Initial combination of metformin, sitagliptin, and empagliflozin in drug‐naïve patients with type 2 diabetes: Safety and metabolic effects

Compared with traditional stepwise add-on therapy, proactive combination therapy with antidiabetic agents having a different mode of action has shown high efficacy for glycaemic control in patients with type 2 diabetes (T2D).1 A study using an initial triple combination with metformin, pioglitazone, and exenatide showed significantly better long-term glycaemic control than a conventional stepwise approach.2 Similarly, in Korean patients, initial triple combination therapy with metformin, sitagliptin (a dipeptidyl peptidase-4 inhibitor [DPP-4i]), and lobeglitazone (a thiazolidinedione), showed superior achievement of HbA1c targets over conventional therapy with fewer adverse events.3 DPP-4is comprise a class of oral antidiabetic agents that block the enzyme DPP-4. The mechanism of a DPP-4i is to increase incretin levels and inhibit glucagon release, both of which potentiate insulin secretion, and decrease the gastric emptying rate and blood glucose levels. Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) increase the urinary excretion of glucose, thereby promoting glycaemic control independent of insulin action.4 Recent cardiovascular outcome trials have shown the cardiovascular safety of DPP-4is and the cardiovascular benefit with SGLT-2is.5 The clinical benefits of using an SGLT-2i for patients with T2D include lowering blood pressure, weight loss, and a reduced risk of major adverse cardiovascular and renal events.6 Therefore, both types of agent are an attractive option in the management of T2D because of their complementary mechanism of action. In randomized controlled trials, SGLT-2is, when used in combination with DPP-4is, have shown to be effective in reducing HbA1c levels, body weight, and blood pressure.7 Another study reported that triple therapy with dapagliflozin added on to saxagliptin plus metformin was a durable, effective, and well-tolerated intervention for the treatment of patients with T2D.8 It has also been shown that the co-administration of these drugs does not pose safety concerns.9 However, the extent to which the SGLT-2i–induced changes in the urinary excretion of glucose and electrolytes are altered by the added components has not been investigated. In this pilot study of drug-naïve patients with T2D, we tested an initial triple regimen combining metformin, sitagliptin, and empagliflozin, and measured longitudinal changes in serum and urinary metabolic profiles over 4 months of treatment. The study protocol was approved by an independent Ethics Committee/Institutional Review Board (B-2008/630-104). The study participants (n = 53; 33 men, age 47 ± 13 years) were selected from 2017 to 2021 according to the following criteria: (a) age 19 years or older; (b) an HbA1c level of 9.0% or higher at diagnosis; and (c) being drug-naïve for 6 months or longer prior to enrolment. Because of their high HbA1c levels, the patients were hospitalized with consent to undergo rehydration (≥2 L/day), metabolic stabilization, and diabetes education. The mean duration of hospitalization was 7 days, and anthropometric and biochemical variables were measured at this endpoint to investigate how early these variables changed with the initial triple therapy compared with baseline values. At 15-16 weeks after the 1-week hospitalization (4 months from baseline), the participants were scheduled to visit for further evaluations. Of all 53 study participants, 39 received small doses of basal insulin (12 U/day on average), but only during hospitalization. In this study, three antidiabetic agents were administered separately: a 100-mg tablet of sitagliptin and a 10-mg tablet of empagliflozin were given after breakfast, and a 500-mg tablet of metformin was given after breakfast and dinner (total metformin dosage 1000 mg/day). Patients underwent an oral glucose tolerance test at baseline, 1 week, and 4 months after starting triple treatment. Height, body weight, weight circumference, and systolic and diastolic blood pressures were measured by standard methods. Fasting glucose, insulin, C-peptide, and HbA1c levels, and serum concentrations of total ketones (β-hydroxybutyrate and acetoacetate), were measured as reported.10 The homoeostatic model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-β) were calculated. In this study, body composition was measured using validated bioelectrical impedance analysis (BIA; InBody720, InBody, Seoul, Korea).11, 12 After the subjects had fasted overnight and emptied their bladders, a trained nurse measured their body composition (body water, fat mass, and muscle mass), with the subject wearing light clothing. In a validation study with subjects with obesity, a high correlation of fat and muscle mass was found between the data by InBody720 BIA and dual energy X-ray absorptiometry examinations (intraclass correlation coefficients .832 and .899, respectively).13 We validated the concordance between visceral fat area (VFA) estimated by BIA or computed tomography in 1006 Korean individuals (age 19-87 years; body mass index 17-46 kg/m2).12 Plasma metabolites, including free fatty acids (FFA), β-hydroxybutyrate and acetoacetate, triglycerides, HDL-cholesterol, LDL-cholesterol, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), uric acid, sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), and phosphorus (P) levels were measured by standard methods. The serum creatinine level was measured using Jaffe's kinetic method. The estimated glomerular filtration rate (eGFR) was calculated using the creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation.14 Using spot urine samples, the ratios of urinary protein or albumin to creatinine (Cr) concentrations were used to gauge proteinuria or albuminuria, respectively. The fractional excretion rates (%) of glucose, Na, K, Cl, Ca, and P were calculated using the following formula: urine solute × serum Cr / serum solute × urine Cr. The blood and urine samples were taken on the same day. Paired Student's t tests were used for statistical analysis (R Development Core Team, Vienna, Austria). For these analyses, variables with a skewed distribution were log-transformed. P less than .05 was considered significant without multiplicity control. Baseline characteristics are shown in Table S1 and the changes in metabolic variables are presented in Table 1. One week after initiating triple therapy, fasting and 2-hour plasma glucose concentrations were reduced markedly. Along with these glycaemic improvements, body water increased, and blood pressure decreased; eGFR was unchanged. With regard to the metabolic profile, fasting insulin and C-peptide levels fell below baseline, as did the HOMA-IR, FFA, ketone, triglyceride, LDL- and HDL-cholesterol, and AST and ALT levels. The HOMA-β estimates increased sequentially at 1 week and 4 months. In the urine, glucose and protein/albumin excretion were decreased significantly, whereas fractional glucose excretion was increased (Table 1 and Figure 1). Of the 53 patients, 50 (94%) completed the 4 months of treatment; the other three did not appear at the review visit. After 4 months of treatment, HbA1c levels were halved and most metabolic changes were maintained or strengthened, with the exception of fasting insulin and C-peptide levels, which returned to baseline levels, and serum Na, K, and Cl concentrations, which increased above baseline (Table 1 and Figure 1). Lean body mass increased by 1.5 kg, whereas fat mass decreased by 1.8 kg after 4 months of initial triple combination therapy (both P < .05 vs. baseline). In addition, there was a significant reduction in abdominal VFA (Figure 1). No serious adverse events, such as hypoglycaemia, genitourinary infection, ketoacidosis, or retinopathy progression, were observed during the study period (Table S2). In these drug-naïve patients with decompensated T2D, initial triple therapy using metformin, sitagliptin, and empagliflozin resulted in rapid, satisfactory, and sustained glucose control without adverse events. The decrease in HbA1c levels was impressive (~6%), and the inclusion of an SGLT-2i combined glycaemic benefits with favourable changes in the metabolic profile. In particular, the reduction in blood pressure, proteinuria, and liver enzymes expected from SGLT-2 inhibition was unaffected by the companion drugs, and the lipid profile was actually better than expected,15 with clinically significant decreases in both LDL-cholesterol and triglycerides and maintenance of HDL-cholesterol. Therapeutic lifestyle modifications and statin therapy in three subjects might explain the significant LDL-cholesterol reduction. By contrast, the accelerated loss of glucose through the urine resulted in a decrease rather than an increase in plasma FFA and ketones, even although their levels were elevated at baseline, and despite the transient increase in the glucagon: insulin ratio at 1 week (Table 1). In fact, in about one-third of participants, baseline ketones were in the millimolar range (1.68 ± 2.04 mmol/L) and decreased to 0.17 ± 0.24 mmol/L at 4 months. Drug-specific effects of DPP-4 inhibition, such as the reduction in the glucagon: insulin ratio, efficient renal elimination of ketones, improved glucose control, and patient education, probably contributed to keeping lipolysis and ketonaemia in check (Figure 1). This finding helps alleviate concerns regarding "euglycaemic diabetic ketoacidosis", a rare but serious adverse event of SGLT-2 inhibition in decompensated T2D. Notably, the HOMA-IR measure was attenuated from week 1 and remained low after the triple therapy. HOMA-β increased sequentially at 1 week and 4 months, indicating improved β-cell function. At 4 months, body weight had increased despite a reduction in the VFA, suggesting a return to a healthier lean body mass; whether such weight control might extend beyond the duration of this study remains to be assessed. Urinary electrolyte excretion increased slightly after the triple therapy, but the corresponding serum electrolyte levels were not altered. This finding suggests the involvement of other solute exchange systems, such as the sodium–hydrogen exchanger (NHE3), Na–Cl co-transporter, epithelial sodium channel, Na–K–2Cl co-transporter, aquaporin 2, and urea transporters for electrolyte balance.16, 17 As a compensatory response to the natriuresis induced by SGLT-2is, these sodium transporters are activated to increase sodium uptake in the renal tubules, resulting in balanced sodium homoeostasis.18 Our data appease the safety concerns regarding electrolyte imbalance with SGLT-2i use.5 Canagliflozin treatment was associated with a higher incidence of fractures in a study including patients with a high risk or a history of cardiovascular disease.19 Although data are inconclusive, evidence supports the idea that SGLT-2i therapy might affect bone health by modulating the homoeostasis of Ca, P, parathyroid hormone, or fibroblast growth factors.20 These findings suggest that Ca and P metabolism might be affected by SGLT-2i therapy. Here, urinary Ca and P excretion rates also increased slightly at week 1 but decreased at 4 months. Serum Ca and P levels did not change, which is consistent with a finding from a nationwide Medicare cohort in the United States, showing that initiating treatment with an SGLT-2i was not associated with an increased risk of fractures in older adults with T2D compared with incretin-based therapy.17 In the current study, low doses of metformin and empagliflozin were chosen because 500 mg of metformin taken twice-daily is commonly used as a starting dose for Asian subjects. As for empagliflozin, 10 mg is typically used as a starting dose, particularly in Asian countries, because there is little difference in glucose-lowering efficacy between 10 and 25 mg.21 This study has some limitations. First, it was a single-arm study that did not allow comparison with different regimens. Second, of the 53 patients, 39 received insulin therapy during an average of 7 days of admission, which might have affected some of the results. Third, the study only included Korean subjects. In previous studies, early combination therapy with incretin-based therapy, thiazolidinedione, and metformin was proven to be better for glycaemic control than metformin and sulphonylurea.2, 3 By contrast, here we used empagliflozin, an SGLT-2i, which proved to have cardiovascular benefits in a long-term cardiovascular outcome trial.5 In conclusion, this pilot study showed that in drug-naïve Korean T2D patients with high HbA1c levels, an initial combination with metformin, sitagliptin, and empagliflozin can decrease glucose levels rapidly and markedly without clinically significant adverse events. Further benefits in blood pressure, insulin sensitivity, body composition, and metabolic profiles including lipids, liver enzymes, and proteinuria, were also identified with this novel approach. Thus, initial triple combination therapy targeting different pathophysiological abnormalities can be considered a viable option to induce euglycaemia rapidly and safely in drug-naïve patients with T2D. Randomized controlled trials comparing initial triple therapy with initial dual therapy with metformin and a SGLT-2i or DPP-4i are needed to verify these results. This work was supported by the Seoul National University Bundang Hospital Research Fund. The authors have no conflicts of interest relevant to this article to disclose. SL conceived the study, extracted and analysed data, and wrote the manuscript. MS and EF helped conceive the study, assisted in data analysis, and reviewed and edited the manuscript. YS helped conceive the study and reviewed and edited the manuscript. SL is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The peer review history for this article is available at https://publons.com/publon/10.1111/dom.14627. Data are available from the authors upon reasonable request. Appendix S1: Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.