Role of Adipsin in the Mechanism of Glucose Intolerance by Statin Therapy
- Conditions
- No diseaseTaken as controlNewly diagnosed patients of dyslipidimia
- Registration Number
- CTRI/2017/11/010341
- Lead Sponsor
- Dr Jahnavi Maini
- Brief Summary
Statins, well established group of lipid lowering drugs, are widely employed in contemporary approaches for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD).[1-4]
Statins are usually well tolerated by the patients but are associated with wide range of adverse drug reactions like myalgia, rhabdomyolysis, impaired cognition, hepatotoxicity and neuropathy.[5-8] Recent studies and meta-analysis have reported that the use of statins modestly increased the risk of diabetes as compared to placebo.[9] However, little is known about the mechanism involved in their diabetogenic effect. Yada et al found that statins inhibit the glucose-induced calcium signaling-dependent insulin secretion leading to diabetogenic effect.[10] In addition, statins suppress the synthesis of ubiquinone (CoQ10), an essential factor in the mitochondrial electron-transfer system, resulting in reduced production of adenosine tri-phosphate (ATP) which inhibits insulin secretion.[11] Furthermore, Nakata et al demonstrated that statins decrease the expression of glucose transporter type 4 (Glut4) on adipocytes, resulting in impaired glucose tolerance.[12]
Adipsin is an adipokine, earlier known as complement factor D which has recently been postulated to have a role in maintaining β cell function. Adipsin generates peptide C3a which acts on islets to augment ATP levels, respiration and cytosolic free Ca2+ leading to insulin secretion.[13] In a recent clinical study, Bhandari et al studied 218 proteins in serum of 11 patients receiving statins for primary prevention of cardiovascular risk and reported downregulation of adipsin protein.[14] It is established that adipsin modulate pancreatic β-cell function.[13] This warrants the need to study the effect of statin therapy on serum adipsin levels which may give an insight to understand the mechanism of development of glucose intolerance following statin use.
**LACUNAE IN KNOWLEDGE**
Various mechanisms have been proposed to explain how statins increase the risk of new onset diabetes. However, how statins modulate serum adipsin levels and beta cell function is not available in literature.
Study protocol was approved by the Institutional Ethical Committee of Lady Hardinge Medical College, New Delhi (Annexure I). Treatment naive patients of dyslipidemia started on statins and fulfilling aforementioned inclusion and exclusion criteria were enrolled. NHV were also screened for inclusion and exclusion criteria before enrollment. Written informed consent was obtained from all the enrolled patients as well as NHV. The selection of statin and its dose was purely a decision of the treating physician.
Patients’ profile, demography, medical history and treatment history was recorded in Clinical Record Form (Annexure II). Venous blood sample of each patient in the statin treatment group and in the NHV group was taken to assess baseline serum adipsin and insulin levels by enzyme-linked immunosorbent assay (ELISA). Other baseline investigations like Liver Function Test (LFT), Kidney Function Test (KFT), Complete Blood Count (CBC), Lipid profile, HbA1c, Fasting blood sugar (FBS) and Post prandial blood sugar (PPBS) levels were additionally recorded in the individual Investigation Performa (Annexure III). These parameters were repeated only in the statin treatment group after 12 weeks of statin therapy. The patients were asked to visit the Medical-OPD for follow up after 4 weeks, 8 weeks and 12 weeks of initiation of statin therapy (Table 1) for routine clinical examination (Annexure IV) and for monitoring the appearance of any adverse drug reaction (ADR) (Annexure V). Any suspected ADR was recorded in ADR reporting form of Pharmacovigilance Programme of India (PvPI) (Annexure VI).
**Table 1: Follow up visit schedule and investigation plan for the statin treatment group.**
| | | | | |
| --- | --- | --- | --- | --- |
|**Parameters**
**Follow up visit schedule**
|**Visit 1**
**Visit 2**
**Visit 3**
**Visit 4**
|Day from start of therapy
0
(Enrollment)
4 weeks
8 weeks
12 weeks
|Patient’s profile
√
×
×
×
|Demography
√
×
×
×
|S. Adipsin
√
×
×
√
|S. Insulin
√
×
×
√
|FBS and PPBS
√
×
×
√
|HbA1c
√
×
×
√
|Lipid profile
√
×
×
√
|LFT/KFT/CBC
√
×
×
√
|ADR Monitoring
×
√
√
√
|Clinical examination
√
√
√
√
**RESEARCH QUESTION**
Does statin therapy influence serum adipsin levels?
**HYPOTHESIS**
Statin therapy decreases serum adipsin levels leading to glucose intolerance.
**AIMS AND OBJECTIVES**
1. To study the effect of statin therapy on serum adipsin levels.
2. Correlate the levels of adipsin with serum insulin levels and HbA1c.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 55
Treatment naive dyslipidemic patients (Low-density lipoprotein ≥100mg/dl) or patients with ASCVD having dyslipidemia requiring statin therapy.
- 1.Patient with comorbid Type 1 and Type 2 Diabetes Mellitus.
- 2.Patients prescribed lipid lowering agents other than statins.
- 3.Any known history of condition(s) which may cause secondary dyslipidemia (e.g. nephrotic syndrome, glycogen storage disease etc.).
- 4.Any history of condition(s) which may affect euglycemia (pancreatic impairment or disease).
- 5.History of previous or current muscular or neuromuscular disease.
- 6.History of drugs which impair lipid profile or glycemic parameters.
Study & Design
- Study Type
- Observational
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 1.To estimate and compare the change in serum adipsin levels in dyslipidemic patients from baseline with that of serum adipsin levels after 12 weeks of statin therapy 12 weeks
- Secondary Outcome Measures
Name Time Method To estimation and comparison of serum levels of adipsin (mean ± SD) in statin treatment group and NHV baseline 2.To study the correlation of serum adipsin levels with serum insulin & HbA1c levels following 12 weeks of statin therapy 12 weeks
Trial Locations
- Locations (2)
Department of Medicine
🇮🇳Central, DELHI, India
Department of Pharmacology
🇮🇳Central, DELHI, India
Department of Medicine🇮🇳Central, DELHI, IndiaDr Jahnavi MainiPrincipal investigator9582976766jahnavi.maini@gmail.com