Evaluation of glycemic status among hypercholesterolemic patients on atorvastatin in a tertiary care hospital - A retrospective study.

INTRODUCTION: Statins are effective in reducing low-density lipoprotein cholesterol and are favorable in primary and secondary prevention of cardiovascular disease. Recent large trials have linked the use of statins and increased incidence of new-onset diabetes mellitus, the possibility of worsening of glucose level in individuals with diabetes following statin therapy, and this possibility is increased with the use of atorvastatin. This study was undertaken to analyze the possibility of the diabetogenic potential of atorvastatin among hypercholesterolemic patients.
MATERIALS AND METHODS: This retrospective cohort study was conducted in the cardiology department from July 2019 to December 2019. Patients on atorvastatin for more than 6 months with normoglycemia on commencement of therapy were included. The occurrence of prediabetes or new-onset diabetes mellitus after atorvastatin therapy is the outcome of the study. Adverse drug effects to atorvastatin were also recorded and WHO-UMC causality assessment was performed. Descriptive statistics were performed for baseline and demographic characteristics.
RESULTS: Sixty study participants were included in the study. Eighteen (30%) study participants developed prediabetes with an HbA1c value of 5.97 ± 0.22 and 17 (28%) of participants developed new-onset diabetes mellitus with an HbA1c value of 7.24 ± 0.50. Atorvastatin at dose of 40 mg was found to be the most frequently prescribed dose.
CONCLUSION: Atorvastatin has a dose-dependent risk of developing new-onset diabetes mellitus. Hence, the following statin therapy glycemic status should be periodically monitored especially in patients with a large dose of atorvastatin and also in patients with higher risk factors for diabetes.

Introduction

Cardiovascular disease (CVD) now has become the foremost reason for death globally which includes coronary artery disease, peripheral artery disease, and cerebrovascular disease, is mostly caused by atherosclerosis and its considerable risk factor is an elevation of low-density lipoprotein cholesterol (LDL-C) level.[123] According to the WHO Global Action Plan 2013, non-communicable disease will account for 80% of the global disease burden by 2020.[4] Premature mortality before the age of 70 years has increased drastically in India due to CVDs and metabolic disorders.[3] The Framingham heart study revealed the correlation between hypercholesterolemia and CVD. Endothelial dysfunction and insulin resistance are characteristic of coronary heart disease and statins have beneficial effects on atherosclerosis by decreasing LDL-C and improving endothelial function.[5] Statin therapy will be recommended and intensively used to treat the South Asian population suffering from hypercholesterolemia.[3]

Statins act by inhibiting an essential enzyme for the synthesis of cholesterol, 3-hydroxy-3-methyl-glutaryl coenzyme-A reductase and it is the quality care for treating hypercholesterolemia in recent medical practice. Statins are effective in reducing LDL-C and proven to be favorable in the prevention of CVD.[678] Besides their LDL-C-lowering properties the pleiotropic actions of lipophilic statins may give rise to disadvantageous metabolic effects such as depletion of insulin secretion and worsening of insulin resistance.[5] Current huge trials encounter the use of statins and increased incidence of new-onset diabetes mellitus (NODM), the probability of worsening of blood glucose level in diabetic patients following statin therapy in a higher dose, and this likelihood is raised with the use of atorvastatin.[8]

Randomized, placebo-controlled, double-blind multicenter JUPITER trial had shown that therapy with rosuvastatin was related with 25% surge in the new occurrence of diabetes. A wide-ranging complex meta-analysis that enclosed 29 trials with 1,63,039 contributors, had shown that statin usage predisposes to diabetes by 12% and also that atorvastatin 80 mg was linked with 34% increased risk of diabetes, followed by 17% increased risk for rosuvastatin. There is some evidence to say that there is a positive correlation between the long duration of statin therapy and diabetes.[3467]

Lately, the United States Food and Drug Administration has suggested recent security description modification for the dose-dependent statin therapy and the greater possibility for increased fasting plasma glucose and glycosylated hemoglobin (HbA1c).[69] There are many hypotheses concerned with statins and evolution of NODM, one of them is impaired insulin secretion and diminished insulin sensitivity and another one is, it might encourage beta-cell apoptosis to amplify the production of nitric oxide.[69] Koh et al. in their study had shown that study participants treated with atorvastatin had a significant increase in HbA1C level accompanied by increased fasting glucose level.[5] Hence, this study was conducted to analyze the possibility of the diabetogenic potential of atorvastatin among hypercholesterolemic patients.

Materials and Methods

Ethical consideration

The study was conducted after approval from the Institutional Ethical Committee (Ref No: 1535/2019, Government Tirunelveli Medical College). Informed written consent was obtained from all the study participants in local vernacular language before their inclusion in the study. The study was conducted according to the Declaration of Helsinki. The present study is a retrospective cohort study conducted in the Cardiology Department, Tirunelveli Medical College, Tirunelveli, Tamilnadu, India, for 6 months from July 2019 to December 2019.

Selection criteria

Patients attending cardiology out-patient department irrespective of gender, with age more than 18 years diagnosed with hypercholesterolemia on atorvastatin therapy for more than 6 months with baseline fasting blood glucose (FBG) <100 mg/dl or random blood sugar <140 mg/dl during the commencement of therapy were considered for the study and hence included. The study participants with a known case of diabetes, family history of diabetes, history of gestational diabetes, patients on concomitant medication like corticosteroids, thiazide diuretics, atypical anti-psychotics, or any other medication that may raise blood glucose levels were excluded from the study. The baseline investigations like serum lipid profile, FBG level, and glycosylated hemoglobin level done in laboratories other than the study center were excluded from the study.

Study procedure

The study participants were enrolled in the study as per the inclusion criteria. The demographic details, personal history, family history, drug history, and clinical characteristics like body mass index (BMI), waist circumference were recorded from the old medical records of the study participants. The duration and dosage of atorvastatin therapy given for each participant were recorded from the old medical documents of the study participants. The baseline laboratory investigations such as serum lipid profile, FBG level, and glycosylated hemoglobin level that were done in the laboratory in the study center were recorded from the old medical documents of the study participants. Similarly, the laboratory investigations were estimated once during the 6 months’ study period in the same laboratory of the study center for all the enrolled patients and recorded. Adverse drug effects to atorvastatin were also recorded and the WHO-UMC causality assessment was performed. The data collected were entered into an excel sheet and statistically analyzed. The end result of this research was the occurrence of prediabetes or NODM among patients with hypercholesterolemia on atorvastatin therapy.

Analysis of statistical data

The analysis of statistical data was performed using Excel Microsoft Windows operating system. Descriptive statistics were performed for baseline and demographic characteristics. Continuous variables were expressed as mean ± standard deviation. Categorical variables were expressed as the number of patients (n) and percentage (%). Correlation between dose and duration of atorvastatin therapy and change in glycosylated hemoglobin were expressed as numbers and percentages. Adverse drug reactions were expressed by descriptive statistics.

Results

As per the inclusion criteria, a total of 60 study participants were enrolled in the study. Among the 60 study participants, 41 (68%) and 19 (32%) study participants were males and females respectively, and mean age of study participants was 58.78 ± 13.03 years. The majority of patients were between the age groups of 51–65 years. The BMI of 20 (33.3%) study participants were in the normal category, 23 (38.3%) were in the overweight category and 17 (28.3%) were in the obese category. The mean waist circumference of the male was 95.97 ± 6.30 and the female was 87.48 ± 4.64. 32 (53%) study participants had a clinical history of smoking and 19 (32%) had a history of alcohol intake, 56 (93%) were on a mixed diet and finally 38 (63%) study patients were leading a sedentary life. Nearly 21 (35%), 20 (33%), and 14 (23%) of study participants had hypertension, ischemic heart disease, and coronary artery disease, respectively. A total of 43 (72%) of patients received Angiotensin converting enzyme inhibitors/Angiotensin receptor blockers (ACEI/ARBs) followed by low-dose aspirin by 38 (63%) patients [Table 1].

Table 1

Baseline demographic parameters of the patients included in the study

Parameters	Value (n=60)
Male/female, n (%)	41 (68)/19 (32)
Age (years), mean±SD	58.78±13.03
BMI (kg/m2), mean±SD
Normal (n=20; 33.3%)	23.79±0.69
Over weight (n=23; 38.3%)	26.93±1.20
Obese (n=17; 28.3%)	33.37±1.39
Waist circumference (cm), mean±SD
Male	95.97±6.30
Female	87.48±4.64
Concomitant disease, n (%)
Hypertension	21 (35)
Ischemic heart disease	20 (33)
Coronary artery disease	14 (23)
No comorbidity	5 (8)
Concomitant medication, n (%)
ACEI/ARBs	43 (72)
Aspirin low dose	38 (63)
Clopidogrel	28 (47)
Diuretics	32 (53)
Antianginal drugs	12 (20)
Others, n (%)
Smokers	32 (53)
Alcoholics	19 (32)
Mixed diet	56 (93)
Physical activity
Sedentary	38 (63)
Mild to moderate	22 (37)

n is number of patients and is expressed in percentage. BMI=Body mass index, SD=Standard deviation, ACE=Angiotensin converting enzyme inhibitors, ARBs=Angiotensin receptor blockers

The blood lipid profile, FBG level, and glycosylated hemoglobin level are shown in Table 2. Mean total cholesterol was 212.75 ± 25.32, triglyceride was 180.26 ± 19.61, low-density lipoprotein was 156.33 ± 14.13, and high-density lipoprotein was 37.25 ± 7.10. The mean FBG and glycosylated hemoglobin before initiating statin therapy were 88.01 ± 7.89 and 4.78 ± 0.46, respectively. After initiating atorvastatin therapy the mean glycosylated hemoglobin was 6.08 ± 0.86 and 18 (30%) of study participants were prediabetic with a value of 5.97 ± 0.22 and 17 (28%) of participants had NODM with a value of 7.24 ± 0.50 [Table 2]. The prevalence of NODM among the study participants on atorvastatin therapy based on glycosylated hemoglobin was 28% [Table 2].

Table 2

Mean distribution of lipid profile and blood glucose and glycosylated hemoglobin of study population

Parameters	Mean±SD
Lipid profile (mg/dl)
Triglycerides	180.26±19.61
Total cholesterol	212.75±25.32
Low-density lipoprotein	156.33±14.13
High-density lipoprotein	37.25±7.10
FBG (mg/dl)
Before statin therapy	88.01±7.89
After starting statin	116.1±29.69
Normal, n (%)=22	85.38±6.64
Prediabetes, n (%)=20	110.95±7.79
NODM, n (%)=18	153.66±20.09
HbA1c level (%)
Before statin therapy	4.78±0.46
After starting statin	6.08±0.86
Normal, n (%)=25	5.25±0.51
Prediabetes, n (%)=18	5.97±0.22
NODM, n (%)=17	7.24±0.50

n is number of patients and are expressed in percentage. SD=Standard deviation, NODM=New-onset diabetes mellitus, HbA1c=Glycosylated haemoglobin, FBG=Fasting blood glucose

Table 3 shows the glycemic status of study participants based on the duration of atorvastatin therapy. 2% and 5% of the study participants on statin therapy for more than 12 years had shown to be prediabetic and diabetic respectively [Table 3]. Table 4 shows the glycemic status of study participants based on dose of atorvastatin therapy. Different strengths of atorvastatin were prescribed out of which 40 mg (47%) was commonly prescribed followed by 20 mg (38%) [Table 4].

Table 3

Glycemic status of study participants based on the duration of atorvastatin therapy

Duration of atorvastatin	Frequency, n (%)	Total, n (%)
6 months-3 years
Normal	22 (37)	25 (42)
Prediabetic	3 (5)
NODM	Nil
>3 years–6 years
Normal	2 (3)	13 (21)
Prediabetic	5 (8)
NODM	6 (10)
>6 years–9 years
Normal	1 (2)	13 (22)
Prediabetic	8 (13)
NODM	4 (7)
>9 years–12 years
Normal	Nil	5 (8.3)
Prediabetic	1 (2)
NODM	4 (7)
>12 years
Normal	Nil	4 (7)
Prediabetic	1 (2)
NODM	3 (5)

n is number of patients and is expressed in percentage. NODM=New-onset diabetes mellitus

Table 4

Glycemic status of study participants based on dose of atorvastatin therapy

Dose of atorvaststin therapy	Frequency, n (%)	Total, n (%)
20 mg atorvastatin
Normal	10 (17)	23 (38)
Prediabetic	5 (8)
NODM	8 (13)
40 mg atorvastatin
Normal	13 (22)	28 (47)
Prediabetic	9 (15)
NODM	6 (10)
80 mg atorvastatin
Normal	4 (6.6)	9 (15)
Prediabetic	4 (6.6)
NODM	1 (1.6)

n is number of patients and is expressed in percentage. NODM=New-onset diabetes mellitus

Table 5 shows the correlation between dose and duration of atorvastatin therapy and change in glycemic status based on glycosylated hemoglobin. Among nine study participants on 80 mg atorvastatin therapy, 3 (33%) study participants became prediabetic with the duration of therapy for more than 6 years to 9 years. A total of 63 adverse drug reactions (ADRs) were noted in 46 (76.7%) study participants. The most common ADR was myalgia (41.26%) followed by headache (25.39%) and dizziness (15.87%). Table 6 shows the ADRs related to statin therapy were categorized according to the WHO-UMC causality assessment scale.

Table 5

Correlation of dose and duration of atorvastatin therapy and change in glycemic status based on glycosylated hemoglobin

Dose of atorvastatin, n (%)	Parameters	6 months–3 years, n (%)	>3 years–6 years, n (%)	>6 years–9 years, n (%)	>9 years–12 years, n (%)	>12 years, n (%)
20 mg, 23 (38)	Normal	9 (15)	0	1 (2)	0	0
	Prediabetes	2 (3)	2 (3)	0	1 (2)	0
	NODM	0	2 (3)	2 (3)	3 (5)	1 (2)
40 mg, 28 (47)	Normal	9 (15)	2 (3)	2 (3)	0	0
	Prediabetes	1 (2)	4 (7)	3 (5)	0	1 (2)
	NODM	0	2 (3)	2 (3)	1 (2)	1 (2)
80 mg, 9 (15)	Normal	4 (7)	0	0	0	0
	Prediabetes	0	1 (2)	3 (5)	0	0
	NODM	0	0	0	0	1 (2)

n is number of patients and is expressed in percentage. NODM=New onset diabetes mellitus

Table 6

Adverse drug reactions profile of the study participants on atorvastatin

Type of ADRs	Frequency (n=63), n (%)	Causality assessment
Myalgia	26 (41.26)	Possible
Headache	16 (25.39)	Possible
Dizziness	10 (15.87)	Possible
Nausea	8 (12.69)	Possible
Tingling	2 (3.17)	Possible
Hepatitis	1 (1.58)	Probable

n is number of patients and is expressed in percentage. ADRs=Adverse drug reactions

Discussion

The present retrospective cohort study showed that treatment with statin increased the risk of prediabetes and NODM with a significant surge in FBG level and HbA1c after statin therapy. The development of diabetes can be predicted by risk factors such as older age, increased weight, and metabolic syndrome and is linked with a 12 times likelihood of diabetes and a three times likelihood of atherosclerosis, hence statin therapy can expose diabetes in patients with risk factors.[4]

The mean age of study participants in the present study was 58.78 ± 13.03 years. Aiman et al. in their study had shown that there was an increased incidence of diabetes seen in the mean age of 66 years and the results described in the Anglo-Scandinavian Cardiac Outcomes Trial– Lipid-Lowering Arm (ASCOT-LLA) trial 63 years was the mean age for the evolution of diabetes.[46] In this study, greater number of patients were between 51 and 65 years. Sattar et al. in their study had authenticated that, between the age of 55–76 years held greater chance of acquiring diabetes.[10] Similarly, Preiss et al. and Navarese et al. had documented that between the age of 55 and 65 years had greater chance of developing diabetes.[1112] In this study male study participants (68%) were among the patients on statin therapy. In the ASCOT-LLA trial, about 81% of study participants were male.[4]

Normal BMI was found in 33.3% of study participants, 38.3% were overweight and 28.3% were obese category in the present study. In a study conducted by Thomson et al. normal BMI was found in 56.7% of patients whereas 27.9% were overweight and 7.7% were obese.[4] Similar to the present study, in West of Scotland Coronary Prevention Study, Long-term Intervention with Pravastatin in Ischemic Disease and ASCOTT trials, overweight group was maximum in number.[4] Cassuto et al. had reported in their study that there is an independent association with a heightened possibility of evolution of diabetes, between obesity and statin therapy.[13] The mean waist circumference of the study participants in the present study was 95.97 ± 6.30 among males and 87.48 ± 4.64 among females. In the study conducted by Thomson et al., 86.41 ± 9.13 cm was the mean waist circumference.[4] Recent studies have demonstrated that there is an increased possibility of developing type 2 diabetes in patients with large waist circumference independent of BMI.[14]

In the present study, 18 (30%) study participants had impaired HbA1c level and 17 (28%) participants developed NODM. In a study conducted by Padmavati et al., 36.4% of the study participants had impaired HbA1c level and 27.2% developed NODM.[9] Meta-analysis conducted by Rajpathak et al., six studies were considered and 57,593 patients were randomized, during their follow-up, a total of 2,082 new cases of diabetes were reported. The study results showed substantial possibility of surge in diabetes among patients on therapy with statin.[15] In a meta-analysis conducted by Sattar et al. in which thirteen trials were included and they inferred that statin was related with increased chance of occurrence of diabetes in ratio of 1:255 patients on statin therapy for 4 years.[10] In the present study the mean FBG before statin therapy was 88.01 ± 7.89 and after statin therapy irrespective of the duration of therapy, 20 (33%) study participants were prediabetic with a mean FBG of 110.95 ± 7.79, and 18 (30%) participants developed NODM with a mean FBG level of 153.66 ± 20.09. In a study conducted by Padmavathi et al., the mean RBG before therapy was 96.72 ± 5.1 and after therapy was 112.63 ± 31.1.[9] In the present study, patients with a dosage of 20 mg atorvastatin for a duration of more than 3–6 years had shown that 3% of study participants became prediabetic and diabetic. Similarly with a dosage of 40 mg for a duration of more than 3–6 years had shown that 7% and 3% of study participants had become prediabetic and diabetic, respectively. Sukhija et al. noticed in their study that the meantime of 2 years is needed to produce a change in FBG and concluded that statin therapy is related with a surge in FBG in study participants irrespective of age with respect to their diabetic or nondiabetic status.[16]

Atorvastatin is the most commonly used statin in India.[3] The most common dosage of atorvastatin taken by the study participants in this study was 40 mg (n = 28, 47%) followed by 20 mg (n = 23, 38%) and 80 mg (n = 9, 15%). This is similar to the study conducted by Thomson et al., where 61 (58.6%) study participants were on 40 mg of atorvastatin followed by 24 (23%) 20 mg and 8 (7.6%) on 80 mg.[4] The correlation of dose and duration of statin therapy in the present study had shown that with 40 mg statin for a period of more than 6–9 years had shown that 5% and 3% had developed prediabetes and NODM, respectively. Similarly, study participants on 80 mg statin for more than 12 years had shown that 2% developed NODM. The meta-analysis conducted by Presiss et al. confirmed that there is a correlation between the dose and diabetogenic potential of statin and has shown that when compared to low-dose statins, a higher dose of statins developed a 12% risk of NODM with 4.9 years of median follow-up.[11] Navarese et al. in their meta-analysis concluded, the occurrence of NODM with a dosage 80 mg atorvastatin was 15%.[12]

A total of 46 (76.7%) study participants reported 63 atorvastatin-related ADRs. The most common ADR reported was myalgia in 26 (41.26%) participants followed by headache in 16 (25.39%) study participants. This is similar to the study conducted by Rao et al., where 55.7% of study participants had myalgia followed by 40% with headache as ADRs to statin.[3] Thomson et al. have shown in their study that 48.4% had myalgia and 21.21% had a tingling sensation.[4]

The causality assessment of ADRs showed possible causality to atorvastatin therapy except for hepatitis which showed probable causality and atorvastatin was discontinued for the same. The finding of this study was found to be consistent with studies conducted by Thomson et al. and Rao et al.[34] The strength of the study was the association of statin therapy with prediabetes and NODM with parameters of FBG and HbA1c. The limitations of the present study are retrospective study with smaller sample size, short duration, and single-centered study. To overcome the limitations, it is good to do a prospective study with an increase in sample size with a longer duration of time and probably multicenter study.

Conclusions

Statins are the most commonly prescribed drug in hypercholesterolemic patients to prevent cardiovascular disorder. Patients on statin therapy should be periodically monitored for glycemic status especially in patients on larger dosage of atorvastatin and also in patients with greater threat for diabetes. The medical practitioner should have knowledge of this and prescribe statin with caution in view of the development of prediabetes or NODM and should educate the patients about glycemic monitoring after starting statin therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.