Edited by: Ondrej Šeda, Charles University, Czechia
Reviewed by: Maria Ida Maiorino, Second University of Naples, Italy; John Reyes Ussher, University of Alberta, Canada
This article was submitted to Clinical Diabetes, a section of the journal Frontiers in Endocrinology
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Sodium–glucose co-transporter 2 (SGLT2) inhibitors are a new family of antidiabetic drugs that reduce blood glucose independent of insulin. In this review, we present the advantages and adverse effects of SGLT2 inhibitors plus insulin therapy as a treatment regimen for patients with type 2 diabetes (T2D). Compared with placebo, SGLT2 inhibitors plus insulin therapy could significantly decrease fasting blood glucose and HbA1c, thereby reducing the daily required dose of insulin. A reduction in body weight and improvements in insulin resistance and β-cell function have also been widely reported with this therapy, and other potential advantages, including the reduction in blood pressure, adverse cardiovascular outcomes, and visceral adipose tissue volume, have been revealed. SGLT2 inhibitors cause a greater reduction than dipeptidyl peptidase-4 (DPP-4) inhibitors in body weight and the risk of cardiovascular disease. Furthermore, compared with glucagon-like peptide-1 (GLP-1) agonists, SGLT2 inhibitors reduce blood pressure, and heart failure. As this therapy is an oral preparation, an improvement in patient compliance is also achieved. Despite these advantages, however, combination therapy with SGLT2 inhibitors and insulin has several risks. Although no difference has been found in the incidence of hypoglycemic events and urinary tract infection between the administration of this combination and that of placebo, the risk of genital tract infections was reported to increase with the combination therapy. Additionally, bone adverse effects, euglycemic diabetic ketoacidosis, and volume depletion—and osmotic diuresis—related adverse effects have been observed. Altogether, we could conclude that SGLT2 inhibitors plus insulin therapy is an efficient treatment option for patients with T2D, especially those requiring high daily insulin doses and those with insulin resistance, obesity, and a high risk of cardiovascular events. However, careful monitoring of the adverse effects of this combination is also warranted.
The incidence of type 2 diabetes (T2D) is continuously increasing. Owing to acute complications, such as ketoacidosis and hypertonic coma, or chronic complications, such as nephropathy, vasculopathy, neuropathy, and retinopathy, the health and quality of life of patients with T2D have been severely affected, thereby increasing the health burden. Although numerous oral antidiabetic drugs are available, including sulfonylureas, meglitinides, metformin, thiazolidinediones, glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors, maintaining long-term optimal blood glucose control has been difficult in most patients with T2D, even those administered with antidiabetics plus insulin (
Sodium–glucose co-transporter 2 (SGLT2) inhibitors are a new family of antidiabetic drugs that reduce blood glucose independent of insulin sensitivity and secretion. As a result, these inhibitors differ from other oral antidiabetic drugs. Currently, there are four types of SGLT2 inhibitors available in Europe, America, and Japan, namely, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin, the first three of which are also available in China. Three other types of SGLT2 inhibitors, namely, tofogliflozin, ipragliflozin, and luseogliflozin are also available in Japan. Among the different SGLT2 inhibitors, empagliflozin is 2,500-fold more selective for SGLT2 than SGLT1; whereas tofogliflozin, dapagliflozin, ipragliflozin, and canagliflozin are 1,875, 1,200, 550, and 250-fold, respectively, more selective for SGLT2 than SGLT1 (
The insulin-independent hypoglycemic mechanism indicates that theoretically, SGLT2 inhibitors might be effective in patients with any stage of diabetes and particularly effective in those with severe insulin resistance and receiving high-dosage insulin therapy. Previously, SGLT2 inhibitors plus insulin therapy was reported to improve glycemic control, reduce daily insulin requirements, and mitigate insulin-related weight gain. However, the side effects of SGLT2 inhibitors should be considered.
In this review, we aimed to elucidate the benefits and risks of SGLT2 inhibitors plus insulin therapy on patients with T2D and identify patients that may benefit from the use of SGLT2 inhibitors as a first-line therapy.
In 2017, a meta-analysis of nine randomized controlled trials consisting of a total of 3,069 patients revealed that patients administered with SGLT2 inhibitors plus insulin therapy, compared with the control patients, had a reduction in HbA1c level [
A double-blind randomized controlled clinical trial called the Canagliflozin Cardiovascular Assessment Study reported that 100 and 300 mg of canagliflozin plus insulin therapy vs. placebo reduced the level of HbA1c by 0.62% (95% CI 0.54–0.69;
Comparison of the SGLT2 inhibitors and placebo combined with insulin therapy for the treatment of T2D.
Wilding et al. ( |
Dapagliflozin | 12 | 10 mg | −0.70 (−1.1 to −0.3) | −15.4 (−38.4, 7.5) | −3.1 (−10.7, 4.6) [−5.57%] | −2.6 (−4.0 to −1.2) | −7.2 /−1.2 |
20 mg | −0.78 (−1.2 to −0.4) | −27.4 (−50.3 to −4.6) | −2.5 (−10.2 to 5.1) [−4.49%] | −2.4 (−3.8 to −1.0) | −6.1 /−3.9 | |||
Wilding et al. ( |
Dapagliflozin | 24 | 2.5 mg | −0.40 (−0.54 to −0.25) | No data | −7.60 (−10.32 to −4.87) [−9.58%] | −1.35 (−1.90 to −0.80) | −0.66 (−3.32 to 2.00) |
5 mg | −0.49 (−0.65 to −0.34) | −6.28 (−8.99 to −3.58) [−7.91%] | −1.42 (−1.97 to −0.88) | −2.37 (−5.01 to 0.26) |
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10 mg | −0.57 (−0.72 to −0.42) | −6.82 (−9.56 to −4.09) [−8.59%] | −2.04 (−2.59 to −1.48) | −3.11 (−5.79 to −0.43) |
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48 | 2.5 mg | −0.32 (−0.48 to −0.16) | −0.54 (−1.05 to −0.04) | −11.4 (−15.5 to −7.4) [−13.53%] | −1.78 (−2.53 to −1.03) | −3.81 (−6.65 to −0.97) |
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5/10 mg | −0.49 (−0.65 to −0.33) | −0.68 (−1.18 to −0.17) | −10.2 (−14.3 to −6.2) [−12.11%] | −1.82 (−2.56 to −1.07) | −2.84 (−5.67 to −0.01) |
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10 mg | −0.53 (−0.70 to −0.37) | −0.92 (−1.43 to −0.41) | −11.2 (−15.3 to −7.2) [−13.30%] | −2.43 (−3.18 to −1.68) | −2.61 (−5.48 to 0.27) |
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104 | 2.5 mg | −0.21 (−0.41 to −0.01) | −0.14 (−0.73 to 0.45) | −14.3 (−20.5 to −8.0) [−15.49%] | −2.81 (−3.87 to −1.75) | No data | ||
5/10 mg | −0.39 (−0.59 to −0.18) | −0.89 (−1.48 to −0.31) | −16.8 (−23.1 to −10.5) [−18.20%] | −2.86 (−3.92 to −1.80) | −2.6/−2.9 | |||
10 mg | −0.35 (−0.55 to −0.15) | −0.31 (−0.89 to 0.28) | −19.2 (−25.5 to −12.9) [−20.80%] | −3.33 (−4.38 to −2.27) | −7.5/−4.0 | |||
Rosenstock ( |
Empagliflozin | 18 | 10 mg | −0.44 (−0.59 to −0.29) | −1.17 (−1.62 to −0.71) | No data | −1.31 (−1.82 to −0.80) | −2.4 (−4.7 to −0.2) |
25 mg | −0.52 (−0.67 to −0.37) | −1.55 (−2.00 to −1.09) | −1.88 (−2.39 to −1.37) | −1.7 (−3.9 to 0.6) |
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52 | 10 mg | −0.38 (−0.59 to −0.16) | −0.69 (−1.23 to −0.15) | −8.8 (−14.8 to −2.8) [−8.70%] | −2.39 (−3.40 to −1.39) | −0.6 (−3.4 to 2.3) |
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25 mg | −0.46 (−0.67 to −0.25) | −0.79 (−1.33 to −0.26) | −11.2 (−17.2 to −5.2) [−11.07%] | −2.48 (−3.48 to −1.47) | −0.9 (−3.7 to 1.9) |
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Rosenstock and Ferrannini ( |
Empagliflozin | 18 | 10 mg | −0.6 (−0.8 to −0.4) | −1.6 (−2.1 to −1.1) | No data | −1.7 (−3.3 to −0.1) | −3.4 (−6.0 to −0.8) |
25 mg | −0.7 (−0.9 to −0.5) | −1.6 (−2.1 to −1.1) | −0.9 (−2.5 to 0.8) | −3.0 (−5.7 to −0.4) |
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78 | 10 mg | −0.5 (−0.7 to −0.2) | −0.7 (−1.2 to −0.2) | −6.7 (−10.9 to −2.4) [−12.74%] | −2.9 (−4.3 to −1.5) | −4.2 (−7.0 to −1.3) |
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25 mg | −0.6 (−0.9 to −0.4) | −1.0 (−1.5 to −0.5) | −5.9 (−10.4 to −1.5) [−11.22%] | −2.8 (−4.2 to −1.3) | −2.4 (−5.4 to 0.5) |
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Neal et al. ( |
Canagliflozin | 18 | 100 mg | −0.62 (−0.69 to −0.54) | −1.2 (−1.4 to −0.9) | No data | −1.9 (−2.2 to −1.6) | −2.3 (−3.7 to −1.0) |
300 mg | −0.73 (−0.81 to −0.65) | −1.6 (−1.8 to −1.3) | −2.4 (−2.7 to −2.1) | −4.1 (−5.5 to −2.8) |
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52 | 100 mg | −0.58 (−0.68 to −0.48) | −1.1 (−1.4 to −0.9) | −2 [−3.33%] | −2.8 (−3.3 to −2.4) | −3.1 (−4.6 to −1.7) |
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300 mg | −0.73 (−0.83 to −0.63) | −1.5 (−1.7 to −1.2) | −4.3 [−7.17%] | −3.5 (−3.9 to −3.0) | −6.2 (−7.7 to −4.8) |
Recent head-to-head studies reported that GLP-1 agonists cause superior reduction in the level of HbA1c relative to SGLT2 inhibitors (
A 2017 meta-analysis reviewed nine randomized controlled trials that compared SGLT2 inhibitors plus insulin therapy with placebo plus insulin therapy. Trials that administered multiple daily subcutaneous injections of basal plus bolus insulin therapy and insulin pump were included. Based on the findings, SGLT2 inhibitors could decrease the total daily dosage of insulin (
Several randomized controlled clinical trials have reported a reduction in total daily insulin dose (i.e., basal plus bolus insulin dose or the total daily dose of continuous insulin infusion pump) after a group administered with SGLT2 inhibitors plus insulin was compared with a group administered with placebo plus insulin (
According to a meta-analysis by Min et al. combining insulin therapy with SGLT2 and DPP-4 inhibitors results in a greater reduction in the total daily insulin dose than combining insulin therapy with placebo (WMD 6.40 IU/day, 95% CI 3.82–8.97 IU/day,
Insulin therapy often results in an increase in body weight (
Several clinical trials (
Animal studies have also demonstrated the achievement of weight loss owing to treatment with SGLT2 inhibitors. After 8 weeks of tofogliflozin intake, high fat diet (HFD)-induced hepatic steatosis and weight gain were inhibited in rats (
DeFronzo et al. employed a glucose clamp test to measure insulin resistance in patients with T2D after 2 weeks of treatment with SGLT2 inhibitors. Compared with the placebo group, muscle glucose uptake was significantly increased in the SGLT2 inhibitor group, indicating an improvement in peripheral insulin resistance (
A study using a rat model of T2D with pancreatectomy found that chronic glycosuria induced by phlorizin improved insulin resistance and restored β-cell function (
The Empagliflozin Cardiovascular Outcome Event Trial, which consisted of 7,020 T2D patients, found that routine treatment with empagliflozin significantly reduced cardiovascular mortality by 38% [hazard ratio (HR) 0.62, 95% CI 0.49–0.77,
GLP-1 agonists have been reported to reduce the risk of cardiovascular disease; however, SGLT2 inhibitors cause a relatively significant reduction in systolic blood pressure and play a unique role in the prevention of heart failure relative to GLP-1 agonists (
None of the current studies sought to directly compare combination therapy with SGLT2 inhibitors and insulin with monotherapy with SGLT2 inhibitors on cardiovascular outcomes. Therefore, whether SGLT2 inhibitors plus insulin combination therapy could affect the notable improvement in cardiovascular outcomes achieved with SGLT2 inhibitor monotherapy remains unclear. Nonetheless, SGLT2 inhibitors plus insulin therapy has definitive cardiovascular benefits compared with those of monotherapy with insulin or combination therapy with insulin and other drugs.
In the trials performed with dapagliflozin and canagliflozin combined with insulin, the albumin-to-creatinine ratio was significantly improved (
The kidneys play a key role in glucose metabolism. After glucose filtration by the glomerulus, glucose is reabsorbed in the proximal tubule. Thereafter, it is transported through the phospholipid bilayer of the cell membrane via glucose transporters. SGLTs are a class of transporters found in the small intestinal mucosa and proximal convoluted tubules of the kidney. Of these transporters, SGLT2 is predominant (
In patients with T2D, the expression level of SGLT2 is enhanced in renal cells (
Body weight loss is not only due to the calorie loss induced by glycosuria and negative energy balance (
The potential mechanism of sodium–glucose co-transporter 2 (SGLT2) inhibitors on glycemia reduction, weight reduction, insulin resistance, β-cell function improvement, and reduction of cardiovascular complications. (
Current studies have analyzed the potential mechanisms whereby SGLT2 inhibitors improve insulin resistance and β-cell function in patients with T2D (
Long-term mild inflammation is correlated with obesity, insulin resistance, and T2D (
In patients with T2D, serum leptin (
Owing to increased cell proliferation and decreased β-cell apoptosis, a larger pancreatic β-cell mass was observed in mice treated with luseogliflozin. Additionally, the β-cell-related factors were significantly increased in the luseogliflozin-treated mice, and the insulin gene transcription factors, MafA and PDX1, and insulin levels were increased (
Currently, there is no evidence of a synergistic or antagonistic effect between SGLT2 inhibitors and insulin on the cardiovascular system. Further studies are thus needed to clarify the mechanisms underlying their combination effects. However, as an add-on therapy to insulin, SGLT2 inhibitors result in significant cardiovascular benefits. Here, we mainly discussed the mechanisms employed by SGLT2 inhibitors in the cardiovascular system.
First, the protective effects of SGLT2 inhibitors against cardiovascular diseases and death may be partly explained by their effects on energy metabolism. SGLT2 inhibition exerts direct effects on pancreatic α-cells, increasing glucagon concentrations and decreasing insulin level, which ultimately promote ketone production (
Second, the effects of SGLT2 inhibitors on renal function may contribute to its cardiovascular benefits (
Third, SGLT2 inhibitors exhibit positive effects on myocardia. High concentrations of sodium and calcium in cardiomyocytes are early markers and drivers of cardiovascular death and heart failure (
Finally, SGLT2 inhibitors play a role in cardiac remodeling. After 3 months of treatment with empagliflozin, improvement in diastolic function and a reduction in the left ventricular mass index were observed in patients with T2D (
Other potential mechanisms could also exist. SGLT2 inhibitors can reduce oxidative stress and inflammation, which play a role in the initiation and progression of atherosclerosis (
In a prior meta-analysis, there was no difference in hypoglycemia risk between treatment with SGLT2 inhibitors plus insulin therapy and that with placebo (OR 1.18, 95% CI 0.86–1.61,
Genital tract infection (GTI) and urinary tract infection (UTI) are the major adverse effects of SGLT2 inhibitors. A meta-analysis reported that UTI and GTI were more common with the administration of SGLT2 inhibitors than with placebo (OR 1.42, CI 1.06–1.90 and OR 5.06, CI 3.44–7.45, respectively) (
Many studies have shown that the risk of ketoacidosis might increase in patients administered with SGLT2 inhibitors (
The FDA has added the increased risk of fracture and decreased bone mineral density (BMD) as adverse effects on the canagliflozin label. Both animal studies and clinical trials have revealed that canagliflozin might affect bone microarchitecture, increase bone resorption, and reduce total hip BMD (
Studies on other types of SGLT2 inhibitors, such as ertugliflozin and dapagliflozin, did not identify their detrimental effects on bone turnover and BMD (
A decrease in estimated glomerular filtration rate (eGFR) level occurred during the initial treatment with canagliflozin; this decrease was weakened over time and was recognized to be unrelated to the severe renal adverse events (
In this review, we have summarized the findings of current studies on SGLT2 inhibitors. We have reported the advantages and adverse effects of SGLT2 inhibitors plus insulin therapy for the treatment of T2D (
The main benefits and risks of SGLT2 inhibitors plus insulin therapy.
1. Significant glycemia-lowering effect | 1. Hypoglycemia (in the short term) |
2. Reduction in daily insulin requirement | 2. Genital and urinary tract infections |
3. Weight loss | 3. Diabetic ketoacidosis |
4. Insulin sensitivity and β-cell function improvement | 4. BMD reduction and fractures |
5. Cardiovascular benefits |
5. Other side effects: Dizziness, orthostatic hypotension, syncope, pollakiuria, nocturia, micturition frequency, and thirst |
6. Others possible benefits |
SGLT2 inhibitors combined with insulin might serve as a promising therapy for the treatment of T2D. SGLT2 inhibitors have several advantages, and when combined with insulin, a significant decrease in HbA1c and FBG levels is achieved, enabling a reduction in the daily administered with insulin dose. Additionally, these inhibitors reduce body weight via glycosuria-induced calorie loss and negative energy balance, thereby increasing fat and sugar utilization and β-oxidation of fatty acids. SGLT2 inhibitors polarize M2 macrophages, affect adipocyte-derived hormones, and promote the expression of different β-cell-related factors, consequently improving insulin resistance and β-cell function. Other potential advantages of these inhibitors include a reduction in blood pressure, cardiovascular events, and visceral adipose tissue volume. SGLT2 inhibitors exhibit better glycemic control and cause higher body weight loss, higher blood pressure reduction, and lower cardiovascular events than do DPP-4 inhibitors. However, these inhibitors exhibit similar insulin-reducing effects. Although SGLT2 inhibitors caused less HbA1c reduction and, controversially, body weight loss than did GLP-1 agonists, their reduction of blood pressure and heart failure was more significant than those of the GLP-1 agonists. Further, as SGLT2 inhibitors are administered orally, therapy compliance can be improved.
The main risk of treatment with SGLT2 inhibitors combined with insulin therapy is mild GTIs; however, a good response is achieved with therapy. No difference in the incidence of hypoglycemic events and UTI was noted by treatment with the inhibitors compared to placebo. As euglycemic diabetic ketoacidosis, bone adverse effects, and other adverse effects have been reported, further studies are warranted. According to the findings of recent studies, treatment with SGLT2 inhibitors plus insulin is a suitable regimen for patients with T2D, especially those requiring a high insulin dose daily and those with insulin resistance, obesity, or high risks of cardiovascular disease. Large-scale and long-term clinical studies are, however, needed to confirm such findings.
All authors contributed equally to the writing, revision, and editing of this manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.