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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 2  |  Page : 83-86

Study on glycaemic control by canagliflozin and its effect on insulin resistance and plasma ketone in type 2 diabetes mellitus patients


1 Department of General Medicine, SRM Medical College Hospital and Research Centre, Kattankulathur, Tamil Nadu, India
2 Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India

Date of Web Publication26-Apr-2019

Correspondence Address:
Dr. J S Kumar
Department of General Medicine, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur - 603 203, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jod.jod_11_18

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  Abstract 


Aims: The aim is to study the effect of glycaemic control by canagliflozin and its effect on insulin resistance (IR) and plasma ketone in type 2 diabetes mellitus (DM). Settings and Designs: The study was done at the Diabetes Clinic, General Medicine Department of the hospital. The study designed to be a prospective observational open-label study. Subjects and Methods: The study was conducted in 60 patients for 3 months. The patients were divided into two groups test and standard. Canagliflozin is given to test over- and above-standard treatment, and standard group is given to the standard treatment. Blood samples are collected at the beginning and at the end of the study. Parameters such as body weight, waist circumference, fasting blood glucose, haemoglobin A1c (HbA1c), plasma ketone and homeostatic model assessment-IR (HOMA-IR) were analysed. Statistical Analysis Used: Data obtained from the present studies were collected and analysed statistically using software IBM SPSS version 21. Results: Various parameters such as HbA1c and weight loss showed a significant difference before and after the study in both standard and test group, respectively. Whereas, other parameters such as HOMA-IR, waist circumference and fasting blood sugar levels showed significant difference only in the test group. Conclusions: Canagliflozin provided better glycaemic control in type 2 DM patients along with decreased IR and marked weight loss. Increased plasma ketone levels were noted during the course of the therapy to an extent which can be used up by the body as a fuel and not cause ketoacidosis.

Keywords: Canagliflozin, haemoglobin A1c, homeostatic model assessment-insulin resistance, plasma ketone, waist circumference


How to cite this article:
Kumar J S, Karthickeyan K, Patel BR, Haroon Meeran K I, Karishma G, Raveendran VT. Study on glycaemic control by canagliflozin and its effect on insulin resistance and plasma ketone in type 2 diabetes mellitus patients. J Diabetol 2019;10:83-6

How to cite this URL:
Kumar J S, Karthickeyan K, Patel BR, Haroon Meeran K I, Karishma G, Raveendran VT. Study on glycaemic control by canagliflozin and its effect on insulin resistance and plasma ketone in type 2 diabetes mellitus patients. J Diabetol [serial online] 2019 [cited 2019 Aug 18];10:83-6. Available from: http://www.journalofdiabetology.org/text.asp?2019/10/2/83/257203




  Introduction Top


Diabetes is a group of metabolic disorder characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action or both.[1] People with type 2 diabetes mellitus (DM) are at increased risk for microvascular (neuropathy, nephropathy and retinopathy) and macrovascular (peripheral vascular disease, cerebrovascular disease and cardiovascular disease) complications in addition to metabolic syndrome, which further increases the risk of cardiovascular manifestations, including stroke and myocardial infarction.[2]

It is estimated that 366 million people had DM in 2011; by 2030, this would have risen to 552 million. The number of people with type 2 DM is increasing in every country with 80% of people with DM living in low- and middle-income countries. DM caused 4.6 million deaths in 2011.[3] The prevalence among adults aged 20–70 years is expected to rise from 285 million in 2010 to 438 million by the year 2030.[4]

Early and effective intervention in type 2 DM is to obtain good glycaemic control and is vital to reduce the risk of long-term diabetes complications. Lifestyle modification particularly regarding weight control in overweight/obese individuals is crucial component of type 2 DM therapy, but most patients usually require glucose-lowering pharmacotherapy to control hyperglycaemia.

Sodium glucose co-transporter 2 (SGLT2) inhibitors present a new class of antidiabetic drugs having an insulin-dependent mechanism that offers a considerable advantage of increasing urinary glucose excretion without inducing hypoglycaemia. SGLT2 is a protein in humans that facilitates glucose reabsorption in the kidney. SGLT2 inhibitors block the reabsorption in kidney, increase glucose excretion and lower blood glucose level. The mechanism of action of this new class of drugs also offers further glucose control by allowing increased insulin sensitivity and uptake of glucose in the muscle cells, decreased gluconeogenesis and improved first-phase insulin release from the beta-cells.[5]


  Subjects and Methods Top


The study was approved by Institutional Ethics Committee – SRM Medical College Hospital and Research Centre, Tamil Nadu, India.

A total of 60 type 2 DM patients aged between 18 and 60 years were enrolled in the study of which 30 in each group, test group (canagliflozin over- and above-standard treatment) and standard group. Patients with estimated glomerular filtration rate <45 ml/min, on dialysis, pancreatic disorder suggesting insulin deficiency, leukaemia, recent history of ketoacidosis and frequent urinary tract infection along with pregnant and nursing women were excluded from the study. Patients already on Sodium Glucose Co-transporters 2 (SGLT2s) inhibitors such as canagliflozin, empagliflozin and dapagliflozin were also excluded from the study.

Patients were included in the study after obtaining written informed consent form and were selected based on inclusion and exclusion criteria. Patients' demographic details, anthropometric measurements along with the past medical and medication history, comorbid conditions, diabetic history and complications if any were recorded. Complete information on oral hypoglycaemic agents (OHAs) and insulin was also noted.

Laboratory investigation including fasting and postprandial blood sugar (PPBS) levels, glycosylated haemoglobin (HbA1c), fasting insulin levels for calculating homeostatic model assessment-insulin resistance (HOMA-IR) using the formulae, fasting insulin × fasting glucose/405. Plasma ketone level was determined after overnight fasting on scheduled date. All the above tests were done at the beginning and end of the study for both tests and standard group.

HbA1c was measured by high-pressure liquid chromatography method, fasting blood sugar (FBS) and PPBS were measured using hexokinase and fasting insulin level and plasma ketone were done using fluorescent enzymatic immunoassay.

The patient in test group administered a single dose (100 mg) of canagliflozin once daily over and above the current medication as mentioned in [Table 1], whereas standard group patients were on OHA or insulin as prescribed.
Table 1: Oral hypoglycaemic agents prescribed for both standard and test groups (%)

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Statistical analysis

Data obtained from the present studies were collected and analysed statistically using software IBM SPSS version 21, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India. Student's t- test, paired and unpaired t- test were used to compare continuous variables and the Chi-square test to compare categorical variables between the groups. Data were considered significantly different if P < 0.05.


  Results Top


The project entitled 'Study on glycaemic control by canagliflozin and its effect on IR and plasma ketone in type 2 DM' was conducted as described in the earlier sections for 3 months. During this period of study, a total of 60 patients were enrolled for the study, 30 patients were on canagliflozin over- and above-standard treatment group and 30 patients on standard treatment group based on the inclusion and exclusion criteria, of which three patients were dropped out from the test group and three patients from standard group due to personal reasons. Both males and females were equally distributed in the test and standard group, respectively.

Demographic variables

Based on age and gender of the patients, males and females were equally distributed between the age group of 18 and 60 years as shown in [Table 2]. Glycaemic parameters are shown in [Table 3].
Table 2: Age and gender distribution of patients in standard and test group

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Table 3: Clinical and biochemical characteristics of patients in standard and test group

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Haemoglobin A1c level

The P value of HbA1c at the start and end of the study for both test and standard group was calculated statistically using paired t-test. The resultant P value of standard and test group is 0.004 and 0.001, respectively. Hence, there is a significant difference between before and after test among HbA1c levels in both standard and test group at 95%.

Fasting blood sugar

The P value of FBS levels at the start and end of the study for both test and standard group was calculated statistically using paired t-test. The resultant P value of standard and test group is 0.210 and 0.001, respectively. Hence, there is a significant difference between before and after test among FBS levels in the test group at 95% and no significant difference between before and after test among FBS levels in the standard group at 95 % IR is shown in [Table 3].

Homeostatic model assessment-Insulin resistance

The P value of HOMA-IR at the start and end of the study for both test and standard group was calculated statistically using paired t-test. The resultant P value of standard and test group is 0.072 and 0.014, respectively. Hence, there is a significant difference between before and after test among HOMA-IR levels in the test group at 95% and no significant difference between before and after test among HOMA-IR in the standard group at 95%.

Plasma ketone

Beta-hydroxybutyrate level

The P value of plasma ketone at the start and end of the study for both test and standard group was calculated statistically using paired t-test. The resultant P value of standard and test group is 0.082 and 0.553, respectively [Table 3]. Hence, there is no significant difference between before and after test among plasma ketone levels in both standard and test group at 95%.

Weight loss

In [Table 3], P value of weight (kg) at the start and end of the study for both test and standard group was calculated statistically using paired t-test. The resultant P value of standard and test group is 0.001 and 0.001, respectively. Hence, there is a significant difference between before and after test among weight (kg) in both standard and test group at 95%.

Waist circumference

The P value of waist circumference at the start and end of the study for both test and standard group was calculated statistically using paired t-test [Table 3]. The resultant P value of standard and test group is 0.148 and 0.001, respectively. Hence, there is a significant difference between before and after test among waist circumference in test group at 95% and no significant difference between before and after test among waist circumference in standard group at 95%.


  Discussion Top


Due to the high prevalence of type 2 DM globally, new therapy which provides better glycaemic control than existing hypoglycaemic agent as monotherapy or add-on therapy is encouraged. The measure of good glycaemic control can be done using assessing parameters such as HbA1c, FBS and PPBS.

Furthermore, most of the existing hypoglycaemic drugs enhance the insulin sensitivity thus decreasing its resistance and measure of this can be done by HOMA-IR. Obesity is the best predictor of diabetes as people who are overweight or have obesity have added pressure on their body's ability to use insulin to properly control blood sugar levels and are, therefore, more likely to develop diabetes. Hence, weight loss is favoured along with diet, and physical activity can be provided by few hypoglycaemic agents.

SGLT2 inhibitors present a new class of antidiabetic drugs having an insulin-dependent mechanism that offers a considerable advantage of increasing urinary glucose excretion without inducing hypoglycaemia. SGLT2 is a protein in humans that facilitate glucose reabsorption in the kidney. SGLT2 inhibitors block the reabsorption in the kidney, increase glucose excretion and lower blood glucose level. The mechanism of action of this new class of drugs also offers further glucose control by allowing increased insulin sensitivity and uptake of glucose in the muscle cells, decreased gluconeogenesis and improved first-phase insulin release from the beta-cells.

Hence, canagliflozin is effective for the treatment of type 2 DM as once daily dosing along with ongoing treatment showed improvement in HbA1c, FBS, HOMA-IR and weight loss, and decrease in waist circumference was recorded in the results when compared to the standard treatment. Hence, canagliflozin can be used as an add-on therapy owing to its different mechanisms of action to treat type 2 DM patients.

  • In earlier studies on effects of canagliflozin were studied in patients aging around 18–60 years Devineni, et al.[6] In the present study, patients in the same age group as the above study were included and evenly distributed between both genders owing to population available in the hospital between the set age group
  • In various earlier studies William, et al., Schernthaner, et al.,[7],[8] it has been concluded that canagliflozin can be used as an add-on therapy to classic OHAs and insulin to achieve better glycaemic control. In the present study, the same has been adopted, and canagliflozin was given as add-on therapy to existing treatment
  • In previous study conducted [K. Stenlof, et al.,][9] reduction in HbA1c, FBG, PPBG were observed with Canagliflozin doses which is similarly done in this study, the HbA1c in test group gave effect of 2.044 compared to standard 0.296. Also there was marked effect in FBS in test group of 33.481 compared to standard 7.851
  • In the present study, the HOMA-IR a method to assess β-cell function and IR from basal glucose and insulin showed the effect of 0.938 in the test group compared to standard 0.192
  • In the previous study by Taylor, et al.,[10] it was concluded that the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Hence, in the present study, plasma ketone was obtained, but none of the patients developed ketoacidosis during the period of study though plasma ketone seen to be increased not to the extent of causing adverse drug reaction
  • In previous study (Cefalu, et al.,)[9] concluded 'in patients with type 2 diabetes, canagliflozin provided clinically meaningful body weight reductions and the weight loss contributed to reductions in HbA1c. In the present study, the weight loss was recorded in test group with effect 2.437 compared to 1.107 in the standard.



  Conclusions Top


The aim of the study was to determine the effect of canagliflozin on glycaemic control and its effect on IR and plasma ketone in Type 2 DM patients.

A total of 60 patients were enrolled for the study, 27 patients under canagliflozin group, as an add-on to the standard treatment, and 27 patients under standard group were added based on the inclusion and exclusion criteria, of which 3 dropped out from canagliflozin group and three from standard group due to personal reasons.

Canagliflozin provided better glycaemic control in type 2 DM patients along with decreased IR and marked weight loss. Increased plasma ketone levels were noted during the therapy to an extent which can be used up by the body as a fuel and not cause ketoacidosis

Acknowledgement

We wish to place our earnest thanks to Dr. K S Lakshmi, Dean, SRM College of Pharmacy for her moral support and in acknowledging all the facilities provided for use at the institution enabling us to do work of this magnitude.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2013;36 Suppl 1:S67-74.  Back to cited text no. 1
    
2.
Tahrani AA, Bailey CJ, Del Prato S, Barnett AH. Management of type 2 diabetes: New and future developments in treatment. Lancet 2011;378:182-97.  Back to cited text no. 2
    
3.
International Diabetes Federation. Global Burden of Diabetes. Diabetic Atlas. 8th ed. Brussels: International Diabetes Federation; 2017. Available from: https://diabetesatlas.org/. [Last accessed on 2011 Dec 18].  Back to cited text no. 3
    
4.
Unwin N, Whiting D, Gan D, Jacqmain O, Ghyoot G, editors. IDF Diabetes Atlas. 4th ed. Brussels: International Diabetes Federation; 2009.  Back to cited text no. 4
    
5.
Kaushal S, Singh H, Thangaraju P, Singh J. Canagliflozin: A novel SGLT2 inhibitor for type 2 diabetes mellitus. N Am J Med Sci 2014;6:107-13.  Back to cited text no. 5
    
6.
Devineni D, Morrow L, Hompesch M, Skee D, Vandebosch A, Murphy J, et al. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab 2012;14:539-45.  Back to cited text no. 6
    
7.
Cefalu WT, Stenlöf K, Leiter LA, Wilding JP, Blonde L, Polidori D, et al. Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia 2015;58:1183-7.  Back to cited text no. 7
    
8.
Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: A 52-week randomized trial. Diabetes Care 2013;36:2508-15.  Back to cited text no. 8
    
9.
Stenlöf K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:372-82.  Back to cited text no. 9
    
10.
Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab 2015;100:2849-52.  Back to cited text no. 10
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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Abstract
Introduction
Subjects and Methods
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