→ MicroPublications: five clinical papers worth five minutes

→ Feature: what ACHIEVE-4 actually tells UK prescribers about oral orforglipron

→ NICE round-up: fertility guideline refresh, kidney cancer pathway, and fezolinetant moves into NG23

→ ICYMI and From around the web

You can get a full breakdown of every relevant NICE guideline and how it affects you - on our NICE guidelines page.

Five clinical papers. Fifty words each. Five minutes.

Introducing the first edition of Medicine Central's MicroPublications, your comprehensive digest of five cutting-edge clinical studies, readable within 5-minutes. Curated to support your weekly publication monitoring.

1. Oral GLP-1 RA meets cardiovascular non-inferiority in high-risk T2D

Oral orforglipron met non-inferiority vs insulin glargine on MACE-4 in 2,749 high-CV-risk adults with T2D (HR 0.84, 95% CI 0.59–1.20), with superior A1c (−1.6% vs −1.0%) and weight (−8.8% vs +1.7%) reductions at 52 weeks, persisting to 104. A pre-planned 57% lower all-cause mortality signal (HR 0.43, 95% CI 0.25–0.75) is hypothesis-generating pending peer-reviewed publication. Lilly plans US T2D filing in Q2 2026.

Lilly topline, 16 April 2026

2. Magnetic seizure therapy non-inferior to ECT with less memory loss

In 239 adults with treatment-resistant depression across three North American sites (CREST-MST), magnetic seizure therapy met non-inferiority vs. right-unilateral ultrabrief ECT on HRSD-24 remission (22.5% vs 27.8%; difference 5.3%, 95% CI −4.4 to 14.9; p=0.048), with markedly less autobiographical-memory worsening (2.7% vs 17.3%; p=0.0003). Enrolment stopped early before the planned sample size.

Lancet Psychiatry, 15 April 2026

3. Stopping beta-blockers non-inferior one year after MI

Beta-blocker discontinuation was assessed in 2,540 stable post-MI adults (LVEF ≥40%, no HF, median 4.7 years post-MI) in the open-label SMART-DECISION RCT. They found that beta-blocker discontinuation was non-inferior to continuation for the composite of death, recurrent MI or HF hospitalisation at median 3.1 years (7.2% vs 9.0%; HR 0.80, 95% CI 0.57–1.13; p<0.001 non-inferiority). Predominantly Korean, largely male cohort; contrasts with prior ABYSS signal.

NEJM, 30 March 2026

4. Oral PCSK9 inhibitor crushes oral non-statin comparators on LDL-C

In 301 statin-treated adults in the active-comparator phase 3 CORALreef AddOn trial, oral enlicitide 20 mg reduced LDL-C by 64.6% at 8 weeks, versus bempedoic acid (−56.7 percentage points, 95% CI −64.3 to −49.0), ezetimibe (−36.0) and their combination (−28.1). 78% of enlicitide patients reached LDL-C <1.4 mmol/L with ≥50% reduction. Safety comparable; CV outcomes trial ongoing (n=14,500).

JACC, 30 March 2026

5. Medicinal cannabis ineffective for depression, anxiety, PTSD

In a systematic review and meta-analysis of 54 RCTs (1980–2025) of cannabinoids across mental-health and substance-use disorders, pooled effects showed no meaningful benefit for depression, anxiety or PTSD, with only weak low-certainty signals in insomnia, Tourette, autism and cannabis-use disorder, and a harm signal (increased cravings) in cocaine-use disorder. Heterogeneous products/doses and low-to-moderate certainty limit inferences.

Lancet Psychiatry, 20 March 2026

This week’s headline result is also the most over-hyped: findings of 57% lower all-cause mortality with orforglipron compared to insulin glargine.

The ACHIEVE-4 topline from Lilly delivered on its primary endpoint. In a study of 2,749 adults with type 2 diabetes and elevated cardiovascular risk, oral orforglipron was non-inferior to insulin glargine. This was measured by major adverse cardiovascular events over a median of 3.1 years. Hazard ratio was 0.84 (95% CI 0.59–1.20). A1c reductions were superior (−1.6% vs −1.0% at 52 weeks), as was weight change (−8.8% vs +1.7%), both persisting to 104 weeks.

The biggest finding was a 57% lower all-cause mortality with orforglipron compared to insulin glargine (HR 0.43, 95% CI 0.25–0.75). It is also the number to handle with most care. This was a pre-planned but non-multiplicity-controlled analysis. It is hypothesis-generating, not confirmatory. Until the full manuscript is peer-reviewed and the methodology can be inspected, it is premature to position orforglipron as a cardioprotective agent; in the way we do for semaglutide after SELECT or tirzepatide after SURPASS-CVOT.

For UK primary care, the clinically relevant story sits elsewhere. Orforglipron is a once-daily, small-molecule, non-peptide GLP-1 receptor agonist. It needs no cold chain, no injection, and no food or water restrictions. If the FDA filing leads to approval in late 2026, followed by MHRA licensing and NICE appraisal, the UK would gain an oral GLP-1 RA. This would bypass much of the supply, storage, and patient-preference issues that currently limit access to injectable therapies. The scalable manufacturing argument matters as much as the efficacy one.

Safety signals in ACHIEVE-4 were consistent with the class. Most common adverse events were gastrointestinal (nausea, vomiting, diarrhoea, constipation, decreased appetite). Discontinuation due to adverse events was 10.6% over the 52-week minimum treatment period, which is in line with existing injectable comparators. No new hepatic safety signals were reported.

Two main factors warrant attention before a UK launch. First, the full peer-reviewed publication will be critical for its mortality analysis methodology and cause-of-death breakdown. Second, NICE must decide how to treat an oral GLP-1 RA while injectable semaglutide and tirzepatide have established cardiovascular and renal outcome data that oral orforglipron currently lacks. Non-inferiority to insulin glargine is not the same as the placebo-controlled superiority trials. These trials are what support the current class positioning in UK practice.

For now, the practical takeaway for prescribers is narrower than the headline suggests. Orforglipron seems to effectively lower glucose and weight. It has a consistent GI side-effect profile and no new cardiovascular safety issues. The mortality signal is interesting and worth watching. It is not yet evidence on which prescribing decisions can rest.

To understand how NICE positions GLP-1 receptor agonists in UK primary care, read our coverage of the GLP-1 revolution. You can also find the broader class safety picture in the MHRA semaglutide vision loss update. Finally, our report on Ozempic for Alzheimer’s illustrates how similar hypothesis-generating signals can collapse in other therapy areas.

References

NG237 Fertility problems: assessment and treatment: Published March 2026, replacing 2013 guidance. Significant updates to investigation and referral pathways, including revised AMH testing thresholds and earlier specialist referral criteria. Full guideline.

NG245 Kidney cancer: diagnosis and management: New guideline covering renal cell carcinoma in adults. Relevant to primary care for the earliest-stage symptom pathways, haematuria investigation, and follow-up surveillance coding. Full guideline.

NG23 Menopause: Updated 31 March 2026 to cross-reference the new fezolinetant technology appraisal (TA1143). Our coverage of the fezolinetant appraisal.

→ The GLP-1 revolution: the good, the bad and the ugly

→ SGLT2i vs GLP-1 RA: which offers more kidney protection?

→ MHRA safety update: semaglutide and rare vision loss

→ Pulse Today: What GPs are actually prescribing for GLP-1 weight management in 2026 - useful real-world UK prescribing picture.

→ BJGP: Editorial on managing discontinuation of GLP-1 receptor agonists in primary care - practical take on the QS253 one-year monitoring recommendation.

→ MHRA Drug Safety Update (April 2026): latest class alerts and monitoring advice - worth a scan!

→ GPonline: How primary care teams are coping with the 2026 menopause demand surge - service-side reporting on NHS Health Check workflow impacts.