Daily Endocrinology Research Analysis
Analyzed 28 papers and selected 3 impactful papers.
Summary
A nationwide cohort links SARS-CoV-2 infection to sustained elevations in prediabetes and type 2 diabetes risk over years. A network meta-analysis shows that emerging oral PCSK9 inhibitors produce large short-term LDL-C reductions with acceptable safety, while a randomized trial in older adults finds no mitochondrial or functional benefits from 12 weeks of oral nitrite, highlighting age- and tissue-specific pharmacology.
Research Themes
- Post-infectious cardiometabolic risk
- Emerging oral biologics for lipid lowering
- Aging, mitochondria, and tissue-specific pharmacology
Selected Articles
1. Safety and efficacy of oral PCSK9 inhibitors in hypercholesterolemia: A systematic review and network meta-analysis.
Across four multicenter RCTs (N=1387), oral PCSK9 inhibitors produced large LDL-C reductions (≈59–63% depending on agent/dose) versus placebo, with generally similar safety aside from increased diarrhea risk. Secondary lipid parameters improved and more patients achieved LDL-C goals; longer trials are needed to establish cardiovascular benefits.
Impact: Oral PCSK9 inhibitors could transform lipid management by combining potent LDL-C lowering with oral convenience, addressing adherence and access barriers of injectables.
Clinical Implications: If confirmed in longer outcome trials, oral PCSK9 inhibitors may offer a potent, convenient option for statin-intolerant patients or those needing additional LDL-C lowering, with counseling on gastrointestinal AEs (notably diarrhea).
Key Findings
- Four low-bias multicenter RCTs (N=1387; 8–52 weeks) showed oral PCSK9 inhibitors markedly reduced LDL-C versus placebo.
- Enlicitide high dose and NNC0385-0434 high dose achieved the largest LDL-C reductions (MD −62.6% and −61.8%).
- Safety was similar to placebo except for higher diarrhea risk (risk ratio 3.25).
- Secondary lipids improved (TC, HDL-C, non-HDL-C, ApoB, Lp(a)), and more patients met LDL-C targets; some regimens reduced triglycerides.
Methodological Strengths
- Frequentist random-effects network meta-analysis integrating only randomized controlled trials
- Consistent efficacy rankings with P-scores; low risk of bias across included studies
Limitations
- Short follow-up (8–52 weeks) and modest total sample size limit long-term safety and cardiovascular outcome inference
- Heterogeneity in agents/doses and limited AE characterization beyond diarrhea
Future Directions: Conduct large, long-duration outcomes RCTs to assess MACE reduction and long-term safety; head-to-head trials versus injectable PCSK9i and in statin-intolerant populations.
OBJECTIVES: Oral PCSK9 inhibitors show promise for the management of hypercholesterolemia, but a systematic review and network meta-analysis (NMA) is needed to inform clinical practice; we aimed to fill this gap. METHODS: Multiple databases were searched through November 14, 2025, to identify randomized controlled trials (RCTs) comparing oral PCSK9i with placebo in adults with hypercholesterolemia. Primary outcomes were adverse events (AEs) and percent change in low-density lipoprotein cholesterol (LDL-C); secondary outcomes included LDL-C goal attainment and changes in other lipids. Meta-analyses were conducted using RevMan and NMA in R, employing a frequentist approach and random-effects models. RESULTS: Four multicenter, low-bias RCTs (N=1387, follow-up 8-52 weeks) were included. Oral PCSK9i showed a safety profile similar to placebo, except for a higher risk of diarrhea (risk ratio: 3.25). All oral PCSK9i outperformed placebo in the percent reduction of LDL-C, with enlicitide high dose (HiD) (MD -62.6%, P score = 0.88) and NNC0385-0434 HiD (MD -61.8%, P score = 0.88) being the most effective, followed by enlicitide medium dose (MeD) (MD -59.1%, P score = 0.77). A higher proportion of patients receiving enlicitide (any dose) achieved LDL-C targets. All oral PCSK9i also improved total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein B, and lipoprotein(a). NNC0385-0434 HiD increased HDL-C; NNC0385-0434 HiD, enlicitide HiD, and MeD reduced TG. CONCLUSIONS: Limited short-term data suggest that oral PCSK9i are reasonably safe and effective, reducing LDL-C and improving other lipids. Longer, larger RCTs are required to confirm safety, efficacy, and cardiovascular benefits before broader use.
2. Benefits of Oral Nitrite Supplementation on Mitochondrial Respiration and Physical Function In Older Adults.
In a randomized, double-blind, placebo-controlled trial of sedentary adults ≥70 years (n=64), 12 weeks of oral sodium nitrite did not improve skeletal muscle mitochondrial respiration, exercise capacity, or physical function. Acute dosing increased plasma nitrite 16–30-fold but only ~1.6-fold in skeletal muscle and altered platelet respiration, indicating tissue-specific PK/PD in older adults.
Impact: This rigorously negative RCT refines translational expectations for nitrate/nitrite therapies in aging, emphasizing tissue-specific delivery barriers and age-related pharmacology.
Clinical Implications: Routine oral nitrite to enhance muscle mitochondrial function in adults ≥70 years is not supported; platelet bioenergetic responses may serve as a pharmacodynamic biomarker. Consider age- and tissue-specific delivery strategies in future interventions.
Key Findings
- No improvement in skeletal muscle CI&II MaxOXPHOS after 12 weeks of oral nitrite versus placebo in adults ≥70.
- Acute oral nitrite increased plasma nitrite 16–30-fold but only ~1.6-fold in skeletal muscle; platelet respiration changed significantly.
- No gains in exercise capacity or physical function, suggesting limited efficacy in older adults due to tissue-specific PK/PD.
Methodological Strengths
- Randomized, double-blind, placebo-controlled design with prespecified primary bioenergetic endpoint
- Comprehensive assessment including muscle and platelet bioenergetics plus functional outcomes
Limitations
- Modest sample size (n=64) and fixed dosing regimen may limit detection of subgroup benefits
- Not powered for clinical events; generalizability beyond sedentary older adults is uncertain
Future Directions: Evaluate alternative dosing, delivery routes, or combination strategies to enhance skeletal muscle bioavailability in older adults; validate platelet bioenergetics as a pharmacodynamic biomarker.
BACKGROUND: Age-associated decline in mitochondrial oxidative capacity is associated with increased risk of disease, frailty, and disability. Oral nitrite and nitrate supplementation have been demonstrated to improve mitochondrial energetics and physical function in younger adults, but effects in older adults (age ≥70 years) remain unclear. METHODS: Randomized, placebo controlled, double-blind, 2-arm trial with a parallel group design to examine the effect of 20 mg sodium nitrite supplements administered three times a day for 12 weeks versus placebo in older (age ≥70 years) sedentary adults. Change in muscle mitochondrial respiration (complex I and II supported maximal oxidative phosphorylation [CI&II MaxOXPHOS]) was the primary outcome. Platelet bioenergetics, cardiorespiratory fitness, and other physical function measures were also assessed. RESULTS: 64 adults (75.7 ± 5.7 years) completed the trial. Nitrite supplementation was not associated with improvements in skeletal muscle mitochondrial respiration, nor improvements in exercise capacity and physical function. However, platelet mitochondrial respiration changed significantly following an acute dose of oral nitrite. Notably, while nitrite levels increased 16 to 30-fold in plasma following an acute dose, levels increased only 1.6 fold in skeletal muscle. CONCLUSIONS: The divergent response of skeletal muscle versus platelet mitochondrial respiration in response to nitrite supplementation suggest tissue-specific pharmacokinetics and pharmacodynamics that likely impact on the efficacy of nitrite supplementation. Results also suggest there may be age-related changes in drug delivery, metabolism, and mitochondrial responsiveness compared to nitrite/nitrate previously demonstrated in younger adults.
3. Long-term Risk of Prediabetes and Type 2 Diabetes Following SARS-CoV-2 Infection: A Nationwide Cohort Study.
In a nationwide cohort (n=5,084,889), SARS-CoV-2 infection was associated with higher incident prediabetes (HR 1.23) and type 2 diabetes (HR 1.40). Risk peaked in the first month post-infection (both HR ≈1.87) and remained elevated for up to five years, despite attenuation.
Impact: Quantifies sustained post-COVID dysglycemia risk at population scale, guiding screening intensity and duration after infection.
Clinical Implications: Clinicians should implement proactive glucose monitoring (e.g., HbA1c/fasting glucose) after COVID-19, particularly in the first months, and maintain vigilance for several years in high-risk patients.
Key Findings
- Nationwide cohort of 5,084,889 adults with propensity score matching and Cox models
- SARS-CoV-2 positivity increased incident prediabetes (HR 1.23) and type 2 diabetes (HR 1.40) over follow-up
- Risks peaked in the first month post-infection (both HR ~1.87) and remained elevated up to 5 years (T2D HR 1.48)
Methodological Strengths
- Very large population-based sample with propensity score matching
- Time-to-event analyses (Kaplan–Meier, Cox) with temporal risk profiling
Limitations
- Observational design susceptible to residual confounding and detection bias
- Median follow-up 2.6 years (not all reached 5 years); evolving variants/vaccination may influence generalizability
Future Directions: Define risk modifiers (severity, vaccination, reinfection) and test targeted prevention (lifestyle/pharmacologic) strategies post-COVID for dysglycemia.
OBJECTIVE: To assess the long-term association between SARS-CoV-2 infection and the incidence of prediabetes and type 2 diabetes over a five-year period. METHODS: We conducted a nationwide, population-based cohort study including adults who had a positive COVID-19 test (599,744) and adults with a negative COVID-19 test (4,485,145) between January 1, 2020, and December 31, 2020. Participants did not have a history of prior SARS-CoV-2 infection, diagnosis of prediabetes or type 2 diabetes, and were followed for 5 years. Propensity score matching was used to control confounding, and time-to-event analyses were performed using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS: Among 5,084,889 individuals followed for a median of 2.6 years, those with confirmed SARS-CoV-2 infection exhibited a significantly increased risk of developing prediabetes (HR 1.23; 95% CI, 1.21-1.25) and type 2 diabetes (HR 1.40; 95% CI, 1.37-1.43) compared to uninfected individuals. The risk was most pronounced within the first month following infection (prediabetes: HR 1.87; 95% CI, 1.75-1.98; type 2 diabetes: HR 1.87; 95% CI, 1.79-1.96) and, although attenuated, remained significantly elevated over the subsequent five years (prediabetes: HR 1.23; 95% CI, 1.20-1.27; type 2 diabetes: HR 1.48; 95% CI, 1.43-1.53). CONCLUSIONS: SARS-CoV-2 infection is associated with a significantly increased risk of developing prediabetes and type 2 diabetes, with the highest incidence observed during the acute post-infection phase and persistent elevation in risk extending up to five years.