventilatory control — exaggerated breathing responses to small CO₂ changes

•     Upper airway collapsibility — anatomic susceptibility to obstruction

•     Poor pharyngeal muscle responsiveness — inadequate dilator muscle activation

 

This endotype mix helps explain why OSA doesn't look the same in every patient — and why symptom clusters (insomnia-predominant, fatigue-without-sleepiness, mood/cognitive, morning/nocturnal, or minimally symptomatic) are so common outside the “classic” presentation.

Who Gets Missed

•     Women, especially peri- and post-menopausal, often present with insomnia, fatigue, depressive symptoms, morning headache, and nightmares rather than witnessed apneas

•     Older adults more often report insomnia, nocturia, cognitive complaints, or falls than sleepiness

•     Young, non-obese patients can have severe OSA driven by craniofacial anatomy (retrognathia, high-arched palate, macroglossia) with atypical symptoms like bruxism and headache

 

⚠ NUANCE TO FLAG FOR LEARNERS Current OSA phenotyping (older adult, female, nonanatomic, REM-related, supine-predominant, symptom-based clusters) does not yet reliably predict clinical presentation or cardiometabolic risk — evidence is strongest for endotype and symptomatic (EDS/insomnia) classification, and weaker for genomic/genetic correlates. Don't over-anchor on any single phenotype label; use it to broaden your differential, not narrow your screening.

 

Case From Practice: Kim, 56

 

CASE FROM PRACTICE Chief complaint: “I’m exhausted all the time, and I stay up all night.”   Kim is 56, BMI 29 kg/m², postmenopausal since age 52. Over the past two years she's developed insomnia, frequent nightmares, trouble concentrating, and worsening mood, plus morning headaches. Her history includes resistant hypertension and depression. She's unsure if she snores but wakes 2–4 times nightly, feels unrefreshed, and denies obvious daytime sleep episodes. Exam is notable for Mallampati Class III, mild retrognathia, a crowded posterior oropharynx, chronic nasal congestion, and a history of jaw clenching/bruxism.   What makes Kim easy to miss: She's female, postmenopausal, non-obese, and reports insomnia rather than sleepiness — none of which fit the classic OSA script. But her symptom cluster (insomnia, fatigue, cognitive complaints, mood changes, morning headache), resistant hypertension, and airway exam findings are exactly the picture non-anatomic endotypes and craniofacial risk factors predict.   Next steps for a patient like Kim:

•     Take a full sleep history — sleep pattern, nighttime awakenings, snoring, witnessed gasping/apneas, and daytime impact

•     Ask about nasal obstruction, chronic congestion, or prior ENT surgery

•     Examine the airway (Mallampati class, tonsil size, retrognathia) and calculate BMI/neck circumference

•     Use a validated screening tool to support — not replace — clinical judgment, and refer for sleep testing even if the score isn't high, given her risk factors and resistant hypertension

 

Screening & Diagnosis in Primary Care

Validated Screening Tools

Tool	Description	Sens.	Spec.
Berlin Questionnaire	11 items across snoring/apneas, fatigue/sleepiness, obesity/hypertension	77%	44%
STOP-Bang	8 items: snoring, tiredness, observed apnea, pressure, BMI, age, neck size, sex	90%	36%
Epworth Sleepiness Scale (ESS)	Self-administered sleepiness tendency across 8 situations	47%	62%

 

No single tool is diagnostic, and none were designed to capture non-classical presentations — they're a starting point for risk stratification, not a gate that determines who gets tested.

Who Should Be Screened Annually (AASM)

Per the American Academy of Sleep Medicine's OSA Screening Health Advisory, annual screening is recommended for adults with:

•     Heart failure

•     Elevated blood pressure

•     Atrial fibrillation

•     Resistant hypertension

•     Type 2 diabetes

•     Stroke

 

Also screen patients with BMI ≥30 kg/m², nocturnal dysrhythmias, pulmonary hypertension, coronary artery disease, or those preparing for bariatric surgery.

Confirming the Diagnosis

Per AASM criteria, OSA is diagnosed when either:

•     (A) One or more of: sleepiness/nonrestorative sleep/fatigue/insomnia, waking with gasping/choking, bed-partner-reported snoring or breathing interruptions, or a diagnosis of hypertension, mood disorder, cognitive dysfunction, CAD, stroke, CHF, AFib, or T2D AND (B) ≥5 predominantly obstructive respiratory events/hour on PSG or HSAT

•     OR (C) ≥15 predominantly obstructive respiratory events/hour on PSG or HSAT alone

 

PSG (in-lab polysomnography) remains the gold standard, particularly for patients with significant comorbidities or suspected non-OSA sleep disorders, and should be strongly considered when HSAT is inconclusive in a high pretest-probability patient. HSAT (home sleep apnea testing) is a validated, more convenient alternative for uncomplicated, high-probability OSA, but it hasn't been adequately validated in all populations, doesn't record actual sleep or include ECG, and may underestimate severity.

Severity is classified by AHI (apneas + hypopneas per hour of sleep): mild ≥5, moderate ≥15, severe ≥30 events/hour.

 

⚠ NUANCE TO FLAG FOR LEARNERS AHI counts events but doesn't capture how deep or how long desaturations last. Two patients can share an AHI of 30 and have very different hypoxic burden — and hypoxic burden may better reflect cumulative oxygen stress and downstream cardiometabolic risk than AHI alone. This is an evolving research metric, not yet a routine clinical reporting standard, but worth knowing as terminology you'll increasingly encounter.

 

✦ CLINICAL BOTTOM LINE ~80% of patients with OSA have comorbid cardiovascular or metabolic disease, and PCPs are uniquely positioned to catch this during routine chronic-disease visits — annual screening in high-risk groups, paired with a low threshold for testing in atypical presentations, is where primary care moves the needle.

 

The Treatment Paradigm Is Expanding

Treatment should be individualized to severity, symptoms, comorbidities, and patient preference, with early reassessment of adherence and efficacy.

Foundational and Device-Based Options

•     CPAP remains first-line for most adults, especially severe OSA — CPAP use ≥4 hours/night is associated with a 57% lower risk of major adverse cardiovascular events. Adherence drops over time (from ~77% at year 1 to ~53% by year 3), driven by nasal congestion, dryness, mask discomfort, claustrophobia, and inconvenience.

•     Mandibular advancement devices (MADs) advance the lower jaw and are recommended for patients who prefer them or can't tolerate CPAP — less efficacious than CPAP but generally better tolerated.

•     Surgery (maxillomandibular advancement, UPPP, and others) is considered for patients unable or unwilling to use CPAP; MMA shows the largest AHI reductions in observational data (~87%), though evidence quality across surgical options is generally low.

•     Hypoglossal nerve stimulation activates the genioglossus during inspiration to advance the tongue and reduce collapse in selected CPAP-intolerant patients.

•     Weight loss and positional therapy are important adjuncts — 10% weight loss can improve OSA, 30% yields the best AHI reductions, and non-supine positioning can reduce AHI by roughly 7.4 events/hour.

Emerging Pharmacotherapy — a Real Shift in the Paradigm

•     Tirzepatide (Zepbound) was approved for adults with obesity and moderate-to-severe OSA based on the SURMOUNT-OSA phase 3 program: AHI reductions of roughly 20–24 events/hour more than placebo, ~16–17% placebo-adjusted weight loss, and improvements in hypoxic burden, hsCRP, and systolic blood pressure. GI adverse effects (diarrhea, nausea, vomiting, constipation) were common but mostly mild-to-moderate. Other incretin-based agents (amycretin/zenagamtide, bofanglutide) are in phase 3 OSA trials.

•     AD109 (aroxybutynin/atomoxetine) is a once-nightly, fixed-dose oral combination under FDA review. Atomoxetine (a selective norepinephrine reuptake inhibitor) increases noradrenergic drive to the hypoglossal motor neurons; aroxybutynin (an antimuscarinic) blocks acetylcholine-mediated suppression of hypoglossal output — together increasing upper airway muscle tone. In the SynAIRgy phase 3 trial (n=646, adults who refused or couldn't tolerate CPAP), AD109 produced a 44% AHI reduction from baseline vs. 18% with placebo at 26 weeks, and a substantially larger reduction in hypoxic burden. Common adverse events were dry mouth, nausea, insomnia, and urinary hesitation.

 

These agents target the pathophysiology directly — pharyngeal dilator muscle tone, airway collapsibility via weight loss, and respiratory control stability — rather than mechanically bypassing the anatomy, which is a genuinely new direction for a condition long defined by devices and surgery.

 

Board Prep: Quick-Hit Facts

•     OSA prevalence in U.S. adults: 83.7 million; ~80% of clinically significant OSA is undiagnosed

•     AASM annual screening acronym for high-risk comorbidities: H-E-A-R-T-S (heart failure, elevated BP, AFib, resistant HTN, T2D, stroke)

•     Diagnostic criteria: (A + B) or (C alone) — symptoms/comorbidity + AHI ≥5, or AHI ≥15 regardless of symptoms

•     Severity cutoffs: mild ≥5, moderate ≥15, severe ≥30 events/hour

•     PSG = gold standard; HSAT = validated alternative for uncomplicated, high pretest-probability patients only

•     First-line therapy for severe OSA: CPAP; consider MAD when CPAP is not tolerated/preferred

•     CPAP use ≥4 hrs/night → 57% lower MACE risk

•     Newest FDA-approved pharmacotherapy: tirzepatide (obesity + moderate-to-severe OSA, per SURMOUNT-OSA)

•     AD109 (aroxybutynin/atomoxetine) mechanism: antimuscarinic + noradrenergic reuptake inhibition → increased hypoglossal muscle tone; currently under FDA review

 

Key Takeaways

1.   OSA is common and underdiagnosed (~80% of cases), and untreated disease drives cardiometabolic, neurocognitive, quality-of-life, and safety harm.

2.   Non-anatomical endotypes explain much of OSA's clinical heterogeneity — don't rule it out because the presentation isn't “classic.”

3.   Systematic screening and diagnostic testing beyond classic symptoms and AHI are needed to catch atypical cases.

4.   Treatment is expanding well beyond CPAP — oral appliances, surgery, lifestyle change, and new pharmacotherapies (tirzepatide, AD109) are reshaping the OSA care pathway.

 

References

1. Sönmez I et al. Respir Med. 2025;248:108348.

2. Boers E et al. Lancet Respir Med. 2025.

3. Veasey SC et al. N Engl J Med. 2019;380(15):1442-1449.

4. Iannella G et al. Diagnostics (Basel). 2025;15(9):1088.

5. Yacoub M et al. J Sleep Disord Ther. 2017;7(1):283.

6. Xu J et al. Chest. 2026.

7. Zhang X et al. Ann Med. 2026;58(1):2622175.

8. Tasali E et al. Circ Res. 2025;137(5):764-787.

9. Su K et al. Sleep Breath. 2025;29(6):323.

10. Guo S et al. BMC Psychiatry. 2025;25(1):790.

11. Young T. WMJ. 2009;108(5):246-249.

12. Gottlieb DJ et al. JAMA. 2020;323(14):1389-1400.

13. Dutta R et al. Ann Am Thorac Soc. 2021;18(4):656-667.

14. Finnsson E et al. Front Sleep. 2023;2:1188052.

15. Malhotra A et al. Curr Opin Pulm Med. 2020;26(6):609-614.

16. American Academy of Sleep Medicine. Sleep Apnea Screening Health Advisory. Accessed July 9, 2026.

17. Aurora RN et al. J Clin Sleep Med. 2016;12(8):1185-1187.

18. Sateia M. Chest. 2014;146(5):1387-1394.

19. Rundo J. Cleve Clin J Med. 2019;86(9 Suppl 1):2-9.

20. Mazzotti DR et al. Am J Respir Crit Care Med. 2019;200:493-506.

21. Kent DT et al. J Clin Sleep Med. 2021;17:2499-2505.

22. Caples SM et al. Sleep. 2010;33(10):1396-1407.

23. Strollo PJ Jr et al. N Engl J Med. 2014;370(2):139-149.

24. Malhotra A et al. N Engl J Med. 2024;391:1193-1205.

25. Strollo PJ Jr et al. Am J Respir Crit Care Med. 2026.

26. Eckert DJ. Drugs. 2026;86(2):143-159.

 

Content adapted for educational purposes from: “The New Era of Obstructive Sleep Apnea (OSA) Care: From Underdiagnosis to an Evolving Treatment Paradigm,” Reena Mehra, MD & Vani Potluri, MD, Pri-Med Institute, supported by an educational grant from Apnimed Inc.