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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.
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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
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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.
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graduates since 2012.
