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Background: Although statins are indispensable in dyslipidaemia management, increasing evidence indicates that some statins adversely affect glucose metabolism and insulin sensitivity. These metabolic effects vary among individual statins and may have long-term clinical consequences, particularly in populations at high risk for diabetes mellitus. Objective: To compare the effects of atorvastatin and pitavastatin on insulin resistance, fasting insulin levels, and metabolic safety parameters in statin-naïve patients with newly diagnosed dyslipidaemia. Methods: This prospective, randomized, open-label controlled trial enrolled statin-naïve adults with primary dyslipidaemia. Participants were randomized to receive atorvastatin 20 mg/day or pitavastatin 2 mg/day for six months. Fasting insulin levels were measured using chemiluminescent immunoassay, and insulin resistance was assessed using the homeostasis model assessment (HOMA-IR). Secondary outcomes included fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipid profile, and adverse metabolic events. Results:
Atorvastatin therapy was associated with a significant increase in fasting insulin (+2.4 ± 2.1 µIU/mL) and HOMA-IR (+0.82 ± 0.61) at six months (p < 0.001). In contrast, pitavastatin demonstrated minimal changes in fasting insulin (+0.6 ± 1.8 µIU/mL) and HOMA-IR (+0.18 ± 0.47). Between-group comparisons revealed significantly lower insulin resistance in the pitavastatin group (p < 0.001). Both statins achieved comparable lipid-lowering efficacy. The incidence of dysglycaemic adverse events was significantly higher in the atorvastatin group. Conclusion: Pitavastatin exhibits a metabolically safer profile with minimal impact on insulin resistance compared to atorvastatin. These findings support the preferential use of pitavastatin in dyslipidaemia patients at risk of insulin resistance and diabetes mellitus.
Insulin resistance represents a central pathophysiological mechanism linking dyslipidaemia, metabolic syndrome, and type 2 diabetes mellitus (T2DM). It is characterized by impaired biological response to insulin in peripheral tissues, leading to compensatory hyperinsulinaemia and progressive β-cell dysfunction. In populations predisposed to diabetes, such as South Asians, insulin resistance occurs early and at lower body mass indices, amplifying cardiometabolic risk.
Statins are the cornerstone of dyslipidaemia management and are universally recommended for both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Their efficacy in reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular events is well established. However, mounting evidence suggests that statins are not metabolically neutral and may exert variable effects on glucose metabolism and insulin sensitivity.
Large randomized controlled trials and meta-analyses have demonstrated an association between statin therapy and increased risk of new-onset diabetes mellitus (NODM). The diabetogenic effect appears to be dose-dependent and varies across statin molecules. High-potency, lipophilic statins such as atorvastatin have been more consistently associated with worsening insulin sensitivity and increased diabetes risk. In contrast, pitavastatin, a newer statin with distinct pharmacokinetic properties, has been suggested to have neutral or even favorable effects on insulin resistance.
Mechanistic studies propose several pathways through which statins may influence insulin sensitivity. These include reduced expression of glucose transporter-4 (GLUT-4), impaired insulin receptor signaling due to inhibition of isoprenoid synthesis, altered adipokine secretion, and mitochondrial dysfunction within pancreatic β-cells. Lipophilicity and extrahepatic tissue penetration appear to play a key role in mediating these effects.
Pitavastatin differs from other statins in several respects. It undergoes minimal cytochrome P450 metabolism, exhibits greater hepatic selectivity, and has been shown to increase adiponectin levels—an adipokine known to enhance insulin sensitivity and exert anti-inflammatory effects. These properties suggest that pitavastatin may preserve insulin signaling pathways and mitigate statin-induced insulin resistance.
Despite growing interest in statin-specific metabolic effects, direct head-to-head comparisons between atorvastatin and pitavastatin focusing on insulin resistance are limited. Moreover, most studies have included heterogeneous populations or patients with established diabetes, limiting interpretation in statin-naïve individuals with newly diagnosed dyslipidaemia.
The present study was designed to address this gap by prospectively comparing the effects of atorvastatin and pitavastatin on fasting insulin levels and insulin resistance, assessed by HOMA-IR, in statin-naïve patients. Understanding these differential metabolic effects may facilitate personalized statin selection and improve long-term cardiometabolic outcomes.
Study Design This prospective, randomized, open-label controlled trial was conducted at a tertiary-care teaching hospital in India, following Good Clinical Practice guidelines. Participants Statin-naïve adults aged 30–70 years with newly diagnosed primary dyslipidaemia were recruited. Individuals with known diabetes mellitus, secondary dyslipidaemia, significant hepatic or renal dysfunction, or statin intolerance were excluded. Randomization and Intervention Participants were randomized using a computer-generated sequence into: • Atorvastatin group: Atorvastatin 20 mg once daily •Pitavastatin group: Pitavastatin 2 mg once daily Treatment duration was six months. Lifestyle modification advice was provided uniformly. Assessment of Insulin Resistance Fasting venous blood samples were collected after an overnight fast. Serum insulin levels were measured using chemiluminescent immunoassay. Insulin resistance was calculated using the HOMA-IR formula: Secondary Assessments Secondary outcomes included FPG, HbA1c, lipid profile, and adverse metabolic events. Lipid parameters were measured using standard enzymatic methods. Statistical Analysis Data were analyzed using SPSS software. Continuous variables were expressed as mean ± SD. Paired t-tests were used for within-group comparisons and independent t-tests for between-group comparisons. A p-value <0.05 was considered statistically significant.
In contrast, the pitavastatin group demonstrated minimal changes in fasting insulin (+0.6 ± 1.8 µIU/mL) and HOMA-IR (+0.18 ± 0.47), which were not statistically significant. Between-group analysis showed significantly lower insulin resistance in the pitavastatin group (p < 0.001).
Table 1. Baseline characteristics of statin-naïve dyslipidaemia patients
|
Parameter |
Atorvastatin |
Pitavastatin |
p-value |
|
Age (years) |
52.4 ± 8.6 |
51.9 ± 8.2 |
0.68 |
|
BMI (kg/m²) |
24.8 ± 3.1 |
24.6 ± 3.0 |
0.61 |
|
Waist–Hip Ratio |
0.92 ± 0.05 |
0.91 ± 0.06 |
0.54 |
|
Fasting plasma glucose (mg/dL) |
94.6 ± 8.9 |
95.1 ± 9.2 |
0.77 |
|
HbA1c (%) |
5.32 ± 0.24 |
5.30 ± 0.26 |
0.81 |
|
Fasting insulin (µIU/mL) |
9.6 ± 3.2 |
9.4 ± 3.1 |
0.73 |
|
HOMA-IR |
2.24 ± 0.68 |
2.21 ± 0.65 |
0.79 |
Values are mean ± SD. Independent t-test used.
Table 2. Effect of statin therapy on insulin resistance indices at 6 months
|
Parameter |
Atorvastatin |
Pitavastatin |
p-value |
|
Δ Fasting insulin (µIU/mL) |
+2.4 ± 2.1 |
+0.6 ± 1.8 |
<0.001* |
|
Δ HOMA-IR |
+0.82 ± 0.61 |
+0.18 ± 0.47 |
<0.001* |
Δ = change from baseline to 6 months.
Table 3. Secondary glycaemic outcomes
|
Parameter |
Atorvastatin |
Pitavastatin |
p-value |
|
Δ FPG (mg/dL) |
+4.8 ± 6.2 |
+1.2 ± 4.9 |
0.001* |
|
Δ HbA1c (%) |
+0.18 ± 0.15 |
+0.04 ± 0.12 |
<0.001* |
Table 4. Change in HOMA-IR stratified by BMI and WHR
|
Subgroup |
Atorvastatin Δ HOMA-IR |
Pitavastatin Δ HOMA-IR |
p-value |
|
BMI <23 kg/m² |
+0.56 ± 0.48 |
+0.12 ± 0.39 |
0.004* |
|
BMI ≥23 kg/m² |
+0.96 ± 0.63 |
+0.22 ± 0.51 |
<0.001* |
|
WHR normal |
+0.61 ± 0.52 |
+0.15 ± 0.42 |
0.006* |
|
WHR high |
+1.04 ± 0.68 |
+0.24 ± 0.54 |
<0.001* |
Table 5. Lipid profile changes at 6 months
|
Parameter |
Atorvastatin |
Pitavastatin |
p-value |
|
Δ LDL-C (mg/dL) |
−46.2 ± 21.8 |
−44.7 ± 20.9 |
0.69 |
|
Δ Total cholesterol (mg/dL) |
−52.8 ± 24.6 |
−50.9 ± 23.1 |
0.64 |
|
Δ Triglycerides (mg/dL) |
−38.6 ± 27.4 |
−36.8 ± 26.9 |
0.72 |
|
Δ HDL-C (mg/dL) |
+4.2 ± 2.1 |
+4.5 ± 2.3 |
0.58 |
Glycaemic Parameters
Atorvastatin was associated with modest but significant increases in FPG and HbA1c, whereas pitavastatin maintained near-stable glycaemic indices.
Lipid Profile
Both statins produced significant and comparable reductions in LDL-C, total cholesterol, and triglycerides (p < 0.001), with no significant between-group differences.
Adverse Metabolic Events
The incidence of dysglycaemia-related adverse events was higher in the atorvastatin group. No severe myopathy or hepatotoxicity was observed.
This study demonstrates a clear differential impact of atorvastatin and pitavastatin on insulin resistance in statin-naïve patients with dyslipidaemia. Atorvastatin significantly worsened insulin sensitivity, whereas pitavastatin maintained metabolic neutrality.
The observed increase in fasting insulin and HOMA-IR with atorvastatin is consistent with prior mechanistic and clinical studies. Lipophilic statins may interfere with insulin signaling pathways in skeletal muscle and adipose tissue, leading to reduced glucose uptake and compensatory hyperinsulinaemia. Inhibition of isoprenoid synthesis may further impair insulin receptor substrate phosphorylation and GLUT-4 translocation.
Pitavastatin’s neutral effect on insulin resistance may be explained by its higher hepatic selectivity and limited extrahepatic tissue penetration. Additionally, pitavastatin has been shown to increase adiponectin levels, which enhances insulin sensitivity and suppresses inflammatory pathways implicated in insulin resistance.
The findings are particularly relevant to South Asian populations, who exhibit high baseline insulin resistance and susceptibility to T2DM. Even modest statin-induced deterioration in insulin sensitivity may accelerate progression to overt diabetes in these individuals.
Importantly, both statins achieved equivalent lipid-lowering efficacy, underscoring that metabolic safety can be optimized without compromising cardiovascular protection. These results support a paradigm shift toward individualized statin therapy based on metabolic risk profiling.
Strengths and Limitations
Strengths include randomized design, focus on statin-naïve patients, and direct measurement of insulin resistance. Limitations include open-label design and relatively short follow-up.
Pitavastatin demonstrates a metabolically safer profile compared to atorvastatin, with minimal impact on insulin resistance and fasting insulin levels. In patients with dyslipidaemia who are at high risk for diabetes mellitus, pitavastatin may represent a preferable therapeutic option. Incorporating metabolic safety into statin selection may optimize long-term cardiometabolic outcomes without sacrificing cardiovascular benefit. Further long-term studies are warranted to evaluate the impact of statin choice on diabetes incidence and cardiovascular endpoints.
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