Extreme Heat Is a Clinical Risk Factor Now — Here's What NPs Need to Build Into Practice

 

CLIMATE & HEALTH

Extreme Heat Is a Clinical Risk Factor Now — Here's What NPs Need to Build Into Practice

Heat waves are longer, more frequent, and more intense — and the health effects go far beyond heat stroke.

CLINICAL BOTTOM LINE Heat waves in the US are now twice as frequent as in the 1980s, and the heat wave season is more than three times as long as it was in the 1960s. Extreme heat drives measurable increases in cardiovascular events, kidney injury, respiratory exacerbations, adverse pregnancy outcomes, and mental health crises — not just classic heat stroke. Older adults, patients on common cardiovascular and psychiatric medications, and historically marginalized or low-income communities carry disproportionate risk. A heat-risk review belongs in routine care for any patient with cardiovascular, renal, or psychiatric disease, or who is taking a medication that impairs thermoregulation.

 

The Scope of the Problem

Global mean temperature has already risen 1.1°C since the Industrial Revolution, with projections of 2.5–2.9°C by century's end absent drastic emissions reductions, according to a 2024 New England Journal of Medicine review. In the US, the annual number of heat waves is now twice what it was in the 1980s, and the heat wave season is more than three times as long as it was in the 1960s. More than a third of heat-related deaths across 43 countries between 1991 and 2018 have been attributed to anthropogenic greenhouse gas emissions.

This isn't an abstract environmental issue — it's already showing up in emergency department and hospitalization data. Days in the 95th percentile of local warm-season temperatures were associated with a 7.8% increase in the relative risk of an ED visit for any cause in one large US study, and an analysis of roughly 50 million summertime hospitalizations found increased admissions for cardiovascular, respiratory, diabetes-related, fluid/electrolyte, and renal causes as the daily maximum heat index rose.

Beyond Heat Stroke: The Full Range of Health Risks

Heat stroke and heat exhaustion get the attention, but they represent only a fraction of the overall health burden. Substantial epidemiologic evidence links both heat waves and single days of high temperature to a much broader range of outcomes.

System	Associated Risks
Cardiovascular	Acute MI, arrhythmias, CHF exacerbation, ischemic stroke
Respiratory	Asthma and COPD exacerbations
Renal	Acute kidney injury, electrolyte imbalance
Pregnancy	Preterm birth, stillbirth, low birth weight, congenital heart defects
Mental health	Increased anxiety, depression, suicidality, aggression/violence

 

Risks scale with both the absolute temperature and the deviation from local historical norms — a heat index that would be unremarkable in Phoenix can be dangerous in Seattle, because populations acclimate to their typical climate. This matters clinically: don't rely on a single national temperature threshold to gauge risk for a given patient population.

Why Older Adults Are Physiologically Disadvantaged

A 2020 narrative review in Environment International lays out the mechanisms in detail. Maintaining body temperature during heat exposure depends on cutaneous vasodilation (routing blood to the skin) and sweating — both of which decline with age. Older adults show blunted nitric-oxide-dependent vasodilation, reduced cardiac reserve to support the elevated cardiac output heat stress demands, and attenuated sweat gland output even though the number of heat-responsive sweat glands is preserved. The net effect is greater body heat storage and higher core temperature for the same environmental exposure compared to younger adults.

•     Cardiovascular: smaller increases in cardiac output during heat stress, endothelial dysfunction, stiffer central arteries, and impaired baroreflex-mediated blood pressure regulation.

•     Fluid regulation: diminished thirst response to dehydration, impaired renal water conservation, and reduced ability to concentrate urine — all increasing susceptibility to both hyper- and hyponatremia.

•     Renal: basal renal blood flow already declines roughly 10% per decade after age 40; heat-induced renal vasoconstriction combined with dehydration compounds this, raising acute kidney injury risk.

As much as 90% of heat wave-associated mortality is attributable to major adverse cardiovascular events — and critically, the risk is elevated not only in patients with known cardiovascular disease but in those without it as well.

Medications That Compound Heat Risk

Many of the medications NPs prescribe routinely for chronic disease interfere with the body's ability to dissipate heat, dehydrate patients further, or blunt the cardiovascular compensation heat stress requires. This is worth a specific medication-reconciliation pass before summer or ahead of a forecasted heat wave.

Medication Class	Heat-Related Concern
ACE inhibitors / ARBs	AKI and electrolyte imbalance risk; blunted thirst; impaired renal autoregulation
Diuretics (thiazide, loop, spironolactone)	Dehydration, hypovolemia, blunted cardiac output increase, hypotension
Beta-blockers	Blunted chronotropic reserve limits cardiac output response to heat
Anticholinergics	Impaired sweating, increased heat stroke risk, hypotension
Antipsychotics	Impaired sweating; risk of drug-induced hyperthermia
Antidepressants (SSRIs, tricyclics)	Impaired sweat rate, hyponatremia risk (SSRIs), limited cardiac output (tricyclics)
NSAIDs	Nephrotoxic; compounds AKI risk during heat stress and dehydration

 

None of this is a reason to stop these medications — they treat serious conditions. It's a reason to counsel patients on hydration, watch electrolytes more closely during heat events, and have a specific sick-day/heat-day conversation with anyone on this list who also has cardiovascular, renal, or autonomic disease.

CASE FROM PRACTICE An 81-year-old woman with hypertension (lisinopril, HCTZ) and mild cognitive impairment lives alone in an un-air-conditioned second-floor apartment. During a 4-day heat advisory, her daughter calls reporting confusion and reduced oral intake — she "doesn't feel like drinking water." This profile stacks nearly every risk factor discussed above: advanced age, two medications that impair fluid regulation and heat dissipation, cognitive impairment limiting behavioral thermoregulation (she may not recognize or act on thirst or overheating), social isolation, and no air conditioning. A same-day BMP, orthostatic vitals, and a same-day plan for cooling access (a cooling center, a family member's air-conditioned home) are appropriate — this is not a wait-and-see situation.

 

The Disparities Are Not Fully Explained by Heat Alone

A NOTE ON EQUITY Communities where members of marginalized racial and ethnic groups and low-income populations live face disproportionately high heat-related illness risk — and this is not fully explained by socioeconomic status or air conditioning access alone. Historically redlined neighborhoods — a discriminatory mortgage-lending practice from the 1930s — continue to have more paved surface and less green space than other areas, producing measurably higher ambient temperatures ("urban heat islands"). Low-income urban communities can run as much as 5°C hotter than wealthier ones nearby. Contributing factors include more limited access to care, more frequent occupational heat exposure (factory work without air conditioning, outdoor labor), and a higher baseline prevalence of hypertension, diabetes, and kidney disease. For patients in these circumstances, standard advice ("stay in air conditioning") may not be actionable — screening for access to a cooling center or a cooler environment during heat advisories is a more useful clinical question than assuming air conditioning is available.

 

What NPs Can Actually Do

•     Ask about air conditioning access and living situation for any older or high-risk patient, especially before summer months — this single question identifies a major modifiable risk factor.

•     Review medication lists specifically for heat-interacting drugs (table above) in patients with cardiovascular, renal, autonomic, or psychiatric disease, and add heat-specific counseling, not just general "stay hydrated" advice.

•     Identify socially isolated patients before heat season — they are less likely to have someone checking on them during a multi-day heat event, which is when risk accumulates most.

•     Counsel on individual protective measures: limiting outdoor exposure during peak heat, loose light-colored clothing, adequate hydration, and cooling devices — while noting that air conditioning itself has an environmental cost worth naming for patients who ask.

•     Know your local cooling center resources and heat-alert systems so you can give patients a concrete plan, not just a warning, before a forecasted heat wave.

Board & Practice Prep

•     Heat exhaustion presents with normal mental status; heat stroke involves CNS dysfunction with core temperature typically ≥40°C — this distinction determines emergency triage.

•     A heat wave is generally defined (NOAA) as 2 or more continuous days of unusually high heat relative to local historical norms — not an absolute temperature threshold.

•     There is currently no standardized, universally accepted definition of a "heat-related death," which complicates surveillance and ICD coding of indirect heat effects.

•     Heat-induced hemoconcentration and hypercoagulability contribute to elevated cardiovascular event risk independent of classic heat illness — worth remembering when a patient presents with an MI or stroke during a heat event with no other clear trigger.

•     Mortality displacement ("harvesting") — where heat-related deaths occur mainly in already-frail patients who would have died soon regardless — has been studied and found not to fully explain heat-attributable mortality; the excess risk is real.

The Takeaway

Extreme heat is no longer a seasonal inconvenience to mention in passing — it's a modifiable clinical risk factor with mechanisms as well-characterized as many risk factors NPs already screen for routinely. Building a heat-risk review into care for older adults, patients with cardiovascular or renal disease, and anyone on a heat-interacting medication is a low-cost intervention with a clear evidence base behind it, and it may prevent the kind of quiet decompensation that too often shows up only after a multi-day heat event has already done its damage.

References

Bell ML, Gasparrini A, Benjamin GC. Climate change, extreme heat, and health. N Engl J Med. 2024;390(19):1793-1801. doi:10.1056/NEJMra2210769

Meade RD, Akerman AP, Notley SR, McGinn R, Poirier P, Gosselin P, Kenny GP. Physiological factors characterizing heat-vulnerable older adults: a narrative review. Environ Int. 2020;144:105909. doi:10.1016/j.envint.2020.105909

GLP-1s Are Surging, Bariatric Surgery Is Sliding — and More Than 90% of Patients With Obesity Are Still Getting Neither

 

OBESITY MANAGEMENT

GLP-1s Are Surging, Bariatric Surgery Is Sliding — and More Than 90% of Patients With Obesity Are Still Getting Neither

Two independent real-world analyses, presented within weeks of each other in 2026, land on the same uncomfortable number.

CLINICAL BOTTOM LINE GLP-1 prescribing for obesity has grown more than tenfold in a few years while bariatric surgery volumes have started to fall for the first time in over a decade. Yet across two separate large claims-database studies, more than 90% of patients with obesity received neither treatment. The takeaway for NPs is not GLP-1 vs. surgery — it's that both are underused, and the real work is identifying untreated patients and matching them to whichever tool actually fits their disease severity.

 

Two Studies, One Signal

A UC San Diego team drew on Epic Cosmos records from nearly 20 million patients with severe obesity and no diabetes, presenting at the 2026 ASMBS annual meeting. Separately, researchers from the Analysis Group and Harvard T.H. Chan School of Public Health analyzed national insurance claims from 11.7 million adults with obesity, overweight, or diabetes in a research letter published in JAMA Surgery. Different datasets, different patient populations, same headline finding: GLP-1 use is climbing fast, bariatric surgery use is falling, and the overwhelming majority of eligible patients are receiving no obesity treatment at all.

The Numbers

Study	GLP-1 Growth	Surgery Trend	Untreated
UC San Diego / ASMBS (2018–2025)	~4,600 to 1.4M+ Rx/yr	Rose to ~43K (2023), then fell to <40K	90–95%
Analysis Group / Harvard (2022–2024)	+140.4%	−34.1% (accelerating: −14.4% then −23.0%)	>90%

 

In the UC San Diego data, bariatric surgery utilization rose gradually from 0.03% of the active patient population in 2018 to 0.24% in 2023, then dropped to roughly 0.21% in 2024 and 2025 — the sharpest decline since GLP-1 agonists entered the obesity space. GLP-1 use over the same window climbed from 0.03% to 5.3%. The Harvard/Analysis Group study, covering a broader population including patients with overweight and diabetes, found 9.2% received GLP-1 receptor agonists and just 0.4% received metabolic bariatric surgery during 2022–2024.

The Part That Should Worry Us Most

Lead UC San Diego author Jeffery Reeves, MD, flagged what he called the most unexpected signal in the data: the decline in surgery appears concentrated among patients with the highest degrees of obesity and disease severity — precisely the patients who stand to benefit most from a durable, effective procedure. The Harvard/Analysis Group study reinforces this from the other direction, finding that patients who underwent surgery tended to be more medically complex than those on GLP-1s or receiving no treatment, with roughly a quarter carrying four or more comorbidities.

Put together, these findings raise a real clinical question: are the patients who need surgery most being steered toward, or settling for, a medication instead — and is that substitution actually serving them?

CASE FROM PRACTICE A 44-year-old man with BMI 46, obstructive sleep apnea, and early diabetic kidney changes asks you about "the weight loss shot" after seeing ads online. He has no prior workup for bariatric surgery and assumes surgery is a last resort he isn't ready for. This is exactly the profile these studies suggest is falling through the gap — high disease severity, a GLP-1 request driven by visibility and marketing rather than a comparison of options, and no documented discussion of surgery as a first-line, evidence-based treatment for his BMI class. A referral for a surgical evaluation alongside — not instead of — a GLP-1 conversation keeps both options on the table rather than defaulting to whichever one the patient asked about first.

 

Where GLP-1s and Surgery Actually Meet

The ASMBS authors floated a bridge hypothesis: for some patients, GLP-1 therapy may function as a step toward eventual surgery rather than a permanent alternative to it. A 2025 systematic review and meta-analysis in Langenbeck's Archives of Surgery, pooling 19 studies of GLP-1 agonists used specifically for insufficient weight loss or weight regain after bariatric surgery, supports the idea that these tools are complementary rather than competing. Across liraglutide, semaglutide, and tirzepatide, patients treated post-surgery for inadequate response lost an additional 5.3% to 29.1% of body weight, with tirzepatide outperforming semaglutide, and semaglutide outperforming liraglutide.

•     Non-response (under 5% total weight loss) occurred in 27.1% of liraglutide-treated patients, 19.1% of semaglutide-treated patients, and 2.9% of tirzepatide-treated patients (single study).

•     Adverse events were common (36–80% depending on the study) but overwhelmingly mild gastrointestinal symptoms, and were rarely the reason patients discontinued therapy.

•     Metabolic benefits extended beyond weight — meaningful improvements were reported in HbA1c, blood pressure, and triglycerides across several of the pooled studies.

For NPs following patients longitudinally, this reframes the surgery-vs-GLP-1 framing in the news coverage: for a patient with weight regain or a suboptimal response after bariatric surgery, adjunct GLP-1 therapy already has a reasonable evidence base — it doesn't need to be an either/or decision made once and never revisited.

Reading the Data With Appropriate Caution

A NOTE ON THE NUANCE Both surveillance studies are retrospective claims/EHR analyses — they show association, not causation. They cannot tell us why an individual patient chose (or was steered toward) one treatment over another, or over none. The two studies used different populations (severe obesity without diabetes vs. a broader obesity/overweight/diabetes cohort) and different data sources, so their exact percentages aren't directly comparable — the value is in the convergent direction of both trends, not the precise figures. The bariatric surgery adjunct meta-analysis was limited by high heterogeneity, few RCTs (especially for semaglutide and tirzepatide), and inconsistent reporting of secondary outcomes, which the authors note prevented a full meta-analysis of metabolic endpoints. None of these studies isolate the specific barriers behind the 90%+ untreated figure — insurance coverage, drug cost, surgical access, stigma, and referral patterns are all plausible contributors but weren't directly measured.

 

Board & Practice Prep

•     Metabolic bariatric surgery remains the most effective and durable treatment for severe obesity, with a safety profile comparable to gallbladder surgery, appendectomy, and knee replacement — a fact often underestimated in patient counseling.

•     Only an estimated 1% of patients eligible for weight-loss surgery undergo it in any given year, per ASMBS — a gap that predates the GLP-1 era and isn't fully explained by it.

•     Tirzepatide is a dual GLP-1/GIP receptor agonist, mechanistically distinct from single-target agents like liraglutide and semaglutide, and has shown superior weight-loss outcomes in head-to-head comparisons.

•     Insufficient weight loss (IWL) after bariatric surgery is generally defined as excess weight loss under 50% within 18 months; weight regain (WR) is progressive gain after initial success — but definitions vary across studies, which limits direct comparison of "non-responder" rates.

•     The SELECT trial (semaglutide 2.4 mg vs. placebo, n=17,604) demonstrated a 20% relative reduction in major adverse cardiovascular events, underscoring that GLP-1 benefits extend past the number on the scale.

The Takeaway

The headline of "GLP-1s up, surgery down" undersells the real story: obesity care as a whole remains dramatically underutilized, and the patients with the most severe disease may be the ones least likely to receive the most effective option. NPs are well positioned to interrupt that pattern — by treating a GLP-1 request as an opening to discuss the full continuum of care, including surgical referral, rather than the end of the conversation.

References

As GLP-1 Use Skyrockets and Bariatric Surgery Slows, Most Obesity Goes Untreated [press release]. American Society for Metabolic and Bariatric Surgery; May 5, 2026.

Anderer S. Metabolic bariatric surgery declines as GLP-1 drug use increases. JAMA. 2026;335(24):2099. doi:10.1001/jama.2026.6202

Tan YW, Shang M, Davis S, Gananadha SK. GLP-1 receptor agonists as an adjunct to bariatric surgery for weight loss and metabolic outcome improvement: a systematic review and meta-analysis. Langenbecks Arch Surg. 2025;410:295. doi:10.1007/s00423-025-03831-4

Broad Genomic Profiling in Metastatic Cancer: Why Are So Many Eligible Patients Still Missing It?

 

GENOMICS IN PRACTICE

Broad Genomic Profiling in Metastatic Cancer: Why Are So Many Eligible Patients Still Missing It?

A new JAMA Oncology cohort study puts a number on a gap NPs see every day in oncology and primary care follow-up.

CLINICAL BOTTOM LINE Only about 1 in 5 privately insured patients with newly diagnosed metastatic cancer received broad genomic profiling (BGP) up front, and even in cancers where testing is unequivocally guideline-recommended, uptake topped out under 50%. Older age, frailty, female gender identity, and living outside the Northeast were all independently associated with lower odds of testing. For NPs managing oncology patients, or fielding "has this been done yet?" questions in primary care, this is a call to build genomic testing checks into your own workflow rather than assuming it's been handled.

 

The Study, in Brief

Researchers from Yale and colleagues used a novel claims-based algorithm to identify BGP use in the Blue Cross Blue Shield Axis database, a nationwide administrative claims dataset. They followed 51,908 privately insured adults aged 30 and older who were newly diagnosed with one of the 10 most common metastatic solid tumors between January 2020 and June 2022.

Because BGP does not have one single, universal billing code, the team built an algorithm around BGP-specific codes, "stacked" panels of 10 or more single-gene test codes billed together, and unspecified molecular testing codes billed at $2,000 or more, then checked results against the contemporaneous NCCN testing guidance for each cancer type.

What They Found

•     Overall BGP use was 20.3% across the full cohort of newly diagnosed metastatic cancers.

•     Use rose over the study period, from 15.1% of patients in 2020 to 24.3% in 2022 — real progress, but still leaving roughly three-quarters of patients untested by 2022.

•     Pancreatic cancer saw the largest jump in testing, gaining 21.7 percentage points, though pancreatic adenocarcinoma still carries a guideline recommendation for BGP.

•     Among cancers where BGP is explicitly guideline-recommended, use ranged from 49.0% in metastatic lung cancer down to just 8.8% in metastatic breast cancer — meaning even the best-performing guideline-recommended group left roughly half of eligible patients untested.

•     Among cancers with equivocal recommendations, use ranged from 36.1% in colorectal cancer to 3.7% in thyroid cancer.

•     On multivariable analysis, patients were significantly less likely to receive BGP if they were older, met claims-based frailty criteria, self-reported female gender identity, or lived outside the Northeast census region.

Why This Matters at the Bedside

BGP (sometimes called comprehensive genomic profiling or broad-panel next-generation sequencing, NGS) looks across dozens to hundreds of genes in a tumor sample at once, rather than testing one gene at a time. For cancers like non-small cell lung cancer, identifying an actionable alteration (EGFR, ALK, ROS1, and others) up front can change first-line therapy entirely, sparing a patient a round of chemotherapy that was never going to be the best fit. When testing is delayed, skipped, or done piecemeal, patients can end up starting broad chemotherapy before a targeted option is ever identified — or never having that option surfaced at all.

NPs are often the clinician who orders the actual test in oncology and hematology-oncology practices, and just as often the one who notices a gap when a patient with metastatic disease shows up for a wellness visit, symptom management, or supportive care and there is no genomic testing anywhere in the chart. Either way, this study is a reminder that guideline-recommended does not mean reliably done, and that a routine check of whether BGP has occurred is a meaningful, low-cost intervention.

CASE FROM PRACTICE A 68-year-old woman with newly diagnosed metastatic pancreatic adenocarcinoma is referred to your primary care NP practice for symptom management while she awaits her first oncology appointment. Reviewing the chart, you notice imaging and staging are complete, but there is no mention of molecular or genomic testing anywhere in the records. Consistent with the disparities this study identified — older age and, often, delays tied to frailty and comorbidity burden — this is exactly the patient profile least likely to have BGP ordered promptly. A brief note to the oncology team flagging that BGP/NGS status should be confirmed before treatment planning finalizes can close a gap before it costs the patient a targeted-therapy option.

 

Reading the Data With Appropriate Caution

A NOTE ON THE NUANCE This was a retrospective, claims-based study of privately insured patients only — it does not capture Medicaid, uninsured, or (apart from a Medicare Advantage subgroup) traditional Medicare populations, all groups that may face different or greater testing barriers. Race and ethnicity data were excluded due to high rates of missingness in the claims dataset, so this analysis cannot speak to racial or ethnic disparities in BGP access, which prior literature suggests are also significant. The algorithm identifies billed testing, not confirmed receipt of results or their use in treatment decisions, and the study did not assess downstream outcomes such as whether identified alterations changed therapy or improved survival. Findings reflect histologic subtypes with the most established guidance (e.g., nonsquamous NSCLC, cutaneous melanoma, pancreatic adenocarcinoma) and may not generalize evenly across all subtypes within a cancer type.

 

Board & Practice Prep

A few concepts worth locking in, whether you're prepping for certification or just tightening up oncology-adjacent practice:

•     Broad genomic profiling (BGP) / comprehensive genomic profiling: multi-gene, panel-based tumor testing (often 50–500+ genes), distinct from single-gene testing or narrow hotspot panels.

•     NCCN guidance tiers testing recommendations by cancer type as recommended, useful in certain contexts, or not routinely indicated — know that "guideline-recommended" varies by histologic subtype, not just cancer type.

•     Actionable alterations in metastatic NSCLC (EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, KRAS G12C) are the classic board-exam example of why upfront BGP changes first-line treatment selection.

•     Claims-based frailty indices (e.g., the Kim Frailty Index used in this study) are increasingly used in health services research to identify vulnerable subgroups even without a formal geriatric assessment on the chart.

•     Disparities in cancer biomarker testing are a recurring theme across the literature: age, frailty, gender, geography, insurance type, and (where measurable) race/ethnicity have all been independently associated with lower testing rates.

The Takeaway

Guideline recommendations for genomic testing in metastatic cancer are only as good as their real-world uptake — and right now, that uptake is well under half even for the strongest recommendations. NPs sit at multiple points in this pathway: ordering the test, coordinating with oncology, or simply being the clinician who asks the question. A quick chart check for BGP/NGS status in any patient with newly diagnosed metastatic disease costs little and may be the difference between a patient receiving a targeted therapy and never being offered the chance.

Reference

Wang X, Rothen J, Huang S, et al. Adoption of broad genomic profiling in patients with cancer. JAMA Oncol. 2025;11(6):666-668. doi:10.1001/jamaoncol.2025.0499

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.