Abstract
Objective
To investigate the effects of canagliflozin combined with metformin on insulin sensitivity in patients with type 2 diabetes mellitus (T2DM).
Methods
Patients with T2DM who were treated in the outpatient department of the hospital between May 2023 and May 2024 were selected. Based on different treatment approaches, the patients were divided into a control group (80 cases) and an observation group (80 cases). The control group received metformin treatment, while the observation group was treated with a combination of canagliflozin and metformin. All patients underwent a six-month course of drug treatment. Indicators related to blood glucose control, such as fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPG), and glycosylated hemoglobin (HbA1c), were measured before and after treatment. Pancreatic function indicators, including fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), beta-cell function (HOMA-β), and insulin sensitivity (HOMA-ISI), were also evaluated. Changes in total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), waist circumference, and body mass index (BMI) before and after treatment were compared between the two groups. Adverse reactions during the treatment period were recorded for both groups.
Results
After treatment, HbA1c, FPG, and 2hPG levels in both groups were lower than their respective pre-treatment levels, with the observation group showing significantly lower levels than the control group (P < 0.05). Post-treatment FINS, HOMA-β, and HOMA-ISI levels in both groups were higher than pre-treatment levels, with the observation group exhibiting significantly higher levels than the control group (P < 0.05). HOMA-IR levels in both groups decreased compared to pre-treatment levels, with the observation group demonstrating significantly lower levels than the control group (P < 0.05). Total cholesterol (TC), triglycerides (TG), LDL-C, BMI, and waist circumference in both groups decreased after treatment, with the observation group displaying greater reductions than the control group (P < 0.05). HDL-C levels increased in both groups after treatment, with the observation group achieving higher levels than the control group (P < 0.05). The extent of improvement in patients' HbA1c, TC, BMI, and waist circumference was significantly correlated with changes in HOMA-IR (P < 0.05). Additionally, improvements in HbA1c, BMI, and waist circumference were significantly associated with changes in HOMA-β (P < 0.05). No significant difference was observed in the overall incidence of adverse reactions between the two groups (10.00% vs. 15.00%, P > 0.05).
Conclusion
The combination of canagliflozin and metformin in the treatment of T2DM not only effectively reduces blood glucose levels but also significantly improves insulin sensitivity and pancreatic function, with good safety profiles. For T2DM patients with obesity or insulin resistance, the combination therapy may offer additional benefits in terms of weight management and enhanced insulin sensitivity.
Keywords: Type 2 diabetes mellitus, Canagliflozin, Metformin, Insulin sensitivity, Body weight
Background
The prevalence of type 2 diabetes mellitus (T2DM) is rising globally, affecting 463 million individuals in 2019, with projections exceeding 700 million by 2045. This has become a significant public health issue [1]. Insulin resistance is a key pathophysiological factor contributing to hyperglycemia in T2DM patients, characterized by reduced insulin sensitivity in peripheral tissues, leading to impaired blood glucose regulation [2]. Improving β-cell function or slowing the progression of β-cell dysfunction may aid in the long-term management of T2DM. Therefore, exploring therapeutic strategies that effectively enhance insulin sensitivity holds critical clinical significance.
Current research mainly focuses on the effects of Metformin and Canagliflozin monotherapy on blood glucose control and cardiovascular risk in patients [3, 4]. However, as the disease progresses, metformin monotherapy may not provide sufficient glycemic control, necessitating the addition of other antidiabetic agents to maintain blood glucose levels. Therefore, it is often combined with other hypoglycemic drugs. Among the potential candidate drugs to complement the efficacy of metformin, many antihyperglycemic agents may induce hypoglycemia or weight gain, which could exacerbate insulin resistance. Canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, lowers blood glucose levels by blocking renal glucose reabsorption and reducing the renal glucose threshold, thereby promoting urinary glucose excretion [5]. Recent studies have revealed that canagliflozin not only possesses hypoglycemic effects but also, with prolonged treatment, may enhance insulin clearance and improve insulin sensitivity through various mechanisms, such as weight reduction and improved lipid metabolism [6, 7]. Hao et al. conducted a study to evaluate the effects of canagliflozin treatment on body composition, glycemic control, insulin resistance, and systemic inflammation in patients newly diagnosed with T2DM. The findings confirmed that canagliflozin therapy in newly diagnosed T2DM patients can reduce visceral adipose tissue and improve glycemic levels, insulin resistance, and systemic inflammation [8]. However, previous research has primarily focused on the efficacy of monotherapies such as metformin and canagliflozin, with limited investigation into combination therapies. The concomitant use of canagliflozin with other antidiabetic agents such as metformin may enhance glycemic control and improve pancreatic function through complementary mechanisms of action.This study aims to evaluate, through a randomized controlled clinical trial, the effects of combined treatment with canagliflozin and metformin on insulin sensitivity and β-cell function in patients newly diagnosed with T2DM. The investigation also explores the potential of combination therapy to enhance pancreatic islet function, with the goal of achieving improved glycemic control and long-term outcomes for patients.
Materials and methods
General information
Patients with T2DM who were treated in the outpatient department of the hospital between May 2023 and May 2024 were selected. Based on different treatment approaches, they were divided into a control group (80 cases) and an observation group (80 cases). The control group received metformin treatment, while the observation group was treated with a combination of canagliflozin and metformin. This study protocol was approved by The Affiliated People's Hospital of Ningbo University medical ethics committee (Approval NO: 2,504,250,904,702), and informed consent was obtained from all patients prior to their participation in the study.
Inclusion and exclusion criteria inclusion criteria:
Inclusion criteria
(1) Diagnosed with T2DM based on the relevant diagnostic criteria of the World Health Organization (WHO) [9];
(2) Age ≥ 18 years;
(3) Newly-diagnosed T2DM in the last 6 months;
(4) Had not received treatment with other hypoglycemic agents (including insulin or GLP-1 receptor agonists), or had only undergone lifestyle intervention for no more than three months;
(5) Estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m2;
(6) BMI ≤ 39 kg/m2;
(7) No known allergic reactions to the study drugs;
(8) Fully understanding and cooperating with the study, with complete follow-up data.
Exclusion criteria:
Patients with type 1 diabetes, primary renal glycosuria, or secondary diabetes;
Uncontrolled hypertension or hypotension;
Had used medications within the three months prior to enrollment that could significantly affect blood glucose levels or body weight (e.g., systemic glucocorticoids);
Patients with acute cardiovascular insult as ACS,ischemic stroke elevated liver enzyme;
Chronic systemic steroid use or other conditions that significantly affect glucose metabolism (e.g., thyroid disease, Cushing's syndrome);
History of diabetic ketoacidosis or hyperosmolar hyperglycemic state;
Patients with a history of dialysis or kidney transplantation;
A history of recurrent urinary tract infections or genital infections;
Patients who are pregnant, breastfeeding, or planning to conceive.
Research methods
Prior to initiating pharmacological treatment, all patients received dietary and exercise counseling. Dietary advice was based on the principles of medical nutrition therapy for diabetes, emphasizing control of total caloric intake and balanced nutrition. Exercise advice included at least 150 min of moderate-intensity aerobic activity per week. The control group was treated with metformin (Sino-American Shanghai Squibb Pharmaceuticals Ltd., H20023370), administered with meals 3 times daily, at a dose of 500 mg per administration. The observation group received additional canagliflozin tablets at a dose of 100 mg/d (manufactured by Janssen-Cilag International NV, H20170375), taken before the first meal of the day. All patients underwent continuous treatment for 6 months.
During the treatment period, all patients were followed up either in outpatient clinics every 3 months. The follow-up assessments included evaluations of safety events (such as hypoglycemia, diabetic ketoacidosis, urinary tract infections, etc.) and adherence to the trial treatment regimen. Verify the patient's medication and lifestyle intervention through pill counting, structured questionnaires, and recording missed doses. Provide targeted guidance and encouragement based on the patient's monitoring records to enhance medication adherence and a healthy lifestyle.
Observation indicators
Blood Glucose Control Indicators An automatic biochemical analyzer was used to measure fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPG), and glycosylated hemoglobin (HbA1c) levels before treatment and after 6 months of drug treatment. The glucose oxidase method was employed to measure FPG and 2hPG levels, while HbA1c levels were determined using high-performance liquid chromatography. All tests were completed in the standardized clinical laboratory of our hospital.
Pancreatic Function Indicators An electrochemiluminescence analyzer was utilized to assess fasting insulin (FINS) levels before and after treatment. The homeostasis model method was used to calculate the insulin resistance index (HOMA-IR), beta-cell function index (HOMA-β), and insulin sensitivity index (HOMA-ISI). The formulas applied were: HOMA-IR = (FPG × FINS)/22.5, HOMA-β = (20 × FINS)/(FPG-3.5), HOMA-ISI = l/(FPG × FINS).
Lipid Metabolism Levels Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were measured before and after treatment using an automatic biochemical analyzer.
Obesity-Related Indicators Waist circumference and body mass index (BMI) were measured before and after treatment for comparison. A medical-grade measuring tape with markings was used to measure waist circumference at the midpoint between the lower edge of the rib cage and the anterior superior iliac spine (upper edge of the pelvis) during normal breathing. The BMI was calculated using the formula: BMI = Body weight (kg)/[Height (m)]2.
Adverse Reactions Adverse reactions included hypoglycemia, diabetic ketoacidosis, urinary tract infections, and gastrointestinal reactions [10]. Hypoglycemia included biochemically recorded episodes (fingerstick or blood glucose ≤ 3.9 mmol/L), with or without symptoms, as well as severe episodes (e.g., requiring assistance from another person, or resulting in seizures, loss of consciousness, or cognitive impairment). Adverse reactions related to osmotic diuresis included dry mouth, polydipsia, polyuria, and thirst. Gastrointestinal adverse reactions included diarrhea, nausea, and vomiting.
Statistical methods
The data were processed using SPSS 22.0 software (SPSS Inc., Chicago, IL, USA) and GraphPad Prism 6.0 software (GraphPad Inc., La Jolla, CA, USA). Quantitative data were first subjected to tests for normality and homogeneity of variance. For data conforming to a normal distribution with equal variances, results were expressed as mean ± standard deviation. Between-group comparisons of normally distributed data were performed using independent t-tests, while within-group comparisons before and after six months of treatment were analyzed using paired t-tests. For data not following a normal distribution, results were presented as medians (25th-75th percentiles), and comparisons were conducted using the Wilcoxon rank sum test. Count data were expressed as number (proportion) and compared by the chi-square test. P < 0.05 was considered statistically significant.
Results
Comparison of basic characteristics between the two groups
No statistically significant differences were observed between the two groups in terms of gender, age, BMI, waist circumference, and other general characteristics (P > 0.05) (Table 1).
Table 1.
Comparison of general characteristics between the two groups
| Characteristic | Control Group(n = 80) | Observation Group (n = 80) | χ2/t | P |
|---|---|---|---|---|
| Age (years) | 45.85 ± 5.52++ | 46.13 ± 5.56++ | − 0.314 | 0.754 |
| Gender | 0.228 | 0.633^ | ||
| Male (%) | 46(57.50%)// | 43(53.75%)// | ||
| Female (%) | 34(42.50%)// | 37(46.25%)// | ||
| BMI (kg/m2) | 28.13 ± 3.16++ | 28.45 ± 3.37++ | − 0.619 | 0.537 |
| Waist Circumference (cm) | 96.28 ± 7.71++ | 98.16 ± 7.84++ | − 1.533 | 0.127 |
| Smoking (%) | 32(40.00%)// | 35(43.75%)// | 0.231 | 0.631^ |
| Hypertension (%) | 16(20.00%)// | 12(15.00%)// | 0.693 | 0.405^ |
| Coronary Heart Disease (%) | 7(8.75%)// | 9(11.25%)// | 0.2778 | 0.598^ |
| Disease Duration (month) | 5.0(4.0, 6.0)|| | 5.0(4.0, 6.0)|| | − 1.464 | 0.143# |
| eGFR (ml/min/1.73 m2) | 90.51 ± 11.28++ | 91.23 ± 10.54++ | − 0.417 | 0.677 |
Data are ++ mean ± standard deviation or ||medians (25th-75th percentiles) or //number (proportion) where indicated. BMI, body mass index; eGFR, estimated glomerular filtration rate. P value: t-test. # Wilcoxon rank sum test. ^the chi-square test
Comparison of blood glucose levels before and after treatment between the two groups
Before treatment, there were no significant differences in blood glucose indicators between the two groups (P > 0.05).After six months of treatment, levels of HbA1c, FPG, and 2hPG in both groups were lower than those recorded before treatment, indicating improved glycemic control. Furthermore, post-treatment levels of HbA1c, FPG, and 2hPG in the observation group were significantly lower compared to the control group, with statistically significant differences (P < 0.05) (Table 2).
Table 2.
Comparison of Blood Glucose Levels Before and After Treatment Between the Two Groups
| Characteristic | Group | Before | After | Change | P value Before vs. After |
|---|---|---|---|---|---|
| HbA1c(%) | Control Group | 8.13 ± 0.76++ | 6.95 ± 0.54++ | 1.18 ± 0.22++ | < 0.001 |
| Observation Group | 8.21 ± 0.79++ | 5.23 ± 0.44++ | 2.98 ± 0.35++ | < 0.001 | |
| P value Control Group vs. Observation Group | 0.519 | < 0.001 | < 0.001 | ||
| FPG(mmol/L) | Control Group | 9.21(8.63, 9.82)|| | 7.13(6.69, 7.61)|| | 2.09(1.98, 2.20)|| | < 0.001# |
| Observation Group | 9.18(8.71, 9.69)|| | 5.90(5.54,6.28)|| | 3.29(3.17, 3.41)|| | < 0.001# | |
| P value Control Group vs. Observation Group | 0.910# | < 0.001# | < 0.001# | ||
| 2hPG(mmol/L) | Control Group | 13.16 ± 1.94++ | 8.96 ± 1.05++ | 4.20 ± 0.89++ | < 0.001 |
| Observation Group | 13.52 ± 2.03++ | 7.54 ± 0.82++ | 5.98 ± 1.21++ | < 0.001 | |
| P value Control Group vs. Observation Group | 0.253 | < 0.001 | < 0.001 | ||
Data are ++ mean ± standard deviation or ||medians (25th–75th percentiles) where indicated. HbA1c, glycosylated hemoglobin; FPG, fasting blood glucose; 2hPG, 2 h postprandial blood glucose. Change = variable value at before treatment minus that at 6 months. P value Before vs. After: paired t-test. P value Control Group vs. Observation Group: t-test. # Wilcoxon rank sum test
Comparison of pancreatic function before and after treatment between the two groups
Before treatment, no significant differences were observed between the two groups in terms of all indicators (P > 0.05). After six months of treatment, patients in the observation group showed increased levels of FINS, HOMA-β, and HOMA-ISI, along with decreased levels of HOMA-IR, indicating improved pancreatic islet function and reduced insulin resistance. Moreover, compared to the control group, the observation group demonstrated significantly greater improvements in FINS, HOMA-β, HOMA-ISI, and HOMA-IR, with statistically significant differences (P < 0.05) (Table 3, Fig. 1).
Table 3.
Comparison of pancreatic function before and after treatment between the two groups
| Characteristic | Group | Before | After | Change | P value Before vs. After |
|---|---|---|---|---|---|
| FINS(mU/L) | Control Group | 7.16 ± 0.70++ | 7.91 ± 0.85++ | − 0.84(− 0.94, − 0.74)|| | < 0.001 |
| Observation Group | 7.11 ± 0.68++ | 8.41 ± 0.92++ | − 1.33(− 2.04, − 0.65)|| | < 0.001 | |
| P value Control Group vs. Observation Group | 0.681 | < 0.001 | < 0.001# | ||
| HOMA-IR | Control Group | 2.88(2.52, 3.30)|| | 2.49(2.18, 2.87)|| | 0.39(0.36, 0.42)|| | < 0.001# |
| Observation Group | 2.89(2.57, 3.26)|| | 2.22(2.00, 2.47)|| | 0.68(0.48, 0.90)|| | < 0.001# | |
| P value Control Group vs. Observation Group | 0.993# | < 0.001# | < 0.001# | ||
| HOMA-β | Control Group | 24.71(23.87, 25.56)|| | 43.36(41.24, 45.89)|| | − 18.57(− 20.31, − 17.11)|| | < 0.001# |
| Observation Group | 24.93(24.45, 25.59)|| | 70.68(59.22, 81.11)|| | − 45.97(− 55.80, − 35.04)|| | < 0.001# | |
| P value Control Group vs. Observation Group | 0.162# | < 0.001# | < 0.001# | ||
| HOMA-ISI | Control Group | 0.015(0.013, 0.018)|| | 0.018(0.015, 0.020)|| | − 0.002(− 0.003, − 0.002)|| | < 0.001# |
| Observation Group | 0.015(0.014, 0.017)|| | 0.020(0.018, 0.022)|| | − 0.005(− 0.006, − 0.003)|| | < 0.001# | |
| P value Control Group vs. Observation Group | 0.935# | < 0.001# | < 0.001# | ||
Data are ++ mean ± standard deviation or ||medians (25th–75th percentiles) where indicated. FINS, fasting insulin; HOMA-IR, insulin resistance index; HOMA-β, beta-cell function index; HOMA-ISI, insulin sensitivity index. Change = variable value at before treatment minus that at 6 months. P value Before vs. After: paired t-test. P value Control Group vs. Observation Group: t-test. # Wilcoxon rank sum test
Fig. 1.
Changes of Pancreatic Function Indexes in Patients with Control Group and Observation Group Before and After Treatment. (A) FINS; (B) HOMA-IR; (C) HOMA-β; (D) HOMA-ISI. FINS, fasting insulin; HOMA-IR, insulin resistance index; HOMA-β, beta-cell function index; HOMA-ISI, insulin sensitivity index. *P < 0.001。
Comparison of blood lipid levels before and after treatment between the two groups
Before treatment, there were no significant differences in blood lipid indicators between the two groups (P > 0.05). After six months of treatment, patients in the observation group exhibited decreased levels of TC, TG, and LDL-C, along with increased levels of HDL-C, indicating an overall improvement in lipid profiles. Furthermore, compared to the control group, the observation group showed significantly greater improvements in TC, TG, LDL-C, and HDL-C levels, with statistically significant differences (P < 0.05) (Table 4).
Table 4.
Comparison of blood lipid levels before and after treatment between the two groups
| Characteristic | Group | Before | After | Change |
P value Before vs. After |
|
|---|---|---|---|---|---|---|
| TC(mmol/L) | Control Group | 5.21 ± 0.54 | 4.76 ± 0.43 | 0.45 ± 0.11 | < 0.001 | |
| Observation Group | 5.28 ± 0.57 | 4.11 ± 0.38 | 1.17 ± 0.19 | < 0.001 | ||
| P value Control Group vs. Observation Group | 0.425 | < 0.001 | < 0.001 | |||
| TG(mmol/L) | Control Group | 2.86 ± 0.33 | 2.42 ± 0.28 | 0.44 ± 0.05 | < 0.001 | |
| Observation Group | 2.91 ± 0.36 | 2.13 ± 0.19 | 0.78 ± 0.17 | < 0.001 | ||
| P value Control Group vs. Observation Group | 0.367 | < 0.001 | < 0.001 | |||
| HDL-C(mmol/L) | Control Group | 1.25 ± 0.19 | 1.42 ± 0.23 | −0.17 ± 0.04 | < 0.001 | |
| Observation Group | 1.23 ± 0.16 | 1.59 ± 0.27 | −0.36 ± 0.11 | < 0.001 | ||
| P value Control Group vs. Observation Group | 0.464 | < 0.001 | < 0.001 | |||
| LDL-C(mmol/L) | Control Group | 4.19 ± 0.93 | 3.15 ± 0.74 | 1.04 ± 0.19 | < 0.001 | |
| Observation Group | 4.23 ± 0.97 | 2.24 ± 0.53 | 1.99 ± 0.43 | < 0.001 | ||
| P value Control Group vs. Observation Group | 0.791 | < 0.001 | < 0.001 | |||
Data are mean ± standard deviation where indicated. TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Change = variable value at before treatment minus that at 6 months. P value Before vs. After: paired t-test. P value Control Group vs. Observation Group: t-test
Comparison of obesity-related indicators before and after treatment between the two groups
Before treatment, no significant differences were observed between the two groups in terms of obesity-related indicators (P > 0.05). Before treatment, there were no significant differences in BMI and waist circumference between the two groups (P > 0.05). After six months of treatment, patients in the observation group showed reductions in both BMI and waist circumference compared to their baseline levels. Furthermore, post-treatment measurements in the observation group were significantly lower than those in the control group, with statistically significant differences (P < 0.05) (Table 5).
Table 5.
Comparison of Obesity-Related Indicators Before and After Treatment Between the Two Groups
| Characteristic | Group | Before | After | Change |
P value Before vs. After |
|
|---|---|---|---|---|---|---|
| BMI (kg/m2) | Control Group | 28.13 ± 3.16 | 27.04 ± 2.71 | 1.09 ± 0.44 | 0.020 | |
| Observation Group | 28.45 ± 3.37 | 25.19 ± 2.64 | 3.26 ± 0.73 | < 0.001 | ||
|
P value Control Group vs. Observation Group |
0.537 | < 0.001 | < 0.001 | |||
| Waist Circumference(cm) | Control Group | 96.28 ± 7.71 | 91.07 ± 6.59 | 5.21 ± 1.12 | < 0.001 | |
| Observation Group | 98.16 ± 7.84 | 87.69 ± 5.13 | 10.48 ± 2.70 | < 0.001 | ||
|
P value Control Group vs. Observation Group |
0.127 | < 0.001 | < 0.001 | |||
Data are mean ± standard deviation where indicated. BMI, body mass index. Change = variable value at before treatment minus that at 6 months. *P < 0.05 versus the control group at 6 months. P value Before vs. After: paired t-test. P value Control Group vs. Observation Group: t-test
Variables associated with changes in insulin resistance and β-cell function
Patient age, disease duration, and eGFR were not significantly correlated with changes in HOMA-IR or HOMA-β (P > 0.05). However, improvements in HbA1c, TC, BMI, and waist circumference were significantly associated with changes in HOMA-IR (P < 0.05). Additionally, improvements in HbA1c, BMI, and waist circumference were significantly correlated with changes in HOMA-β (P < 0.05) (Table 6).
Table 6.
The relationship between changes in HOMA-IR, HOMA-β and various items
| Characteristic | HOMA-IR | HOMA-β | ||
|---|---|---|---|---|
| r | P | r | P | |
| Age (years) | 0.125 | 0.116 | − 0.007 | 0.932 |
| Disease Duration (months) | − 0.021 | 0.793 | − 0.142 | 0.074 |
| eGFR(ml/min/1.73 m2) | 0.101 | 0.202 | − 0.037 | 0.640 |
| HbA1c change(%) | 0.719 | < 0.001 | 0.508 | < 0.001 |
| 2hPG change(mmol/L) | 0.028 | 0.721 | − 0.022 | 0.785 |
| TC change(mmol/L) | 0.442 | < 0.001 | 0.056 | 0.484 |
| TG change(mmol/L) | 0.140 | 0.078 | 0.048 | 0.543 |
| HDL-C change(mmol/L) | − 0.119 | 0.135 | − 0.101 | 0.204 |
| LDL-C change(mmol/L) | 0.068 | 0.394 | 0.027 | 0.735 |
| BMI change(kg/m2) | 0.607 | < 0.001 | 0.454 | < 0.001 |
| Waist Circumference change (cm) | 0.479 | < 0.001 | 0.413 | < 0.001 |
eGFR estimated glomerular filtration rate, HbA1c glycosylated hemoglobin, FPG fasting blood glucose, 2hPG 2 h postprandial blood glucose; TC total cholesterol, TG triglycerides, HDL-C high-density lipoprotein cholesterol; LDL-C low-density lipoprotein cholesterol, BMI body mass index. P value: Spearman’s rank correlation coefficient
Comparison of adverse reactions between the two groups
The overall incidence of adverse reactions was not significantly different between the two groups (P > 0.05). The percentage of patients with recorded hypoglycemic events was similar in both groups, and no reports of severe hypoglycemia were observed. The urinary tract infections recorded in both groups ranged from mild to moderate in severity and were resolved with local and/or oral antibiotic treatments (Table 7).
Table 7.
Comparison of adverse reaction rates between the two groups
| Characteristic | Control Group(n = 80) | Observation Group(n = 80) | χ2 | P |
|---|---|---|---|---|
| Overall Incidence of Adverse Reactions (%) | 8(10.00%) | 12(15.00%) | 0.914 | 0.339 |
| Hypoglycemia (%) | 3(3.75%) | 4(5.00%) | ||
| Diabetic Ketoacidosis (%) | 1(1.25%) | 0 | ||
| Adverse Reactions Related to Osmotic Diuresis (%) | 0 | 1(1.25%) | ||
| Urinary Tract Infections (%) | 3(3.75%) | 5(6.25%) | ||
| Male | 1(1.25%) | 2(2.50%) | ||
| Female | 2(2.50%) | 3(3.75%) | ||
| Gastrointestinal Adverse Reactions (%) | 1(1.25%) | 2(2.50%) |
Data are number (proportion) where indicated. Hypoglycemia includes biochemically recorded episodes (fingerstick or blood glucose ≤ 3.9 mmol/L), with or without symptoms, as well as severe episodes (requiring assistance or resulting in seizures, loss of consciousness, or cognitive dysfunction). Osmotic diuresis-related adverse reactions include dry mouth, polydipsia, polyuria, and thirst. Gastrointestinal adverse reactions include diarrhea, nausea, and vomiting. P value: the chi-square test
Discussion
Clinically, the progression of T2DM is typically controlled through pharmacological treatments. Metformin, as a first-line treatment recommended by diabetes management guidelines, demonstrates good glycemic control and weight reduction effects. However, the pathogenesis of T2DM is complex and requires long-term treatment. Prolonged use of a single hypoglycemic agent may lead to insulin resistance and progressive decline in β-cell function, which is detrimental to long-term disease management [11, 12]. Previous studies have found that increased visceral fat and insulin resistance in T2DM patients heighten the risk of mortality [13]. Canagliflozin works by inhibiting SGLT2, reducing glucose reabsorption in the proximal tubules, and achieving glycemic control independent of insulin, making it suitable for patients with insulin resistance [14]. The results of this study showed that, compared to the control group receiving monotherapy, the observation group had better improvements in glycemic indicators such as HbA1c, FPG, and 2hPG. Combination therapy has been shown to offer superior glycemic control [15]. In this study, patients receiving dual-drug treatment exhibited a more pronounced reduction in HbA1c levels. This effect may be attributed to the rapid remission following the alleviation of glucotoxicity in newly diagnosed T2DM patients, exceptionally high treatment adherence, and the synergistic mechanisms of the two agents. These findings highlighted the need for vigilance regarding hypoglycemia risk in clinical practice and underscore the importance of individualized treatment adjustments. Furthermore, the observation period coincided with the initial rapid decline phase of hypoglycemic drug efficacy; long-term effects may gradually plateau or even rebound, necessitating extended follow-up to validate the sustainability of therapeutic outcomes.
A study by Jahn et al. [16] demonstrated significant changes in vascular insulin sensitivity following 12 weeks of empagliflozin treatment, providing evidence for the role of SGLT2 inhibitors in enhancing vascular insulin sensitivity in patients with T2DM. The authors suggested that weight reduction and maintenance of glycemic homeostasis may be key factors contributing to improved insulin sensitivity. In another study, Suga et al. [17] investigated the regulation of glucagon secretion by SGLT1 in pancreatic α-cells in mice, offering insights into the distinct molecular mechanisms by which SGLT2 inhibitors such as canagliflozin improve insulin sensitivity. These findings contribute to the understanding of therapeutic classification and selection of SGLT2 inhibitors in diabetes management. Results from the present study indicated that although pancreatic islet function improved in both groups after treatment, patients receiving combination therapy with canagliflozin exhibited a more pronounced increase in insulin sensitivity. Moreover, the degree of HbA1c improvement was significantly correlated with changes in HOMA-IR and HOMA-β. It is hypothesized that canagliflozin, through its insulin-independent glucose-lowering activity, may reduce glucotoxicity and thereby alleviate lipotoxicity-induced stress and apoptosis of pancreatic β-cells. This mechanism may contribute to enhanced β-cell function, improved insulin resistance, and better glycemic control. [17]. Studies have also pointed out that oxidative stress and inflammatory responses induced by hyperglycemia in T2DM patients are closely related to insulin resistance [18, 19]. The beneficial effects of canagliflozin treatment on adipokines and inflammatory biomarkers might contribute to its mechanism in reducing insulin resistance.
Previous studies have shown that, in addition to improving glycemic control, canagliflozin is associated with sustained weight reduction, which may be related to decreased fat mass and increased net caloric loss [20, 21]. Results from the present study indicated that patients in the observation group experienced significantly greater improvements in lipid profile parameters, BMI, and waist circumference compared to those in the control group. Moreover, the extent of improvement in BMI and waist circumference was significantly correlated with changes in HOMA-IR and HOMA-β. In a clinical trial lasting up to 104 weeks, weight reduction associated with SGLT2 inhibitor treatment was sustained [22]. Canagliflozin also induces mild osmotic diuresis, contributing to some degree of weight loss. However, most of the observed weight reduction is attributed to fat mass reduction, likely explained by a shift in substrate utilization from carbohydrates to lipids [23]. These further highlight that reductions in BMI and waist circumference in patients receiving combination therapy with canagliflozin were superior to those in patients receiving monotherapy. This suggests that the combined therapy with canagliflozin for T2DM offers advantages beyond glycemic control.
Since SGLT-2 inhibitors increase urinary glucose excretion, the primary safety concern for canagliflozin is urogenital infections. However, most of these infections are controllable, and severe cases are rare [24, 25]. Patients with pre-existing urogenital infections should use canagliflozin with caution. In this study, the overall incidence of adverse reactions did not significantly differ between the two groups (10.00% vs. 15.00%). The incidence of hypoglycemia was similar in both groups, and no severe hypoglycemic events were reported. The severity of urinary tract infections in both groups ranged from mild to moderate and was resolved with local and/or oral antimicrobial treatments. These findings suggested that combination therapy with canagliflozin and metformin for treating T2DM is relatively safe.
Limitations of the present study include the following: The initial sample size was relatively small, and the follow-up duration was limited. Although longer than that of comparable clinical trials, it was sufficient to observe significant changes in key indicators such as glycemic parameters and insulin resistance. However, the findings should not be directly extrapolated to populations with a longer disease duration or those previously treated with multiple hypoglycemic agents. Further studies with extended follow-up periods are needed to validate the long-term effects on glycemic control, pancreatic β-cell function, and potential clinical benefits. Second, due to considerations of clinical feasibility, this study adopted an open-label design rather than a double-blind protocol. Although the primary endpoints were objective laboratory parameters assessed by blinded evaluators, the possibility of performance bias cannot be entirely excluded. The absence of predefined baseline HbA1c inclusion criteria may have introduced heterogeneity and constituted a potential confounding factor. Future studies employing more stringent glycemic inclusion thresholds will be beneficial for further validating the findings. The study did not include a monotherapy group for canagliflozin, making it difficult to distinguish the independent effects of canagliflozin from the potential synergistic effects of the combination therapy. Future studies may consider a three-arm design (metformin monotherapy, canagliflozin monotherapy, and combination therapy) to further clarify this issue.
Conclusions
In conclusion, canagliflozin combined with metformin for the treatment of T2DM not only reduces blood glucose but also significantly enhances insulin sensitivity, improves pancreatic function, and demonstrates good medication safety. For T2DM patients with obesity or insulin resistance, the combination therapy of canagliflozin and metformin may provide greater benefits in terms of weight reduction and improved insulin sensitivity.
Acknowledgements
Not applicable.
Author contributions
Conceptualization: Yimin Shu; Methodology: Xiaoyu Chen; Data curation: Yimin Shu, Pingfeng Wang; Writing-original draft: Yimin Shu, Xiaoyu Chen; Writing-review and editing: Pingfeng Wang. All authors have made an intellectual contribution to the manuscript and approved the submission.
Funding
Not applicable.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study protocol was approved by The Affiliated People's Hospital of Ningbo University medical ethics committee (Approval No: 2504250904702), and informed consent was obtained from all patients prior to their participation in the study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.