Sodium glucose co-transporter 2 inhibitors safety depending on their adverse drug reactions and glucose monitoring parameters in type 2 diabetes mellitus

Abstract

INTRODUCTION:

SGLT2 inhibitors have a wide extent of restorative movement and higher chance of hypoglycemia because of their affront autonomous action in treating type 2 diabetes. SGLT2 inhibitors have great security and resistance when utilized as monotherapy or in conjunction with other oral hypoglycemic medicines. Since SGLT2 inhibitors can cause hyperglycemia, which results in vaginal and urinary tract infection contaminations. When compared, dapagliflozin had higher contaminations. The key issue displayed is that ketoacidosis and that it may take a little time to analyze it.

OBJECTIVES:

To compare the security of canagliflozin and dapagliflozin by watching the long-term impacts on the urinary volume, changes in renal status, and metabolic changes.

RESEARCH METHODOLOGY:

A Planned Interventional Comparative Ponder conducted among 1726 patients who were conceded to in the General Medicine and Endocrine Departments, Anu Group of hospitals, Vijayawada over 12 months from December 2021 to December 2022. By alluding to the patient’s fasting blood sugar and postprandial blood sugar, renal function test, glycated hemoglobin, blood pressure, and the finding seriousness score of adverse drug reaction (ADR) utilizing Naranjo scale.

RESULTS:

Patients had most common ADRs after utilizing Canagliflozin and Dapagliflozin, were hypotension and dehydration, respectively.

CONCLUSION:

We concluded that in patients had ADRs after utilizing Canagliflozin versus Dapagliflozin where hypotension and dehydration were more common, respectively. ADRs in the control population was weight pick up had the negative impact and hypoglycemia was found to be more in the control population compared to canagliflozin and dapagliflozin endorsed bunches. Weight loss had a positive impact on canagliflozin and dapagliflozin-endorsed groups.

Introduction

SGLT2 inhibitors have good safety and tolerance when used as monotherapy or with other oral hypoglycemic medications or insulin treatment. Due to its insulin-independent activity, SGLT2 inhibitors have been proven to have a low risk of hypoglycemia. In the Phase III development studies, there were no significant occurrences of hypoglycemia observed when SGLT2 inhibitors were taken as monotherapy and a meta-analysis found that the risk of hypoglycemia was low comparable to that of other medicines used to treat type 2 diabetes.[1]

Due to hyperglycemia and glycosuria, diabetes itself is linked to an increased risk of vaginal infection and urinary tract infection (UTI). Because SGLT2 inhibitors cause hyperglycemia, there is a corresponding rise in vaginal and UTI infections, which have been linked to several placebo-controlled studies. When compared to placebo, dapagliflozin caused higher infections (genital infection 4.1%–5.7% vs. 0.9%; UTI 3.6%–5.7% vs. 3.7%).[2] Canagliflozin pooled studies revealed similar results (genital infection 7.5% vs. 1.9% in placebo; UTI 5.1% vs. 4.0% placebo). Similar data for genital tract infections are available for empagliflozin, although there was no statistically significant difference in UTIs.[3]

SGLT2 inhibitors are thought to increase the risk of euglycemic ketoacidosis, which has warnings from the FDA and EMA.[4] The FDA and EMA based on their warnings of 20 and 101 clinical instances, respectively. However, some of the incidents included people with type 1 diabetes too. Both type 1 and type 2 diabetes have been associated with this adverse effect while using SGLT2s.[5] In this case series, insulin decreases, low calorie and fluid intake, concurrent illnesses, and alcohol usage are some of the circumstances that led to ketoacidosis. The key issue presented is ketoacidosis can develop in the presence of euglycemia or little elevated blood glucose and that it may take some time to diagnose it. This might be avoided if ketonuria could be detected. The estimated incidence rates are modest (0.5, 0.8, and 0.2 per 1000 patient-years with Canagliflozin 100 mg, Canagliflozin 300 mg, and comparator, respectively) but more than double with the SGLT2 inhibitor in a comprehensive retrospective analysis of 17,596 people in the CANVAS trial.[6] Therefore, it is important to be aware of the potential consequences, especially if the introduction of SGLT2 leads to a decrease in the dosage of insulin. A decrease in insulin dosage in this situation should not be considered a success in and of itself. The properties of SGLT-2 inhibitors were mentioned in the Table 1.

Table 1.

Properties of sodium-glucose cotransporter 2 inhibitors according to the 2015 American Diabetes Association and the European Association for the Study of Diabetes position statement

Class	Compounds	Cellular mechanism	Primary physiological actions	Advantages	Disadvantages/adverse effects	Cost
SGLT2 inhibitors	Canagliflozin dapagliflozin empagliflozin	Inhibits SGLT2 in the proximal nephron	Blocks glucose reabsorption by the kidney, increasing glycosuria	No hypoglycaemia, weight loss reduces blood pressure, effective at all stages of type 2 diabetes	Genitourinary infections, polyuria, volume depletion, hypotension, dizziness, increases LDL cholesterol, increases creatinine	High

Adapted from ADA/EASD. ^© ADA. LDL=Low-density lipoprotein, SGLT2=Sodium-glucose cotransporter 2, ADA=American Diabetes Association, EASD=European Association for the Study of Diabetes

Methodology

Source of data and study design

• Collect the data from the patients admitted into the General Medicine and Endocrine Department who were diagnosed with type 2 diabetes mellitus

• All the patients admitted during the study duration are followed from the day of prescribing of any anti-diabetic with an SGLT-2 inhibitor up to not <1 year of the treatment or a minimum of glycated hemoglobin (HbA1C) done 3 times.

  • Fasting blood sugar (FBS) and postprandial blood sugar (PPBS) are checked every month

  • Renal function test (Sr. Creatinine, B. Urea and Blood Urea Nitrogen) checked for every 4 months

  • HbA1C checked for every 6 months.

• Group 1: Patients were prescribed Canagliflozin as an Add-on till 4 drug therapy of diabetes

• Group 2: Patients were prescribed with Dapagliflozin as an Add-on till 4 drug therapy of diabetes.

Control

Patients were prescribed with a standard treatment regimen according to the ICMR guidelines from dual-drug therapy to quart-drug therapy.

All groups of canagliflozin and dapagliflozin are compared to control therapy as per their number of anti-hyperglycemic agents, respectively.

Study site

The study was conducted at Anu Group of Hospitals, Main Branch, Suryaraopet, Vijayawada, India.

Study duration

The study was carried out for 1 year from the collection of cases and cases were collected for 3 months.

Study design

The study design was an prospective, interventional, and comparative study.

Study criteria

The study was carried out by considering:

Inclusion criteria

Patients admitted to the general medicine and endocrine department who were diagnosed with type 2 diabetes mellitus

• Age: 35–65 years

• Gender: Both male and female

• Prescribed with SGLT-2 inhibitors as an add-on therapy with other anti-hyperglycemic agent which also includes the insulin

• Prescribed with anti-hyperglycemic agents including insulin.

Exclusion criteria

• Patients with type 1 diabetes, gestational diabetes, and pediatrics

• Patients who were left against medical advice

• Patients who were not willing to participate in the study

• Patients who do not meet the inclusion criteria.

Results and Discussion

A prospective, interventional, and comparative study was conducted in the General Medicine and Endocrine Department, Anu Group of Hospitals, Main Branch, Suryaraopet, Vijayawada, for 12 months in 3456 patients (N), of which 1854 (n₁) patients using Canagliflozin and 1602 (n₂) patients using Dapagliflozin from January 2022 to January 2023. In this study, control group population was 800.

Table 2 and Figure 1 represent patients with adverse drug reactions (ADRs) after the intake of canagliflozin versus dapagliflozin. Hypotension was the most common ADR after taking Canagliflozin, whereas dehydration was the most common ADR after taking Dapagliflozin. We did a Chi-square test for patients with ADRs After taking Canagliflozin versus Dapagliflozin used to treat type-2 diabetes mellitus. 9.12523 is the calculated Chi-square value at 5° of freedom and 5% level of significance (P = <0.1042 – not significant). This shows that there was the slight difference but similar safety by using Canagliflozin versus Dapagliflozin.[7,8,9,10]

Table 2.

Number of patients prescribed with canagliflozin and dapagliflozin

Number of patients prescribed with canagliflozin (n1)			Number of patients prescribed with dapagliflozin (n2)			Total (n)
1854			1602			3456
Dual therapy	Triple therapy	Quadruple therapy	Dual therapy	Triple therapy	Quadruple therapy
636	616	602	582	526	494

Figure 1.

Patients with ADR’s after using canagliflozin versus dapagliflozin

Table 3 represents the number of patients who had Adverse Drug Reactions after using Canagliflozin and Dapagliflozin. This represents Hypotension and dehydration was more common in Canagliflozin and Dapagliflozin using patients respectively.

Table 3.

Patients with adverse drug reactions after using canagliflozin and dapagliflozin

ADR’s	Canag liflozin - Number of patients (%)	Dapagliflozin - Number of patients (%)
Vaginal candidiasis	112 (7)	86 (9)
Hypotension	432 (29)	224 (23)
Ketoacidosis	40 (3)	16 (2)
Weight loss	222 (15)	186 (19)
Polyuria	180 (12)	120 (12)
Dehydration	392 (26)	254 (26)
UTI	50 (3)	40 (4)
Hypoglycaemia	76 (5)	48 (5)
Total	1504 (1504/1854×100=81.12%)	974 (974/1602×100=60.8%)

UTI=Urinary tract infection, ADRs=Adverse drug reactions

Table 4 represents the patients presented with more than one ADR in which dehydration along with hypotension was more common when compared with other ADRs in both Canagliflozin-prescribed and Dapagliflozin-prescribed patients.

Table 4.

Patients presented with more than one adverse drug reaction

ADR’s	Canagliflozin	Dapagliflozin
Hypotension, dehydration, polyuria	134	108
Dehydration and hypotension	209	197
Polyuria and dehydration	161	117
UTI and vaginal candidiasis	46	34
Weight loss, ketoacidosis, vaginal candidiasis	12	6

UTI=Urinary tract infection, ADRs=Adverse drug reactions

We performed a Chi-square test for patients in control, Canagliflozin and Dapagliflozin groups for the mean FBS parameter. 1.304 is the calculated Chi-square value at 24° of freedom and 5% level of significance (P = 0.2535 > 0.05 – not significant). This shows a slight difference but similar safety by using Canagliflozin versus Dapagliflozin.

Table 5 represents the FBS levels and PPBS levels in control group, Canagliflozin group and Dapagliflozin group checked monthly. We performed a Chi-square test for patients in control, Canagliflozin and Dapagliflozin groups for the mean PPBS parameter. 1.407 is the calculated Chi-square value at 24° of freedom and a 5% level of significance (P = 0.4277 > 0.05 – not significant). This shows that there was a slight difference but similar safety by using Canagliflozin versus Dapagliflozin.

Table 5.

Control versus canagliflozin versus dapagliflozin mean fasting blood sugar and postprandial blood sugar levels

	Control group		Canagliflozin		Dapagliflozin
	Mean FBS (mg/dL)	Mean PPBS (mg/dL)	Mean FBS (mg/dL)	Mean PPBS (mg/dL)	Mean FBS (mg/dL)	Mean PPBS (mg/dL)
Day of prescribing SGLT-2 inhibitor	250	320	230	300	230	306
After 1 month	150	225	142	232	140	230
After 2 months	156	238	145	225	145	225
After 3 months	160	255	159	254	155	252
After 4 months	150	240	155	246	155	246
After 5 months	165	250	160	250	163	251
After 6 months	148	236	147	235	148	235
After 7 months	157	245	155	242	152	244
After 8 months	161	252	156	244	159	246
After 9 months	154	248	151	245	151	245
After 10 months	149	245	154	242	148	242
After 11 months	163	254	161	253	161	255
After 12 months	157	244	152	240	152	243

FBS=Fasting blood sugar, PPBS=Postprandial blood sugar, SGLT2=Sodium-glucose co-transporter 2

We performed a Chi-square test for patients in control, Canagliflozin and Dapagliflozin groups for HbA1c parameters. 0.122 is the calculated Chi-square value at 8° of freedom and a 5% level of significance (P = 0.7269 > 0.05 – not significant). This shows that there was a slight difference but similar effect on HbA1c levels by using Control, Canagliflozin and Dapagliflozin.

Table 6 represents the HbA1c levels in control group, Canagliflozin group and Dapagliflozin group. We performed the Chi-square test for patients in Control, Canagliflozin and Dapagliflozin groups for the hypoglycemia parameter. 10.283 is the calculated Chi-square value at 4° of freedom and a 5% level of significance (P = 0.0013 < 0.05 – significant). Hypoglycemia as an ADR is more common in the control group than in the Canagliflozin and Dapagliflozin groups which are evident with Chi-square and P – value.

Table 6.

Control, canagliflozin, and dapagliflozin groups glycated hemoglobin levels

Days (mean of parameters)	Day 0	Day 90	Day 180	Day 270	Day 360
Control group HbA1c level	9	7.5	6.5	6.5	6
Canagliflozin group HbA1c level	9	6.5	5 0.5	5.5	5
Dapagliflozin group HbA1c level	9	6.5	5.5	5.5	5

HbA1c=Glycated hemoglobin

We performed a Chi-square test for patients in the control and Canagliflozin groups for ADRs. 31.868 is the calculated Chi-square value at 3° of freedom and a 5% level of significance (P = 0.0000 < 0.05 – significant). This shows that the canagliflozin and control groups were equally safe with the evidence of Chi-square and P – value.

We performed a Chi-square test for ADRs for patients in the control and dapagliflozin groups. 31.868 is the calculated Chi-square value at 3° of freedom and a 5% level of significance (P = 0.0030 < 0.05-significant). This shows that the dapagliflozin and control groups were not equally safe with the evidence of Chi-square and P – P value.

Conclusion

From this study, we concluded that patients with ADRs after using Canagliflozin versus dapagliflozin in which hypotension was more common ADR after using Canagliflozin, whereas dehydration was more common ADR after using dapagliflozin. ADR’s in the Control group in which weight gain hada negative effect and hypoglycemia was found to be more in the control group compared to canagliflozin and dapagliflozin prescribed groups, whereas weight loss had a positive effect in canagliflozin and dapagliflozin prescribed groups. In accordance with hypoglycemia as an ADR, it is more in control group than in canagliflozin and dapagliflozin groups. This shows that there was a slight difference but similar safety by using canagliflozin versus dapagliflozin.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Crowdfunding.