Previous Atorvastatin Treatment and Risk of Diabetic Foot Infection in Adult Patients: A Case-control Study

Objective. In addition to their lipid-lowering abilities, statins have anti-inflammatory and immunomodulatory properties. Increasing recent evidence suggests the possible role of pretreatment with statins in preventing or decreasing morbidity and mortality from infection. Diabetic foot infection (DFI) is a common complication of diabetes mellitus. The aim of this study was to determine whether previous atorvastatin use is associated with reduced risk of DFI and better outcomes of these infections. Materials and Methods. One hundred ten adult patients admitted with a diagnosis of DFI were enrolled in the experimental group. For the control group, 123 adult patients with diabetes mellitus in an outpatient setting and without a history of DFIs were accepted. Participants in both groups were classified as statin users or non-statin users depending on history of atorvastatin treatment. For all individuals, the demographic, clinical, and laboratory findings were registered. Results. Atorvastatin was used in 49.1% of the experimental group cases and in 66.7% of the control, and it showed a statistically significant difference (P = .007). Logistic regression analysis also showed that previous atorvastatin use significantly reduces the risk of DFI (odds ratio = 0.36; 95% confidence interval, 0.19–0.71; P = .003). Severe DFI, bone involvement, and the need for surgical intervention was lower in the experimental group, but this difference was not statistically significant. Conclusion. Prior therapy with atorvastatin considerably reduces the onset of DFIs. In addition to other effects, statins may be useful in preventing DFIs.

Diabetic foot infection (DFI) is a common complication of diabetes mellitus and a major cause of morbidity and mortality in patients. It is the most common cause of diabetes-related hospital admissions and remains a major cause of lower extremity amputation.¹ A DFI is defined as an infection that develops in the skin, muscles, or bones of the foot below the malleoli as a result of nerve damage and poor circulation associated with diabetes. Its severity ranges from a superficial infection to a deep infection involving muscle and bone with systemic manifestations.²

Several factors predispose patients with diabetes to infections. The most important factors are immunologic disturbances such as impaired leukocyte migration, chemotaxis, phagocytosis, and intracellular killing. Some evidence also suggests cellular immune responses and complement functions are reduced in those with diabetes.³ On the other hand, accelerated atherosclerotic occlusive disease in the arteries of the lower extremities increases the likelihood of ischemia and subsequently foot infection.³ Proper management of DFIs can reduce infection-related morbidities, duration of hospitalization, and incidence of lower limb amputation. Besides basic treatments, several proposed adjuvant therapies may be beneficial in some cases.⁴

The discovery of statins led to significant advances in the management of hypercholesterolemia and improvements in the primary and secondary prevention of coronary artery disease. Like all drugs, statins can cause side effects; however, most people tolerate them well. Potential side effects include dyspepsia, headaches, fatigue, muscle symptoms, elevation in liver transaminases, and cognitive problems. Serious hepatic or musculoskeletal adverse effects rarely occur.⁵ During recent years, various studies have described different beneficial effects of statins in addition to their lipid-lowering ability in some diseases.⁶ These pleiotropic effects have been related to different metabolic pathways. Some of the most important effects are anti-inflammatory, immunomodulatory, endothelium-stabilizing, and vascular inflammation decreasing properties.⁷ The immunologic and inflammatory effects arise from the influence of statins on the inflammatory response, including decreased production of cytokines, increased ability of phagocytes to create extracellular traps, modifying the intercellular interactions, and the cellular chemotaxis of the immune system.⁸

According to these effects, a growing interest (with some controversy) has emerged in the possibility of statins decreasing or preventing morbidity and mortality from infection.⁹ Some epidemiological and clinical studies in humans have shown that treatment with statins is associated with decreased rates and/or mortality in patients with different types of infections.^10-12

Management of dyslipidemia, especially with statins, is a cornerstone of risk-factor modification in patients with diabetes mellitus. Several animal and human studies have indicated that the statins have a favorable effect on diabetic microangiopathy and can restore ischemic limb blood flow. This benefit is mediated by improving endothelial function and reducing oxidative stress.^13,14 Since ischemia plays an important role in the development of diabetic foot ulcers (DFUs) and DFIs, improving oxygenation and tissue perfusion can help to prevent and better treat DFIs.¹⁵ Based on the aforementioned mechanisms, some authors hypothesized that statins can be useful for the prevention and treatment of DFUs and DFIs.^16-18

A few studies^16-18 have investigated the effects of statin use in patients with DFIs. The present authors hypothesized that patients with diabetes using statins are less prone to foot ulcers and infections. This study was designed to explore whether prior treatment with statins impacts the frequency, complications, and outcomes
of DFI.

This case-control study was conducted from June 2013 to September 2015 in a university-affiliated hospital in Semnan, Iran. Subjects who were ≥ 18 years, diagnosed with diabetes mellitus for at least 1 year, and admitted with an episode of DFI were considered for inclusion in the experimental group. Inclusion criteria for the control group consisted of subjects who were ≥ 18 years, diagnosed with diabetes mellitus for at least 1 year, no history of a DFI, and visited the hospital’s diabetes mellitus clinic during the study period. Individuals with a history of another infection within 1 month of their hospital visit, chronic renal diseases, immunocompromised state, or receiving immunosuppressive drugs were excluded in both groups. Written informed consent was obtained from all subjects before enrollment. 

The study protocol received Institutional Review Board approval from the Research Council and Ethical Committee of the Semnan University of Medical Science (Code: IR.SEMUMS.REC.1394.21).

The subjects self-reported their diagnosis of diabetes mellitus and use of oral hypoglycemic agents or insulin. Diagnosis of a DFI and severity categorization based on the criteria developed by the International Working Group on the Diabetic Foot and the Infectious Diseases Society of America¹⁸ were by a board-certified infectious disease specialist. The infection severity categories included mild (involvement of skin and subcutaneous tissue only), moderate (extensive cellulitis or deeper infection), and severe (presence of a systemic inflammatory response syndrome).¹⁹

The following variables were recorded for all subjects: gender, age, body mass index (BMI), duration of diabetes, type of treatment (ie, oral agent, insulin), smoking status,and statin-use condition. For each case, the DFI site, duration, severity, and history, as well as imaging results, types of treatment (medical, surgical), and outcomes were also recorded. All patients were followed from admission until hospital discharge. 

Laboratory assessments included in this study were fasting blood glucose (FBS) level, blood urea nitrogen (BUN), creatinine, triglycerides, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), complete blood count, and erythrocyte sedimentation rate (ESR). 

Both groups were divided into 2 subgroups based on previous statin use: statin user or non-statin user. Statin users included all individuals treated daily with statin for ≥ 3 months prior to enrollment and were considered exposed. The non-statin users were those who did not take statins and other cholesterol-lowering medications. Intermittent statin users and those who received a combination of statins and other cholesterol-lowering drugs were excluded. The statin included in this study was atorvastatin, which is the most common type of statin used in the patients treated at the authors’ institution (dose range, 20–40 mg/d). Subjects were defined as cigarette smokers if they smoked ≥ 5 cigarettes per day for a minimum of 6 months. Intermittent or past cigarette smokers were excluded. Statistical analyses were performed using Shapiro-Wilk, chi-square, t-student, and Mann-Whitney tests as well as logistic regression analysis using SPSS Version 18.00 (SPSS, Inc, Chicago, IL). A value of P < .05 was considered statistically significant.

For this study, 110 patients met the inclusion criteria for the experimental group and 123 for the control. The mean (± standard deviation [SD]) age of the experimental and control subjects was 60.1 ± 11.6 years and 60.2 ± 10.9 years, respectively, which showed no significant difference (P =.926). Mean BMI (± SD) for the experimental subjects was 25.9 ± 4.5, and the control group was 26.9 ± 4. (P = .083). Of the 110 experimental patients, 48 (43.6%) were women; from the 123 control subjects, 72 (58.5%) were women (P = .023). Fourteen experimental participants (12.73%) smoked cigarettes, but the control group only had 4 (3.25%) (P = .007). The mean (± SD) duration of diabetes mellitus was 14.7 ± 8.1 years and 8.2 ± 6.8 years in the experimental and control subjects, respectively (P < .001). Baseline characteristics of the 2 groups are demonstrated in eTable 1. 

Of the 110 experimental subjects with a DFI, 42 were located on the first toe (n = 42) followed by other toes (n = 33), metatarsal heads (n = 29), all toes (n = 5), and first toe and metatarsal heads (n = 1). The patients’ DFI grades at hospital admission were as follows: mild = 53 (48.2%), moderate = 43 (39.1%), and severe = 14 (12.7%). History of previous DFI was positive in 37 (33.6%) cases in the experimental group.

Comparing the laboratory findings between the 2 groups showed the BUN, creatinine, white blood cell, and ESR levels were significantly higher in the experimental group. However, hemoglobulin, triglyceride, cholesterol, and LDL levels were significantly lower in the experimental group (eTable 2). When these laboratory findings were analyzed in the experimental group based on statin use, BUN and creatinine were significantly higher whereas hemoglobulin, FBS, and HDL were lower in the atorvastatin user (P < .05). 

The rate of atorvastatin use was lower in cases with DFI (49.1%) compared with the control (66.7%) and showed a statistically significant difference (P = .007). The mean (± SD) duration of atorvastatin use was 3.0 ± 2.3 years and 3.7 ± 2.6 years in the experimental and control groups, respectively, with no statistically significant difference (P =.065). After adjusting for potential confounders, logistic regression analysis showed previous atorvastatin use significantly reduced the risk of DFI (odds ratio [OR] = 0.36; 95% confidence interval [CI], 0.19–0.71; P =.003). Other variables associated with DFI found to be statistically significant were the duration of diabetes (P < .001) and smoking (P = .008) (eTable 3). 

Bone involvement and the need for surgical intervention was lower in atorvastatin users in both groups, but this difference was not statistically significant. In addition, the rate of severe DFI was more common in non-statin users but no statistically significant difference (eTable 4). 

In this study of adult patients with diabetes,the results showed that using atorvastatin for at least 3 months was associated with a significantly reduced risk of DFI. These findings are in line with several previous studies describing the beneficial effects of statin therapy on reducing the risk of infections. In van de Gardeet al,²⁰ the researchers assessed the effects of statin use on the occurrence of pneumonia in adult patients with diabetes. Results showed that treatment with statins was associated with a significant reduction in the risk of pneumonia (adjusted OR 0.49; 95% CI, 0.35–0.69). They proposed that statins may be useful in preventing respiratory infections in patients with diabetes.²⁰ Trezzi et al²¹ evaluated patients who underwent cardiac operations for infections and mortality after surgery. Postoperative infections were significantly lower in patients who received statins compared with those who did not; investigators reported a protective effect of statin therapy against the development of infections after cardiac operations.²¹ In a cohort study of patients on dialysis,²² Gupta et al reported a lower rate of hospitalizations for sepsis among those receiving statins compared with non-statin users.

The present study extends the aforementioned findings to the possible preventive effect of statins on the incidence of a DFI. Johansen et al¹⁷ investigated the effects of low- and high-dose atorvastatin treatments on DFU healing and the recurrence risk. There were no significant differences in ulcer healing, but the incidence of recurring or new ulcers was significantly lower in patients receiving high-dose atorvastatin therapy. They concluded that the high-dose atorvastatin may protect against the development of DFUs.¹⁷ Nielsen and Nordestgaard²³ conducted a nested matched study of individuals with diabetes in Denmark and evaluated the effect of statin use on the risk of microvascular disease. Compared with non-statin users, statin users had a lower incidence of gangrene of the foot, diabetic retinopathy, and diabetic neuropathy.²³

The mechanisms underlying infection prevention and modification by statins could be related to immunomodulatory, anti-inflammatory, and endothelium-protecting properties of these drugs.^7,24 In addition, statins seem to attenuate the replication and infectivity of several infectious pathogens.^25,26 Chaudhry et al²⁷ studied the role of statins in altering the host response to bacterial infections in an animal model. Their findings showed that cerivastatin protected mice against bacteria-induced death, improved bacterial clearance, and reduced the release of proinflammatory cytokines.²⁷

A number of studies have indicated that statins have a favorable effect on diabetic angiopathy and neuropathy.^13,14,18,28 Because ischemia and neuropathy play an important role in the development of DFUs, it may be assumed that the use of statins can be useful for decreasing the risk of DFUs and DFIs via increased oxygenation and nourishment of the tissues by increasing perfusion.¹⁶

However, not all studies support the protective effect of statin use on infection. For example, in an observational study on patients with ischemic stroke, Rodríguez de Antonio et al²⁹ showed that prior treatment with statins does not appear to influence the rate of intrahospital infections following an acute stroke. In addition, other studies have reported no effect of statin use on the reduced risk of pneumonia,³⁰ postoperative wound infections,^31,32 invasive mold infections,³³ and hospital-acquired infections.³⁴ Difference in these findings might at least partly be explained by the differences in the study design, confounding variables, choice of outcome measures, and the different definition of statin users.

In the present study, the rate of severe DFI was less common among patients taking atorvastatin compared with non-statin users. Also, this difference was not statistically significant but can suggest that statin use may affect the severity of DFIs. Statin users in the study presented herein showed a somewhat better treatment outcome (less need for surgical intervention)compared with the non-statin user, but without a statistically significant difference. Results suggesting an association between statin therapy with less severity, better outcomes, and decreased mortality in infections are reported in several previous studies, and the authors of these studies suggested that the benefit could be related to the anti-inflammatory effects of statins.^10,35-37 In a retrospective cohort study, Sohn et al¹⁸ examined the association between the use of statin and non-statin cholesterol-lowering medications and the risk of lower extremity amputations of patients with diabetes mellitus. They reported a significant association between statin use and diminished amputation risk among patients with diabetes.¹⁸ However, other studies^38,39 found no difference in outcome and mortality from infections in statin users versus non-statin users.

Another variable that was significantly associated with the development of DFI in the present study patients was cigarette smoking. Previous studies^40,41 have found that patients who smoked cigarettes were associated with a higher rate of development of foot ulcers and gangrene than patients with diabetes mellitus. The significant association between smoking and developing postoperative wound infections⁴² and a pressure ulcer has been reported in previous studies.⁴³ Cigarette smoking impairs the function of several cell types, such as neutrophils and macrophages, that are important for inflammatory and bactericidal activity and also compromises oxygen delivery to tissues. In addition,components of cigarette smoke, especially carbon monoxide and hydrogen cyanide, interfere with the wound healing processes.⁴⁴ The literature suggests that smoking exerts deleterious effects on both morphological and functional aspects of skin microcirculation and compromises skin perfusion. The mechanisms of this phenomenon include compromised endothelial-dependent vasorelaxation, thickening of the arteriole walls, and platelet aggregation. Also, collagen synthesis and the deposition of mature collagen in the extracellular matrix are reduced by smoking. This leads to an imbalance between biosynthesis and degradation of dermal proteins.⁴⁵

This study has a few limitations. First, the sample size is relatively small due to the restrictive inclusion criteria. Second, although 2 groups were matched for some basic variables, it is still possible that some unknown or unmeasured variables may have affected the results. A final concern is that statin users take better care of their health, which can have a confounding effect (healthy-user bias). 

The findings of this study showed that previous therapy with atorvastatin (for a minimum of 3 months) was significantly associated with the reduced risk of DFIs in adult patients with diabetes. In addition to other effects, statins may be useful in preventing DFIs and therefore emphasize the indications for use of these drugs especially in patients with diabetes. Future large scale studies, especially clinical trials, are required to more definitively ascertain the relationship between statin use and the risk of infection in patients with diabetes, especially DFIs.

Affiliations: Semnan University of Medical Sciences and Health Services, Semnan, Iran; Social Determinants of Health Research Center, Semnan University of Medical Sciences; and Clinics of Diabetes, Kowsar Hospital, Basij Blvd, Semnan, Iran

Correspondence:
Mohammad Nassaji, MD
Semnan University of Medical Sciences 
Social Determinants of Health Research Center
Dameghan Road
Semnan, Iran
hnassaji@yahoo.com

Disclosure: The authors disclose no financial or other conflicts of interest.