This story got my attention, so I dug deeper:
Lower baseline low-density lipoprotein cholesterol (LDL-C) levels were associated with a higher risk of developing type 2 diabetes (T2D) in individuals without a prior history of T2D and cardiovascular disease, and this association was largely independent of statin use.
METHODOLOGY:
- Researchers conducted a population-based study to assess whether baseline LDL‑C levels were associated with the risk for incident T2D and whether statin therapy modified that association.
- They analysed data of 13,674 participants who were free of T2D and cardiovascular diseases at baseline (mean age, 62 years; 58% men); 52% of participants were on statin therapy.
- Baseline LDL-C levels were measured on fasting blood samples at enrolment; participants were stratified into four groups on the basis of quartiles of LDL-C levels for analysis: low (< 84 mg/dL), medium (≥ 84 to < 107 mg/dL), high (≥ 107 to < 131 mg/dL), and very high (≥ 131 mg/dL).
- The primary outcome was incident T2D, requiring at least two fasting plasma glucose readings ≥ 126 mg/dL, at least one A1c value ≥ 6.5%, or the prescription of antidiabetic therapy for more than 30 days.
- The median follow-up duration was 71.6 months.
TAKEAWAY:
- Overall, 13% of participants developed incident T2D; the incidence was 20% among statin users and 6% among non‑users (P < .001).
- Lower LDL-C levels were associated with a higher risk for incident T2D (P < .001), with participants in the low LDL-C group (< 84 mg/dL) having the highest risk.
- The modifying effect of statin therapy on the risk for T2D was evident only in the very high LDL-C group (≥ 131 mg/dL), and statin users had a higher risk for incident T2D than non-users (P = .018).
- By contrast, the interaction between statin use and the risk for T2D was not statistically significant in the other LDL‑C groups.
https://www.medscape.com/viewarticle/low-ldl-cholesterol-linked-higher-diabetes-risk-2025a1000w1m
My takeaway: Watch Blood Sugar Levels Very Closely
5.4 For “longevity” users chasing ultra-low LDL
For a longevity-focused person without high near-term ASCVD risk who is contemplating pharmacologic strategies to push LDL into very low ranges (e.g., <50 mg/dL):
- This paper and the genetic literature together suggest that pushing LDL very low might come with a non-trivial increase in T2D risk, even independent of statins themselves.
- Given that:
- T2D and even prediabetes are themselves major accelerants of vascular aging, neurodegeneration, and mortality,
- And we lack long-term outcome data in healthy, low-risk individuals with pharmacologically induced ultra-low LDL,
- A sensible stance is:
- Avoid pharmacologic “over-treatment” when ASCVD absolute risk is low.
- Focus first on non-pharmacologic LDL-lowering (dietary pattern, body fat reduction, exercise) and improving global risk (BP, VO₂max, muscle mass, sleep) rather than simply pushing LDL to the floor with drugs.
In-Depth:
Prompt:
summarise, identify novelty and do a critique of this paper linked to here, then Identify any actionable insights from this study what would be relevant to people trying to improve their health and longevity A six-year longitudinal study identifies a statin-independent association between low LDL-cholesterol and risk of type 2 diabetes | | Full Text
CGPT5.1 Response:
Paper: “A six-year longitudinal study identifies a statin-independent association between low LDL-cholesterol and risk of type 2 diabetes” – Cardiovascular Diabetology, 2025. Full text.
1. Concise summary
Design and cohort
- Population-based cohort from the Italian COMEGEN primary-care database (Naples): 202,545 adults screened; 13,674 included after excluding baseline CVD, diabetes, cancer, and major life-limiting disease.
- Mean age 62 years, 58% male; 52% on statins at baseline. Mean LDL-C 105 ± 33 mg/dL.
- Median follow-up 71.6 months (~6 years); 1,819 participants (13%) developed incident T2D, defined by ICD-10 codes, fasting glucose ≥126 mg/dL, HbA1c ≥6.5%, or ≥30 days of glucose-lowering therapy.
Main findings
- Inverse LDL–T2D association:
- Lower LDL-C at baseline was associated with higher risk of incident T2D after adjustment for age, sex, BMI, fasting glucose, creatinine, and hypertension.
- LDL quartiles:
- Low LDL <84 mg/dL – 27.6 T2D cases/1000 person-years
- Medium 84–<107 mg/dL – 17.4/1000
- High 107–<131 mg/dL – 13.5/1000
- Very high ≥131 mg/dL – 8.4/1000T2D incidence was lowest in the ≥131 mg/dL group (all pairwise p<0.001).
- Effect of statins:
- Overall, 20% of statin users vs 6% of non-users developed T2D (p<0.001), and statin therapy was independently associated with higher T2D risk.
- Adjusted HRs for statin use within each LDL quartile:
- LDL <84: aHR 1.75 (95% CI 1.39–2.20)
- 84–<107: aHR 1.63 (1.32–2.00)
- 107–<131: aHR 1.54 (1.22–1.95)
- ≥131: aHR 2.41 (1.64–3.53)
- In a formal interaction model, the statin–LDL interaction reached significance only in the very-high LDL group (≥131 mg/dL; interaction aHR 1.68, 95% CI 1.09–2.58, p=0.018).
- Authors’ interpretation
- There is a strong inverse relationship between LDL-C and incident T2D in the general population, and the excess T2D risk at low LDL-C appears largely independent of statin therapy, suggesting LDL-C level itself (or processes tightly linked to it) may act as a biomarker of T2D susceptibility.
They link this to Mendelian randomization data showing that alleles that lower LDL-C via HMGCR, PCSK9, NPC1L1 and related pathways increase T2D risk, while familial hypercholesterolemia is associated with lower T2D incidence.
2. What is actually novel here?
Relative to prior work (mostly genetic studies and trial/meta-analyses):
- Real-world, general-population phenotype data:
- Prior evidence for “low LDL ↔ higher T2D risk” was largely genetic (HMGCR, PCSK9, NPC1L1 variants, UK Biobank MR).
- This is one of the first large, unselected primary-care cohorts showing an inverse LDL–T2D association at the phenotypic level, outside of special populations or clinical trials.
- Joint modeling of LDL level and statin use over long follow-up:
- The study attempts to disentangle the diabetogenic effect of statins from that of low LDL-C itself by:
- Adjusting for statin use in Cox models
- Testing an LDL×statin interaction
- Re-running models within LDL quartiles.
- Dose–risk structure across LDL quartiles:
- It shows a graded fall in T2D incidence from LDL <84 to ≥131 mg/dL, which visually mirrors some MR estimates and the observation that familial hypercholesterolemia patients have lower T2D prevalence.
- Statin effect heterogeneity by LDL level:
- Although statins increased T2D risk across all LDL strata, the relative excess was largest when baseline LDL was ≥131 mg/dL (aHR ~2.4). This nuance has not been prominent in prior trial meta-analyses, which mostly report an average ~9–10% relative increase in diabetes risk on statins overall.
So the main incremental message is: in routine clinical practice, people with very low LDL-C (especially <84 mg/dL) appear at distinctly higher risk of developing T2D, and this pattern persists even after accounting for statins. That strengthens the case that LDL-lowering biology itself, rather than statins alone, is linked to diabetogenesis.
3. Critique
3.1 Internal validity and methods
Strengths
- Large sample and long follow-up using a unified primary care EMR with repeated measurements and well-coded prescriptions and diagnoses.
- Exclusion of baseline diabetes and CVD reduces reverse-causation from pre-existing disease.
- Reasonable adjustment set: age, sex, BMI, fasting glucose, creatinine, hypertension.
- Multiple sensitivity analyses (LDL as continuous vs categorical, complete cases vs imputation when feasible) with consistent results.
Limitations / potential biases
- Residual confounding and missing key covariates
- No data on diet, physical activity, alcohol, socioeconomic status, or family history of T2D – all major drivers of both LDL and diabetes risk.
- Low LDL in real-world patients may mark chronic illness, frailty, malnutrition, liver disease (even though overt cirrhosis was excluded), or inflammation – all of which could independently predispose to T2D or affect detection rates.
- Baseline-only LDL and treatment exposure
- LDL-C and statin use are treated essentially as baseline covariates; in reality both are time-varying.
- Intensification or de-escalation of lipid-lowering therapy during follow-up is not modeled; this opens the door to time-varying confounding by indication and survivor bias.
- Statin characteristics under-specified
- No data on statin intensity, molecule, or cumulative exposure. The authors acknowledge this and note the dose-dependent diabetogenicity of statins.
- Without intensity data, the finding that high-LDL patients on statins have the strongest relative risk could simply reflect that they are on high-dose, high-potency regimens.
- Outcome and exposure misclassification
- T2D is defined via codes, labs, and prescriptions; this is standard but still vulnerable to underdiagnosis and misclassification, especially if health-care contact differs by LDL or statin status.
- LDL calculation uses Friedewald except when triglycerides >400 mg/dL; fasting status may not be perfectly standardized.
- Missing data / complete-case analysis
- Key variables (BMI, fasting glucose, creatinine, cholesterol) had enough missingness that multiple imputation was limited; final models are based on complete cases only, which may not be fully representative.
- No genetic data
- Given that the mechanistic argument relies heavily on Mendelian randomization and specific genes, the lack of genotyping is a missed opportunity.
Bottom line on causality
The data convincingly show that in this cohort low LDL-C is a marker of higher future T2D risk, and that statin therapy independently increases T2D incidence, consistent with RCT meta-analyses.
However, the study cannot establish that raising LDL-C would reduce diabetes risk, nor that pursuing very low LDL-C for ASCVD prevention is net harmful. Cardiovascular outcome trials still show that LDL lowering substantially reduces ASCVD events, and that the modest increase in diabetes risk is far outweighed by cardiovascular benefit in higher-risk individuals.
4. How does this fit into the broader literature?
- Statins and diabetes: RCT and meta-analytic data (Sattar 2010, CTT 2024) show ~9–10% relative increase in incident diabetes with standard-dose statins and ~30–35% with high-intensity therapy.
- Genetic low LDL and diabetes: MR studies consistently show that LDL-lowering variants in HMGCR, PCSK9, NPC1L1, etc., mildly but significantly increase T2D risk, while familial hypercholesterolemia (high LDL) associates with lower T2D prevalence.
- Mechanistic hints: Increased intracellular cholesterol uptake via LDL receptors may impair β-cell function and promote insulin resistance, consistent with in vitro data cited in the paper.
The present study is broadly consistent with this body of work. Its main value is pragmatic: it shows the same pattern in an unselected primary care population using routinely collected data, rather than genetic abstractions or tightly selected trial cohorts.
5. Actionable insights for people focused on health and longevity
None of what follows is individual medical advice; it’s risk-framing for discussion with a clinician.
5.1 Don’t treat LDL–T2D trade-offs in isolation
- LDL-C remains a causal driver of atherosclerotic cardiovascular disease, and ASCVD is still a dominant cause of morbidity and mortality.
- For people with high absolute ASCVD risk (prior events, very high LDL, high CAC scores, multiple risk factors), the evidence that LDL-lowering reduces CV events is much stronger than any suggestion that slightly higher diabetes risk from low LDL is net harmful.
- This paper is not grounds to deliberately keep LDL high to “avoid diabetes”; that would likely increase CV risk substantially.
5.2 Use LDL-C as one flag in diabetes risk assessment
For someone whose LDL-C is very low (<~80–85 mg/dL) either naturally or due to therapy:
- This study suggests that such individuals, as a group, have a higher probability of T2D onset over ~6 years, even after accounting for BMI, fasting glucose, creatinine, and hypertension.
- Clinically, that might justify:
- More aggressive glycemic surveillance: regular fasting glucose and HbA1c checks if LDL is very low and there are other risk factors (central adiposity, family history, prediabetes, etc.).
- Early intervention for insulin resistance: prioritizing weight control, high cardiorespiratory fitness, resistance training, sleep, and minimizing refined carbohydrate load and ultra-processed foods.
In other words, very low LDL can be treated as a weak additional risk marker, not a primary driver.
5.3 For people on statins
If you or a patient is on statin therapy:
- Accept that there is a real but modest diabetogenic effect, particularly in those already near the diagnostic threshold for T2D.
- Practical steps:
-
Baseline and periodic labs: fasting glucose and HbA1c before starting and periodically thereafter, especially if:
- BMI is high
- There is prediabetes at baseline
- LDL is driven very low by high-intensity statins or combination therapy.
- Dose tailoring: where ASCVD risk is moderate and LDL goals are achieved, consider whether maximal statin intensity is truly necessary versus moderate intensity plus lifestyle, or adjunctive non-statin therapy with more neutral glycemic profiles (e.g., ezetimibe, PCSK9 inhibitors, bempedoic acid – for which MR and trial data so far do not show the same degree of diabetogenicity).
-
Baseline and periodic labs: fasting glucose and HbA1c before starting and periodically thereafter, especially if:
5.4 For “longevity” users chasing ultra-low LDL
For a longevity-focused person without high near-term ASCVD risk who is contemplating pharmacologic strategies to push LDL into very low ranges (e.g., <50 mg/dL):
- This paper and the genetic literature together suggest that pushing LDL very low might come with a non-trivial increase in T2D risk, even independent of statins themselves.
- Given that:
- T2D and even prediabetes are themselves major accelerants of vascular aging, neurodegeneration, and mortality,
- And we lack long-term outcome data in healthy, low-risk individuals with pharmacologically induced ultra-low LDL,
- A sensible stance is:
- Avoid pharmacologic “over-treatment” when ASCVD absolute risk is low.
- Focus first on non-pharmacologic LDL-lowering (dietary pattern, body fat reduction, exercise) and improving global risk (BP, VO₂max, muscle mass, sleep) rather than simply pushing LDL to the floor with drugs.
5.5 Open questions / what further data are needed
For someone like you, trying to interpret this mechanistically and practically:
- We still need:
- Studies integrating time-varying LDL, detailed statin intensity, and other LDL-lowering drugs with longitudinal glycemia.
- Combined genotype + phenotype cohorts to separate causal LDL effects from pleiotropic pathways.
- Trials or very large observational datasets evaluating whether different LDL-lowering strategies (statin vs PCSK9 vs ezetimibe vs bempedoic acid) differ meaningfully in long-term diabetes, microvascular complications, and mortality in various baseline risk strata.
Until then, this paper should mainly influence risk monitoring and therapeutic nuance, not a fundamental reversal of the principle that LDL lowering is beneficial for cardiovascular risk reduction.