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The Statin Paradox: Balancing Cardiovascular Longevity with the Risks of Metabolic Dysregulation

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dr. Karunia Valeriani Japar

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Introduction

Statins, or HMG-CoA reductase inhibitors, have long been established as first-line agents in the management of dyslipidemia and the prevention of atherosclerotic cardiovascular disease (ASCVD). Their primary pharmacological action centres on the competitive inhibition of HMG-CoA reductase, resulting in reduced cholesterol biosynthesis and marked decreases in circulating low-density lipoprotein cholesterol (LDL-C) levels. Statins’ capacity to increase hepatic LDL receptor density facilitates the clearance of LDL particles from the bloodstream, thereby translating biochemical changes into substantial reductions in the risk of myocardial infarction, stroke, and cardiovascular mortality. Large-scale randomized trials and meta-analyses have confirmed that statin therapy confers cardiovascular protection and prolongs life expectancy, with evidence supporting their use for both primary and secondary prevention even among individuals at moderate cardiovascular risk or advanced age.

Beyond lipid lowering, statins exert pleiotropic effects: they improve endothelial function, reduce vascular inflammation, stabilize atherosclerotic plaques, and inhibit platelet aggregation. These mechanisms further reinforce their essential role in metabolic health populations, who frequently present with overlapping cardiometabolic risk factors and for whom the burden of atherosclerotic complications is particularly high. Consequently, statins are widely recommended as a cornerstone of longevity-focused preventive medicine.

However, growing evidence has heightened awareness of the potential metabolic side effects associated with statin therapy. Several observational studies and clinical trials have identified a modest but significant increase in the risk of insulin resistance and new-onset type 2 diabetes among statin users, particularly with higher doses and certain drug subclasses. The mechanisms underpinning this association remain incompletely understood, involving possible impairments in insulin signalling, b-cell function, and glucose metabolism. These findings highlight the importance of balance, individualized decision-making in statin prescribing, especially in populations already at risk for metabolic disorders. Given the broad clinical deployment of statins for longevity and cardiovascular risk reduction, careful considerations of their dual roles, both as protectors of vascular health and as potential contributors to metabolic dysregulation is essential for optimal long-term outcomes.

Statin Pharmacology and Mechanism of Action

Statins exert their primary pharmacological effect through competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway responsible for endogenous cholesterol biosynthesis. By binding to the active site of HMG-CoA reductase, statins induce a conformational change that reduces enzymatic activity, thereby blocking the conversion of HMG-CoA to mevalonate in hepatocytes. This inhibition decreases intracellular cholesterol levels, triggering compensatory upregulation of hepatic low-density lipoprotein (LDL) receptors on the cell surface. The increased expression and activity of LDL receptors enhance the clearance of circulating LDL cholesterol from the bloodstream, resulting in substantial reductions in plasma LDL-C concentrations and subsequent attenuation of atherosclerotic cardiovascular risk [1,2,3,4].

Beyond their lipid-lowering effects, statins exhibit pleiotropic cardiovascular benefits that are independent of cholesterol reduction. These include improvement of endothelial function through enhanced nitric oxide (NO) bioavailability and upregulation of endothelial nitric oxide synthase (eNOS), stabilization of atherosclerotic plaques by reducing inflammation and increasing plaque fibrous cap thickness, reduction in vascular oxidative stress, inhibition of platelet aggregation, and modulation of inflammatory pathways through decreased expression of pro-inflammatory pathways through decreased expression of pro-inflammatory cytokines. Such pleiotropic mechanisms contribute significantly to the overall cardiovascular protection observed in clinical trials and underscore the broader therapeutic value of statins in cardiometabolic disease management [5,6,7,8].

Figure 1. Action of Cholesterol and Statins on The Isoprenoid Biosynthesis Pathway [5]

Statins are pharmacologically classified based on their lipid solubility as either lipophilic (simvastatin, atorvastatin, fluvastatin, lovastatin, pitavastatin) or hydrophilic (pravastatin, rosuvastatin). Lipophilic statins can passively diffuse across cell membranes, allowing widespread distribution into extrahepatic tissues including skeletal muscle, cardiac muscle, adipose tissue, and the central nervous system. This broader tissue penetration has been proposed to account for enhanced pleiotropic effects in non-hepatic tissues, but may also increase the risk of adverse metabolic effects such as impaired insulin secretion and exacerbation of insulin resistance, particularly at higher doses. In contrast, hydrophilic statins exhibit greater hepatoselectivity due to their reliance on active carrier-mediated uptake mechanisms, primarily organic anion-transporting polypeptides (OATPs), which concentrate their activity within the liver and limit extrahepatic exposure. This hepatoselectivity may reduce the potential for non-hepatic adverse effects, although it may also limit certain pleiotropic benefits in peripheral tissues. These pharmacological distinctions carry important clinical metabolic cardiovascular risk profiles [4,9,10,11,12,13].

Insulin Resistance: Pathophysiology and Clinical Relevance

Insulin resistance (IR) is defined as an impaired biological response to insulin stimulation in target tissues, particularly in the liver, skeletal muscle, and adipose tissue. At the molecular level, insulin resistance arises from disruptions in insulin signaling pathways, which may involve decreased insulin receptor density, reduced binding affinity, defective tyrosine kinase activation, or postreceptor abnormalities in signal transduction. Under physiological conditions, insulin binding to its receptor activates a cascade of intracellular events mediated by insulin receptor substrate (IRS) proteins and phosphatidylinositol 3-kinase (PI3K), ultimately promoting glucose uptake via GLUT4 translocation in muscle and adipose tissue, suppressing hepatic gluconeogenesis, and inhibiting adipose lipolysis. In insulin-resistant states, chronic energy surplus and ectopic lipid accumulation-particularly diacylglycerols (DAG) and ceramides impair these signaling mechanisms, leading to compensatory hyperinsulinemia as pancreatic b-cells attempt to maintain euglycemia. When b-cell compensation fails, metabolic decompensation ensues, characterized by hyperglycemia, dyslipidemia, hypertension, endothelial dysfunction and a prothrombotic state [14,15,16,17,18,19].

Insulin resistance is recognized as the pathophysiological cornerstone of metabolic syndrome, prediabetes, and type 2 diabetes mellitus (T2DM). Metabolic syndrome encompasses a cluster of cardiovascular risk factors such as abdominal obesity, impaired glucose metabolism, dyslipidemia, and elevated blood pressure, all of which are mechanistically linked to insulin resistance. In prediabetes, insulin resistance manifests as impaired fasting glucose (100-125 mg/dL) and/or impaired glucose tolerance (140-199mg/dL at 2 hours post-oral glucose load), reflecting early defects in both peripheral insulin sensitivity and hepatic glucose regulation. As insulin resistance progresses and b-cell function deteriorates, overt T2DM develops, further amplifying metabolic dysfunction and cardiovascular risk. The phenomenon of “selective hepatic insulin resistance” adds further complexity; in the liver, insulin signaling for gluconeogenesis suppression becomes impaired, yet lipogenic pathways remain insulin-responsive, resulting in simultaneous hyperglycemia and hepatic steatosis [17,18,19,20,21,22,23].

Beyond its role in metabolic disease, insulin resistance is an independent predictor of cardiovascular morbidity and mortality. Mechanistic studies have demonstrated that insulin resistance elevates cardiovascular risk through multiple pathways including promotion of endothelial dysfunction via reduced nitric oxide bioavailability, induction of chronic low-grade inflammation, exacerbation of oxidative stress, enhancement of platelet aggregation, and acceleration of atherogenesis. Epidemiological investigations confirm that insulin resistance markers such as homeostatic model assessment of insulin resistance (HOMA-IR) and triglyceride-glucose index (TyG) are significantly associated with increased incidence of coronary heart disease, myocardial infarction, stroke, and cardiovascular death, even in individuals without overt diabetes. A meta-analysis by Gao et al. revealed that each one-standard-deviation increase in HOMA-IR was associated with a 46% increase in coronary heart disease risk, underscoring the potent atherogenic influence of insulin resistance [24,252,26,27,28,29].

The relationship between insulin resistance and longevity is complex and context-dependent. While chronic hyperinsulinemia and insulin resistance in midlife are associated with accelerated aging, increased risk of age-related diseases (including neurodegenerative disorders, hypertension, cardiovascular disease, and T2DM), and reduced health span, centenarians and individuals with exceptional longevity often exhibit preserved insulin sensitivity, low fasting insulin levels, and favourable metabolic profiles. Paradoxically, in older adults, particularly those aged ≥75 years, moderate insulin resistance may exert protective effects against all-cause mortality, possibly by providing metabolic reserves during acute illness or energy stress, although it simultaneously increases the risk of frailty and functional decline. This dual effect suggests a threshold phenomenon: while excessive insulin resistance accelerates cardiometabolic disease and premature mortality, very low insulin resistance in the elderly may reflect underlying chronic illness or metabolic frailty. Consequently, maintaining insulin sensitivity throughout midlife and early aging appears critical for promoting healthy longevity and preventing cardiovascular disease, whereas the significance of insulin resistance in advanced old age requires individualized clinical interpretation [30,31,32,33,34,35,36].

Evidence Linking Statins to Insulin Resistance and New-Onset Diabetes

Epidemiological And Clinical Trial Data on Risk of Insulin Resistance, Impaired Glucose Tolerance, And T2D With Statin Use

The association between statin therapy and increased risk of new-onset type 2 diabetes (T2D) has been established through converging evidence from large-scale randomized controlled trials (RCTs), meta-analyses, and observational cohort studies. The landmark meta-analysis by Sattar et al. involving 91,140 participants from 13 placebo-controlled statin trials demonstrated that statin therapy was associated with a 95 increased risk of incident diabetes (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.17) over a median follow-up of 4 years. This finding was subsequently confirmed and extended by Preiss et al., who reported a 12% increased risk of new-onset diabetes (OR 1.12, 95% CI 1.04-1.22) in a pooled analysis of five intensive statin trials [37,38,39,40,41].

More recently, the Cholesterol Treatment Trialists (CTT) collaboration conducted the largest individual participant-level meta-analysis to date, encompassing 154,664 participants from 23 statin trials. This analysis revealed that moderate-intensity statin therapy was associated with a 10% relative increase in new-onset diabetes (relative risk [RR] 1.10, 95% CI 1.04-1.16), corresponding to an absolute annual excess of 0.12% (95% CI 0.04 – 0.20). Importantly, the diabetogenic effect was consistently observed across multiple diagnostic modalities, including physician-reported adverse events, initiation of glucose-lowering medications, biochemical criteria (fasting plasma glucose ³7.0 mmol/L, random glucose ³11.1 mmol/L), and elevated hemoglobin A1c (HbA1c ³6.5%) [38].

Observational studies have generally reported higher absolute risks than RCTs, likely reflecting longer follow-up periods, broader patient populations, and more intensive diabetes screening. A meta-analysis by Engeda et al. comparing eight RCTs and 15 observational studies found that the incidence of new-onset diabetes was substantially higher in observational studies (55% increased risk) compared with RCTs (11% increased risk). The prospective Rotterdam Study, which followed 8,567 participants without baseline diabetes for 15 years, reported that statin use was associated with a 38% increased risk of incident T2D after adjustment for cofounding factors. Similarly, the METSIM cohort study involving 8,749 non-diabetic men demonstrated a 46% increased risk of T2D among statin users during 6-year follow-up. Notably, statin therapy in this cohort was associated with a 24% reduction in insulin sensitivity and a 12% reduction in insulin secretion, indicating that both insulin resistance and b-cell dysfunction contribute mechanistically to statin-associated diabetes [37,39,42].

Individuals with prediabetes or impaired glucose tolerance represent a particularly high-risk subgroup for statin-associated diabetes. In the Diabetes Prevention Program (DPP) and its observational follow-up study (DPPOS), statin use was associated with a 36% increased risk of incident diabetes (hazard ratio [HR} 1.36, 95% CI 1.17-1.58) among participants with impaired glucose tolerance, and this association persisted after adjustment for baseline diabetes risk factors and indications for statin therapy.  Waters et al. reported that among atorvastatin-treated subjects with fasting glucose >100mg/dL (prediabetic range), the conversion rate to diabetes exceeded 10% over approximately 5 years, and higher baseline fasting glucose (³ 95 mg/dL) was associated with further increased risk. Statins have also been shown to impair glucose uptake in cells involved in glucose homeostasis by inducing cholesterol-dependent conformational changes in glucose transporters (GLUTs), providing a molecular basis for their hyperglycemic effects [43,44,45,46].

In patients with established T2D, statin therapy has been shown to worsen glycemic control, albeit modestly. Masi et al. reported that statin users with diabetes had a higher likelihood of initiating insulin treatment, developing significant hyperglycemia, and requiring additional glucose-lowering medications compared with non-users. Although increases in HbA1c among diabetic statin users were moderate (approximately 0.12-0.22 mmol/L increase in glucose concentrations), the progression of diabetes and need for intensified therapy represents a clinically meaningful consequence of statin-induced metabolic effects [38,39,45].

Dose Response and Duration Effects: Associations With Statin Type, Intensity, And Cumulative Exposure

The diabetogenic effect of statins exhibits clear dose-response and duration-dependent relationships, with higher-intensity regimens and longer cumulative exposure conferring greater risk of new-onset diabetes. The meta-analysis by Preiss et al. demonstrated that intensive-dose statin therapy (e.g., atorvastatin 80 mg, rosuvastatin 20-40mg) was associated with a 12% increased risk of new-onset diabetes (OR 1.12, 95%CI 1.04-1.22) compared with moderate-dose therapy (e.g., atorvastatin 10mg, simvastatin 20-40mg). In absolute terms, intensive-dose statin therapy resulted in 2.0 additional cases of diabetes per 1,000 patient-years, corresponding to a number needed to harm (NNH) of 498 per year. The CTT Collaboration confirmed this dose-dependent effect, reporting that high-intensity statin therapy conferred a 36% relative increase in new-onset diabetes (RR 1.36, 95% CI 1.25-1.48) compared with placebo, representing an absolute annual excess of 1.27% (95% CI 0.88-1.69). A recent multicenter cohort study in patients with acute myocardial infarction undergoing percutaneous coronary intervention demonstrated that high-intensity statin therapy was a significant independent predictor of new-onset diabetes (HR 1.316, 95% CI 1.024-1.692) compared with moderate-intensity therapy over 3-year follow-up [12,38,40,41,42,43].

Individual statins exhibit heterogeneous diabetogenic potentials, which appear to correlate with lipophilicity, potency, and tissue-specific metabolic effects. Atorvastatin and simvastatin, both lipophilic statins, have been consistently associated with dose-dependent increases in diabetes risk. In the METSIM cohort, simvastatin and atorvastatin increased the risk of T2D in a dose-dependent manner, with atorvastatin demonstrating the strongest signals for diabetes-related adverse event across different age groups in a recent pharmacovigilance analysis. Rosuvastatin, a hydrophilic statin with high potency, has been reported to increase diabetes risk by 18% (OR 1.18, 95% CI 1.04-1.33) in meta-analyses, and was associated with a 25% higher risk of new-onset diabetes compared with placebo in the JUPITER trial. In contrast, pravastatin, a hydrophilic statin with lower potency, has shown inconsistent diabetogenic effects: some studies suggest no significant increase in diabetes risk or even modest protective effects in certain populations, while others report increased risk particularly in insulin-resistant individuals. Network meta-analyses have confirmed that the incidence of new diabetes is highest with rosuvastatin and lowest with pravastatin [12,38,47,49,50].

Cumulative statin exposure defined by duration of therapy and cumulative defined daily doses (cDDDs) is critical determinant of diabetes risk. A population-based study in women demonstrated that statin associated new-onset diabetes risk was cumulative dose-dependent, with the highest risk observed among women aged 40-64 years who received cumulative doses >60cDDDs. For atorvastatin, the adjusted OR for new-onset diabetes at cDDDs >60 was 8.0 (95% CI 2.57-24.90) among women aged 55-64 years, while for simvastatin it was 15.8 (95% CI 5.77-43.26) in the same age group. In hypertensive patients, the crude incidence of new-onset diabetes was 25.68 per 1,000 person-years among statin users versus lower rates among non-users, with risk increasing progressively with longer treatment duration. The DPP/DPPOS study reported that a 10-year follow up, the cumulative incidence of statin initiation prior to diabetes diagnosis was 33-37%, underscoring the substantial long-term diabetogenic burden of prolonged statin therapy. Importantly, these time- and dose-dependent effects underscore the necessity of continuous monitoring for glycemic deterioration in patients on long-term statin therapy, particularly those with baseline prediabetes, obesity or other features of metabolic syndrome [43,46,49,51,52].

Mechanistic Insights: How Statins Influence Glucose Homeostasis

Effects On Insulin Secretion (Pancreatic bCells) And Insulin Sensitivity (Adipose, Muscle, Liver)

Statins impair glucose homeostasis through dual mechanisms: suppression of pancreatic β-cell insulin secretion and induction of peripheral insulin resistance in key metabolic tissues including skeletal muscle, adipose tissue, and liver. Studies using mouse pancreatic MIN6 β-cells have demonstrated that simvastatin decreases glucose-stimulated insulin secretion by 59% at physiological glucose concentrations (5.5 mmol/L) and by 79% at hyperglycemic concentrations (16.7 mmol/L), whereas pravastatin exhibits no such inhibitory effect. In humans, a 10-week course of high-intensity atorvastatin therapy significantly increased fasting insulin levels and C-peptide area under the curve (AUC), reflecting compensatory hyperinsulinemia in response to statin-induced insulin resistance, along with a dose-dependent shift in the glucose-insulin dose-response relationship. Longitudinal cohort studies confirm that atorvastatin treatment is associated with a 5.75% reduction in β-cell function (as measured by insulin secretion-sensitivity index-2, ISSI-2) and a 5.56% reduction in insulin sensitivity index (ISI) [12,39,53,54].

The mechanisms by which statins impair insulin secretion are multifactorial and involve disruption of several critical signalling pathways in pancreatic β-cells. First, statins inhibit voltage-gated L-type Ca²⁺ channels in β-cells, thereby reducing Ca²⁺ influx and subsequent exocytosis of insulin granules—a calcium-dependent process essential for glucose-stimulated insulin secretion. Rosuvastatin has been shown to directly inhibit Ca²⁺ channels in pancreatic β-cells, leading to reduced insulin granule exocytosis. Second, statins suppress insulin secretion mediated by multiple G protein-coupled receptor (GPCR) pathways, including muscarinic M3 receptors and the free fatty acid receptor GPR40, which normally amplify glucose-stimulated insulin secretion. Simvastatin inhibits insulin secretion stimulated by GPR40 agonists (TAK875 and GW9508) by 33–77%, and also impairs acetylcholine-mediated insulin release. Third, statins disrupt intracellular signalling cascades downstream of glucagon-like peptide-1 (GLP-1) and its receptor, including protein kinase A (PKA) and exchange protein activated by cAMP 2 (Epac2), both of which are critical amplifiers of insulin secretion. Fourth, HMG-CoA reductase inhibition reduces mevalonate synthesis and downstream isoprenoid intermediates (farnesyl pyrophosphate and geranylgeranyl pyrophosphate), which are essential for proper β-cell function, proliferation, and development. Loss-of-function polymorphisms in the HMGCR gene have been associated with increased diabetes risk, further supporting the critical role of the mevalonate pathway in maintaining β-cell mass and glucose homeostasis [39,53].

In peripheral tissues, statins induce insulin resistance through impairment of insulin signalling pathways and glucose transporter (GLUT) function. In skeletal muscle, the primary site of postprandial glucose disposal, statins significantly reduce insulin-stimulated glucose uptake by disrupting the insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/protein kinase B (Akt) signalling cascade. Simvastatin and rosuvastatin treatment in primary human skeletal muscle cells decreases Akt phosphorylation at Ser473 by approximately 50%, thereby impairing insulin-dependent GLUT4 translocation to the plasma membrane. Paradoxically, statins induce chronic activation of AMP-activated protein kinase α (AMPKα) phosphorylation at Thr172, which normally mediates contraction-stimulated glucose uptake; however, prolonged AMPKα activation in the presence of suppressed Akt signalling leads to metabolic inflexibility, wherein skeletal muscle becomes dependent on AMPK-mediated glucose uptake and unable to appropriately respond to insulin stimulation. This dual disruption of insulin and AMPK signalling pathways contributes to progressive insulin resistance with long-term statin exposure [45,55,56].

At the molecular level, statins impair glucose uptake by inducing cholesterol-dependent conformational changes in glucose transporters, particularly GLUT1 and GLUT4. Depletion of membrane cholesterol by statins alters the proteolytic susceptibility and functional conformation of GLUT proteins, as demonstrated by mutagenesis studies of cholesterol recognition/interaction amino acid consensus (CRAC) motifs in the SLC2A1 gene encoding GLUT1. These conformational changes reduce the intrinsic glucose transport capacity of GLUTs, and this effect can be rescued by mevalonic acid supplementation or exogenous cholesterol, confirming the cholesterol dependency of the mechanism. Additionally, statins reduce GLUT4 gene expression and inhibit GLUT4 translocation through depletion of geranylgeranyl pyrophosphate (GGPP), which is required for the geranylgeranylation and membrane anchoring of small GTPases such as RhoA, Rab8a, and Rac1, key regulators of GLUT4 trafficking and insulin signalling. Inhibition of geranylgeranyl transferases I and II mimics simvastatin-induced insulin resistance in skeletal muscle cells, and supplementation with GGPP or geranylgeraniol (GGOH) prevents statin-induced skeletal muscle insulin resistance both in vitro and in vivo [45,55,56].

In adipose tissue, lipophilic statins such as simvastatin and atorvastatin downregulate GLUT4 gene expression and reduce insulin-stimulated glucose transport, effects that can be reversed by mevalonate supplementation. Statins also alter caveolin-3 (CAV3) localization, causing intracellular accumulation rather than plasma membrane localization, which disrupts the formation of cholesterol-rich caveolae microdomains required for efficient GLUT4 docking and insulin receptor signalling. In hepatocytes, statins induce “selective hepatic insulin resistance,” wherein insulin signalling for suppression of gluconeogenesis is impaired while lipogenic pathways remain insulin-responsive, resulting in simultaneous hyperglycemia and hepatic steatosis. Short-term statin therapy in hyperlipidemic mice induces hepatic insulin resistance characterized by impaired Akt phosphorylation, increased expression of gluconeogenic enzymes (phosphoenolpyruvate carboxykinase, PEPCK; glucose-6-phosphatase, G6Pase), and elevated hepatic glucose output [57,58,59].

Molecular And Cellular Pathways: Cholesterol Metabolism, Mevalonate Pathway, LDL-C Toxicity, Mitochondrial Function, Inflammation, And Adipokines

The diabetogenic effects of statins are mediated through complex interactions involving cholesterol metabolism, mevalonate pathway intermediates, LDL cholesterol (LDL-C) toxicity, mitochondrial dysfunction, inflammatory modulation, and adipokine dysregulation [12,39,60,61,62,63].

Inhibition of HMG-CoA reductase by statins reduces mevalonate synthesis, thereby depleting not only cholesterol but also critical isoprenoid intermediates including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These isoprenoids are essential for post-translational modification (prenylation) of small GTPases such as RhoA, Rac1, Rab proteins, and other signalling molecules involved in insulin secretion, GLUT4 trafficking, cell proliferation, and mitochondrial function. Depletion of GGPP impairs geranylgeranylation of RhoA, which is required for cholesterol homeostasis and insulin signalling in skeletal muscle, and disrupts Rab8a geranylgeranylation, which is critical for insulin-stimulated GLUT4 translocation and glucose uptake. Additionally, mevalonate pathway inhibition reduces synthesis of coenzyme Q10 (CoQ10, ubiquinone), a vital electron carrier in the mitochondrial electron transport chain (ETC) [39,56,60,61,64,65].

Statins routinely reduce serum CoQ10 levels by 16–54%, and some studies have documented reductions in skeletal and cardiac muscle tissue CoQ10 concentrations. CoQ10 deficiency impairs mitochondrial oxidative phosphorylation by inhibiting complex I, complex II, and complex III of the ETC, thereby reducing ATP synthesis and increasing generation of reactive oxygen species (ROS). Mitochondrial dysfunction resulting from CoQ10 depletion and direct inhibition of respiratory chain complexes contributes to both statin-induced myopathy and metabolic disturbances including insulin resistance. A study in older guinea pigs demonstrated that lovastatin treatment reduced mitochondrial ATP production by 45% in cardiac tissue, and this effect was reversed by CoQ10 pretreatment. In humans, high-dose statin therapy decreases mitochondrial respiratory function in patients with low muscle ubiquinone levels. Statin-induced mitochondrial dysfunction also disrupts calcium (Ca²⁺) homeostasis, impairs carnitine palmitoyltransferase-2 (CPT-2) expression (thereby reducing fatty acid oxidation), and triggers mitochondrial apoptosis pathways [60,61,66].

Paradoxically, while statins lower circulating LDL-C systemically, HMG-CoA reductase inhibition upregulates hepatic LDL receptor (LDLR) expression, which can transiently increase LDL-C uptake into extrahepatic tissues including pancreatic β-cells. High intracellular concentrations of LDL-C are lipotoxic to β-cells, causing oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, impaired insulin secretion, and ultimately β-cell apoptosis and reduced β-cell mass. This mechanism provides a pathway by which statins, despite lowering plasma LDL-C, may paradoxically impair β-cell function through tissue-specific LDL-C toxicity [60,61].

Statins also modulate inflammatory pathways and adipokine profiles, with differential effects depending on statin type and tissue context. Adipokines are bioactive peptides secreted by adipose tissue that regulate inflammation, insulin sensitivity, and metabolic homeostasis. Adiponectin, an anti-inflammatory adipokine, enhances insulin sensitivity by activating AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα) pathways, suppresses hepatic gluconeogenesis, and reduces vascular inflammation. Conversely, leptin is a pro-inflammatory adipokine that, in states of hyperleptinemia (such as obesity), promotes chronic low-grade inflammation, endothelial dysfunction, oxidative stress, and insulin resistance through activation of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), and c-Jun N-terminal kinase (JNK) pathways [60,61].

Simvastatin treatment significantly increases plasma insulin levels by 127%, reduces adiponectin levels by 10%, decreases insulin sensitivity (measured by QUICKI) by 6%, and increases leptin levels by 35% in hypercholesterolemic patients after 2 months of therapy. In contrast, pravastatin increases adiponectin levels by 9%, improves insulin sensitivity by 6%, and does not significantly alter insulin or leptin levels. Pravastatin has been shown to increase adiponectin mRNA expression, enhance adiponectin secretion from adipocytes, and improve insulin sensitivity in both mice and humans, whereas lipophilic statins (simvastatin, atorvastatin) either reduce or have neutral effects on adiponectin. Statins also decrease leptin expression in human white adipocytes and reduce monocyte chemoattractant protein-1 (MCP-1), an inflammatory chemokine, while increasing adiponectin expression in white adipocytes. However, the net effect on circulating leptin levels varies by statin type, with simvastatin increasing plasma leptin and pravastatin showing no significant change. These differential adipokine effects likely contribute to the distinct metabolic profiles observed with different statins [67].

Differential Metabolic Actions Among Statins (Pravastatin, Atorvastatin, Simvastatin, Etc)

Individual statins exhibit markedly heterogeneous metabolic effects, reflecting differences in lipophilicity, potency, tissue distribution, and interaction with specific molecular targets. Lipophilic statins (simvastatin, atorvastatin, fluvastatin, lovastatin) passively diffuse across cell membranes and achieve widespread extrahepatic tissue penetration, including pancreatic β-cells, skeletal muscle, adipocytes, and the central nervous system. This broad tissue distribution underlies their greater propensity to induce metabolic side effects, including impaired insulin secretion, insulin resistance, and new-onset diabetes. In contrast, hydrophilic statins (pravastatin, rosuvastatin) are hepatoselective due to reliance on active carrier-mediated uptake via organic anion-transporting polypeptides (OATPs), thereby concentrating their activity in the liver and limiting extrahepatic metabolic effects [67,68].

Pravastatin exhibits the most favourable metabolic profile among commonly used statins. Unlike simvastatin and atorvastatin, pravastatin does not impair glucose-stimulated insulin secretion in pancreatic β-cells, does not inhibit GPR40-mediated insulin release, and in some cases mildly increases basal insulin secretion. Pravastatin increases plasma adiponectin levels, enhances insulin sensitivity (QUICKI and HOMA-IR), and does not significantly alter insulin or leptin levels in hypercholesterolemic patients. Large-scale randomized controlled trials and observational studies have demonstrated that pravastatin is associated with a 30% reduction in the incidence of new-onset diabetes compared with placebo, and exhibits a protective long-term effect against diabetes when compared with simvastatin. Pravastatin’s differential effects extend to vascular smooth muscle cells, where it does not alter intracellular Ca²⁺ homeostasis or phenylephrine-induced contractions, in contrast to simvastatin and atorvastatin which markedly inhibit Ca²⁺ signalling through mevalonate-dependent pathways [53,67,68].

Simvastatin, a potent lipophilic statin, exhibits pronounced diabetogenic effects through multiple mechanisms. Simvastatin decreases glucose-stimulated insulin secretion by 59–79% in β-cells via inhibition of Ca²⁺ channels, ATP-sensitive potassium (KATP) channels, GPR40, muscarinic M3, PKA, and Epac2 pathways. In skeletal muscle, simvastatin significantly inhibits glucose uptake and GLUT4 translocation by suppressing the IR/IRS-1/Akt signalling cascade and depleting GGPP required for small GTPase prenylation. In clinical studies, simvastatin increases plasma insulin levels by 127%, reduces adiponectin by 10%, decreases insulin sensitivity by 6%, and increases leptin by 35%. Simvastatin also alters hepatic fatty acid metabolism by increasing activity of elongases and desaturases, thereby modulating the fatty acid composition of plasma lipoproteins and potentially contributing to insulin resistance [55,56,68,69].

Atorvastatin, another lipophilic statin with high potency, demonstrates significant diabetogenic potential. Atorvastatin is associated with dose-dependent increases in diabetes risk, with the highest risk observed at cumulative doses >60 defined daily doses (DDDs), particularly in women aged 40–64 years (adjusted OR 8.0, 95% CI 2.57–24.90). Atorvastatin treatment reduces β-cell function (ISSI-2) by 5.75% and insulin sensitivity (ISI) by 5.56% in longitudinal cohort studies. High-intensity atorvastatin (80 mg daily for 10 weeks) increases insulin resistance and compensatory insulin secretion in individuals without diabetes. Like simvastatin, atorvastatin inhibits Ca²⁺ signalling in vascular smooth muscle cells and β-cells through mevalonate-dependent mechanisms, whereas pravastatin does not [54,69,70].

Rosuvastatin, a hydrophilic statin with very high potency, exhibits an intermediate metabolic risk profile. Despite being hydrophilic, rosuvastatin has been associated with an 18% increased risk of new-onset diabetes (OR 1.18, 95% CI 1.04–1.33) in meta-analyses, and a 25% higher risk compared with placebo in the JUPITER trial. Rosuvastatin directly inhibits Ca²⁺ channels in pancreatic β-cells, leading to reduced insulin granule exocytosis. In skeletal muscle, rosuvastatin impairs Akt phosphorylation and induces chronic AMPKα activation, similar to simvastatin, thereby contributing to insulin resistance. The relatively higher diabetes risk associated with rosuvastatin compared with pravastatin may reflect its greater HMG-CoA reductase inhibitory potency, leading to more pronounced mevalonate pathway suppression despite hepatoselectivity [38,57].

Network meta-analyses confirm that the incidence of new-onset diabetes is highest with rosuvastatin and lowest with pravastatin, with simvastatin and atorvastatin exhibiting intermediate to high risk. These differential metabolic actions underscore the importance of individualized statin selection based on patient-specific diabetes risk factors, existing metabolic syndrome, prediabetes status, and cardiovascular risk profile [11,13,47,68].

Clinical Implications for Metabolic Health and Longevity

Clinical decision-making regarding statin therapy in the context of metabolic health and longevity requires careful risk-benefit assessment. Statins remain foundational for cardiovascular risk reduction, with strong evidence supporting their role in preventing major atherosclerotic events and prolonging lifespan. However, their potential to increase insulin resistance and the risk of new-onset diabetes in susceptible individuals must be weighed against these benefits. The absolute risk of developing diabetes from statins tends to be modest, but may be clinically significant in patients with baseline metabolic vulnerability [38,39,47].

Identification of high-risk populations is critical for individualized care. Patients with prediabetes, established metabolic syndrome, or advanced age are more likely to experience statin-induced metabolic complications. In such groups, baseline insulin sensitivity and glycemic parameters should be periodically monitored to assist in early detection of adverse metabolic shifts [39,48].

Risk mitigation strategies include selecting statins with a lower diabetogenic profile (such as pravastatin when appropriate), optimizing dosing to the minimal effective level, and integrating lifestyle interventions that promote insulin sensitivity, such as physical activity and dietary management. Close clinical monitoring and shared decision-making are advised to tailor therapy to the individual’s cardiovascular and metabolic risk profile, ultimately supporting both long-term vascular protection and healthy aging [39,48,68].

Practical Recommendations and Future Directions

Optimizing statin use in preventive and longevity-focused care calls for nuanced, evidence-based recommendations. Clinicians should practice individualized patient selection, prioritizing those with a clear indication for statin therapy based on cardiovascular risk stratification while considering baseline metabolic status. Ongoing monitoring of glucose metabolism and regular assessment for adverse effects are essential, especially in older adults or those with prediabetes and metabolic syndrome. Engaging patients in shared decision-making where the risks and benefits of statin therapy are clearly discussed, empowers informed choices and strengthens adherence to preventive strategies [38,42,47,68].

Looking forward, future research must address gaps in the mechanistic understanding of statin-induced metabolic disruption, particularly regarding tissue-specific effects and interindividual variability. Long-term studies are needed to clarify the metabolic outcomes of prolonged statin therapy, as well as its impact on functional health and aging trajectories. Priority questions include identifying genetic or biochemical predictors of statin intolerance, understanding how statins interact with lifestyle interventions, and developing personalized protocols for risk mitigation. Ultimately, advancing the science of statin therapy will enable clinicians to balance cardiovascular benefits with metabolic safety, supporting healthy aging and longevity in diverse populations [39,53,69].

Conclusion

In conclusion, statins remain a cornerstone of cardiovascular risk reduction and longevity-focused preventive medicine due to their robust efficacy in reducing LDL cholesterol and protecting against atherosclerotic events. Despite their well-established benefits, substantial clinical and mechanistic evidence highlights a modest yet notable risk of insulin resistance and new-onset type 2 diabetes in susceptible populations, particularly with intensive or prolonged statin therapy and lipophilic subclasses like simvastatin and atorvastatin.

Key pathogenic links involve statin-induced impairment of pancreatic β-cell insulin secretion, deterioration of insulin signalling and glucose uptake in muscle, liver, and adipose tissue, and disruption of crucial molecular pathways such as the mevalonate cascade, isoprenoid synthesis, and adipokine balance. Differential metabolic risk profiles among statins, most favourable for pravastatin, least favourable for lipophilic agents reinforce the need for personalized statin selection and dose optimization.

The overall clinical approach should entail careful risk-benefit assessment, identification of high-risk groups including those with prediabetes, metabolic syndrome, and older age, and proactive strategies for metabolic risk mitigation through lifestyle interventions and regular monitoring. Ongoing shared decision-making and individualized therapy remain essential to maximize vascular protection while minimizing metabolic complications.

Continued research is needed to elucidate the precise mechanisms underlying statin-related insulin resistance, establish long-term metabolic outcomes, and develop tailored protocols that balance cardiovascular benefits with healthy aging across diverse populations.

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