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GLP1 receptor agonist and SGLT2 inhibitor combination: An effective approach in real-life clinical practice
Clinical Therapeutics/Volume xxx, Number xxx, xxxx
GLP1 receptor agonist and SGLT2 inhibitor combination: An effective approach in real-life clinical practice Olaia Díaz-Trastoy, MD1; Rocío Villar-Taibo, MD, PhD2; Mildred Sifontes-Dub on, MD3; Hector Mozo-Pe~ nalver, PharmD4; Ignacio Bernabeu-Mor on, MD, PhD2; Jose M. Cabezas-Agrícola, MD2; Virginia Mu~ noz-Leira, MD2; Roberto Pein o-García, MD, PhD2; Aurelio Martís-Sueiro, MD2; Jose M. García-L opez, MD, PhD2; and Miguel A. Martínez-Olmos, MD, PhD2 1
Endocrinology and Nutrition Department, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain; 2Endocrinology and Nutrition Department, Complejo Hospitalario Universitario de Santiago de Compostela, A Coru~na, Spain; 3Clinical Nutrition and Dietetics Unit, Endocrinology and Nutrition Department, Hospital General Mateu Orfila, Menorca, Spain; and 4Hospital Pharmacy Department, Hospital da Barbanza, Ribeira, Spain ABSTRACT Purpose: The aim of this study was to evaluate the effectiveness and safety of combination therapy with a sodium-glucose cotransporter-2 (SGLT2) inhibitor and a glucagon-like peptide-1 receptor agonist (GLP1RA) in patients with inadequately controlled type 2 diabetes. Methods: A retrospective search of electronic prescriptions of patients undergoing GLP1RA and SGLT2 inhibitor combination therapy was conducted. Once the patients had been identified, demographic data, blood and urine analyses (glycosylated hemoglobin [HbA1c], glucose, renal function, albuminuria, lipid profile, liver enzymes, and uric acid), physical examination (weight, body mass index, and blood pressure), and adverse effects were obtained from their electronic clinical records according to each of the following 3 periods: before the initiation of the combination, the first visit after initiation, and the last available visit. The influence of the duration of diabetes and the drug combination sequence on the effectiveness of the treatment was also analyzed. Statistical analysis was performed with SPSS version 21.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). Quantitative variables are presented as mean and SD and were compared by using the Student t test, one-way ANOVA, or repeated measures ANOVA with
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Bonferroni correction. Categorical variables are expressed as percentages and were compared by using the c2 test. Results: A total of 212 patients were included, with women accounting for 52.4%. The mean age (SD) of the population was 61.5 (9.6) years. A significant reduction in HbA1c (−12 mmol/mol [e1.1%]) was observed with combined therapy (P < 0.001). The target of HbA1c <53 mmol/mol (<7%) was achieved in 42% of the participants. Mean weight loss was −3.5 kg, and almost 40% of the patients attained the weight loss goal of 5% (P < 0.001 in all analyses). Transaminase levels and renal parameters also improved. These benefits persisted over time and bore no relation to the evolution of diabetes. Simultaneous initiation of a combination of a GLP1RA and SGLT2 inhibitor led to faster weight loss and a greater decrease in HbA1c than when they are used sequentially; however, the long-term benefits in terms of metabolic control were similar. Adverse events were rare, and a tendency for a reduced insulin dose was observed. Implications: The findings of this study reveal the combined benefits of a GLP1RA and SGLT2 Accepted for publication December 30, 2019 https://doi.org/10.1016/j.clinthera.2019.12.012 0149-2918/$ - see front matter © 2020 Elsevier Inc. All rights reserved.
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Clinical Therapeutics inhibitor in real-life clinical practice. In general, the combined treatment was well tolerated, and few adverse events were detected. (Clin Ther. xxxx;xxx:xxx) © 2020 Elsevier Inc. All rights reserved. Key words: GLP1 receptor agonist, SGLT-2 inhibitor, type 2 diabetes, clinical practice.
INTRODUCTION Management of type 2 diabetes has evolved from a glucocentric to a cardiometabolic approach. This new attitude toward type 2 diabetes treatment seeks a decrease in glycosylated hemoglobin (HbA1c) levels, which should be accompanied by an improvement in other risk factors (eg, weight or blood pressure), with a low rate of hypoglycemia and a reduction in cardiovascular morbidity and mortality.1 Classical antidiabetic medications, such as secretagogues, glitazones, and even insulin, can be associated with considerable weight gain or a high risk of hypoglycemia.2 On the contrary, glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodiumglucose cotransporter-2 (SGLT2) inhibitors have become more suitable due to their beneficial effects: weight loss, decreased blood pressure, low risk of hypoglycemia, and their relevant cardiorenal protection.3 GLP1RAs and SGLT2 inhibitors have different mechanisms of action, and their effects are additive. They therefore seem to be an ideal duo for combination therapy.4 GLP1RAs enhance insulin secretion, inhibit glucagon secretion, reduce hepatic glucose production, suppress appetite due to a central effect, and promote weight loss, enhancing peripheral insulin sensitivity. SGLT2 inhibitors inhibit renal glucose reabsorption, improving glucotoxicity and insulin sensitivity and increasing beta-cell function. They also cause weight loss, increasing the excretion of calories in urine. However, the effect of an SGLT2 inhibitor on appetite remains unclear; both an increase in calorie intake and a decrease in appetite are described in the literature.5,6 GLP1RAs and SGLT2 inhibitors both reduce visceral fat. Researchers have found that treatment of type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) with SGLT2 inhibitors and GLP1RAs substantially decreases the marker of hepatic inflammation (serum alanine aminotransferase
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[ALT]), improving ultrasound imaging and reducing steatosis, inflammation, and fibrosis in liver biopsy samples.7 Regarding blood pressure, SGLT2 inhibitors induce natriuresis, favoring a reduction in intravascular volume, thus leading to a decrease in blood pressure. GLP1RAs can contribute to this effect with vasodilation and mild natriuresis.8 Furthermore, the effects of both drugs on cardiac and renal disease are highly relevant. On the one hand, GLP1RAs have a cardioprotective effect at the level of the smooth vascular muscle cells of the coronary arteries, the stimulation of which induces vasodilation, anti-inflammatory and antioxidant effects, increased endothelial function, inhibition of smooth muscle proliferation, stabilization of atheroma plaque, and greater tolerance to ischemia.9 All of these factors can explain their cardioprotection and the reduction in myocardial infarction, stroke, and cardiovascular mortality observed in the LEADER (Liraglutide Effect and Action in Diabetes), SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes), and REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) studies.10e13 Several hypotheses attempt to explain cardioprotection with SGLT2 inhibitors: metabolic effects with a reduction in cardiovascular risk factors such as glucotoxicity, perivisceral fat, or uric acid; and hemodynamic effects (osmotic diuresis reduces preload [volemia] and afterload and improves tubuloglomerular balance). Reducing preload decreases myocardial wall tension and can potentially contribute to reducing the risk of ventricular arrhythmias. Hemoconcentration caused by the SGLT2 inhibitor increases hematocrit, which can facilitate the release of oxygen to ischemic tissues. These drugs directly affect the myocardium due to increased plasma levels of betahydroxybutyrate (a source of energy for the diseased myocardium). Finally, there is a direct inhibitory effect on sodium-hydrogen exchanger type 1 of the myocardium, inhibition of cardiac fibrosis, and reduction of proinflammatory adipokines derived from epicardial and perivascular fat.9 This cardiovascular improvement was observed in the EMPA-REG OUTCOME, CANVAS (Canagliflozin Cardiovascular Assessment Study), and DECLARE (Dapagliflozin Effect on Cardiovascular Events) trials and may be additive to the benefit of GLP1RAs.13e15
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O. Díaz-Trastoy et al. The aim of the present study was to investigate the usefulness of the GP1RA/SGLT2 inhibitor combination therapy in our area, evaluating its effectiveness and safety in a real-life practice setting.
PATIENTS AND METHODS This retrospective study was performed in the health care area of Santiago de Compostela (Galicia, Spain), with a total population of 446,798 patients.16 In May 2018, we completed a retrospective search of the electronic prescriptions of the patients in our health area (comprising primary, specialized, and sociosanitary care) with the aim of identifying individuals with type 2 diabetes receiving combination therapy with a GLP1RA (liraglutide, dulaglutide, exenatide, exenatide long-acting release, or lixisenatide) and an SGLT2 inhibitor (dapagliflozin, empagliflozin, or canagliflozin). The hospital's Ethics and Clinical Research Committee approved the study protocol, and patient anonymity was preserved. We identified 212 patients receiving this treatment, and the clinical records of each case were reviewed. According to reimbursement restrictions by the Spanish public health system, all patients treated with a GLP1RA had a body mass index >30 kg/m2 before initiating this therapy. Three clinical visits were selected to evaluate their evolution: the visit before initiating the combination of a GLP1RA and SGLT2 inhibitor (V1), the first visit after starting the therapy (V2), and the last available visit (V3). Study parameters included baseline demographic variables (age, sex, duration of diabetes, and macrovascular and microvascular complications registered on the clinical record and concurrent use of antidiabetic therapies). The characteristics of the combination therapy were also registered, including the type of GLP1RA and SGLT2 inhibitor, the combination sequence, and the prescribing physician. At each visit, certain clinical and analytical variables were recorded: weight, body mass index, blood pressure, basal glycemia, HbA1c value, uric acid, lipid profile (total cholesterol, LDL, HDL, and triglycerides), liver enzymes (aspartate aminotransferase, ALT, gamma-glutamyl transferase, and alkaline phosphatase), and renal parameters (creatinine, glomerular filtration rate [GFR], and albuminuria). We also recorded whether the patients met the HbA1c goal considered appropriate by their physician according to the recommendations of the
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American Diabetes Association.17 Changes in diabetes therapy and adverse events during follow-up were also enumerated. The primary outcome was evaluation of the effectiveness of the combination therapy in terms of glycemic control (reduction in HbA1c level and percentage of patients with HbA1c on target), weight loss (defining relevant weight loss as 5%), and renal benefit (changes in albuminuria). Secondary outcomes included the safety assessment (frequency of adverse events), variation of the type 2 diabetes treatment (the need for new antidiabetic drugs and changes in insulin dose), and the effect on other analytical parameters (lipid profile, liver enzymes, and uric acid) or on blood pressure. Finally, we attempted to determine the influence of long versus short duration of diabetes on the effectiveness of the treatment and the differences in results according to the drug combination sequence. Statistical analysis was performed with SPSS version 21.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). Quantitative variables are presented as mean and SD and were compared by using the Student t test, one-way ANOVA, or repeated measures ANOVA with Bonferroni correction. Categorical variables are expressed as percentages and were compared by using the c2 test. A p value <0.05 was considered statistically significant.
RESULTS Epidemiologic Characteristics of the Sample The baseline (V1) demographic parameters and the background of diabetic drugs are described in Table I. Of the 87 patients treated with insulin, 58 received only basal insulin (66.6%), 16 were on a basal bolus regimen (18.3%), 9 received mixed insulins (10.3%), and 4 received basal and mixed insulins (4.5%). The mean (SD) insulin dose before starting the combination treatment with a GLP1RA and SGT2 inhibitor was 59.3 (38.7) IU. The combination sequence and the frequency of use of any individual drug are also described in Table I. The combination therapy was prescribed in 81.1% of the cases by endocrinologists, followed by primary care physicians (16.5%) and internists (2.4%).
Follow-up and Patients' Evolution For the first follow-up visit (V2), we registered a mean of 5.5 (2.6) months after initiating combination
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Clinical Therapeutics
Table I.
Epidemiologic characteristics of the patients and their treatments. Values are given as mean (SD) unless otherwise indicated.
Characteristic Age, y Female sex Duration of diabetes, y Hypertension Diabetes complications Retinopathy Nephropathy Peripheral neuropathy Autonomic neuropathy Cardiovascular disease Cerebrovascular disease Heart failure Pulmonary edema Use of concomitant diabetes drugs Metformin Sulfonylureas DPP-4 inhibitors Pioglitazone Repaglinide Insulin Combination sequence First drug SGTL2 inhibitor and second drug GLP1RA First drug GLP1RA and second drug SGLT2 inhibitor Simultaneous addition Type of SGLT2 inhibitor Dapagliflozin Empagliflozin Canagliflozin Type of GLP1RA Dulaglutide Liraglutide Exenatide LAR Lixisenatide
Value 61.5 (9.6) 52.4% 12.3 (7.0) 51.1% 14.6% 10.4% 3.3% 1.9% 11.8% 1.4% 0.5% 0.9% 184 (86.8%) 23 (10.8%) 4 (1.9%) 2 (0.9%) 2 (0.9%) 87 (41%) 85 (40.0%) 89 (41.9%) 38 (17.9%) 97 (45.8%) 76 (35.8%) 39 (18.4%) 111 (52.4%) 57 (26.9%) 36 (17%) 8 (3.8%)
DDP-4 ¼ dipeptidyl peptidase-4; GLP1RA ¼ glucagonlike peptide-1 receptor agonist; LAR ¼ longacting release; SGLT2 ¼ sodium-glucose cotransporter-2.
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therapy. The final visit (V3) was performed after 16.4 (6.5) months. The evolution of the patients' anthropometric and metabolic outcomes is summarized in Table II. Figure 1 shows the percentage of our sample who reached the metabolic and weight loss objectives with the combination therapy. More than 70% of the patients achieved a level of HbA1c considered appropriate by their physicians at the time of the follow-up. The mean weight loss was −3.45% (3.75%) at V2 and e3.49% (5.22%) at V3. However, almost 40% of the patients attained the weight loss goal of 5% by the end of the study. Nearly one third of the patients exhibited an excellent response to the combination therapy, reaching the HbA1c and weight loss goals. The univariate analysis did not reveal any association between the desired response to the treatment and the patients' basal characteristics or their parameters at the initial visit. A slight nonsignificant reduction in insulin dose was observed at the end of the study, from 59.3 (38.7) IU at V1 to 54.9 (40.1) IU at V3 (p ¼ 0.341). Of the total sample, 188 patients (88%) did not need any new diabetes treatment. Only 19 patients (9%) required a new antidiabetic drug or insulin during the study period. In terms of renal parameters, serum creatinine levels remained stable during the study period (mean in V1, 61.9 [8.8] mmol/L; mean in V2, 61.9 [8.8] mmol/L; mean in V3, 61.9 [8.8] mmol/L [p¼1]). The mean GFR decreased from 89.4 (10.4) mL/min/1.73 m2 at V1 to 74.3 (12.1) mL/min/1.73 m2 at V2 (p ¼ 0.310). However, at V3, it had stabilized, with a mean value of 75.4 (17.1) mL/min/1.73 m2, and no significant change emerged in V1 (p ¼ 0.889) or V2 (p¼1). Data were available regarding albuminuria at baseline and during follow-up for 127 of the 212 patients. In this subset of patients with available data, significant differences were found with an increase in the rate of normoalbuminuria and a decrease in microalbuminuria (Figure 2). Several patients experienced relevant changes in their albuminuria status. Ten patients experienced progression: 7 progressed from normoalbuminuria to microalbuminuria, 1 patient from normoalbuminuria to macroalbuminuria, and 2 patients from microalbuminuria to macroalbuminuria. Conversely, 13 patients experienced regression: 10 regressed from
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O. Díaz-Trastoy et al. microalbuminuria to normoalbuminuria, 2 from macroalbuminuria to microalbuminuria, and 1 from macroalbuminuria to normoalbuminuria.
Adverse Events of the Combination Therapy The adverse events registered in the clinical records were infrequent and mild. Nineteen patients reported side effects with the combination therapy (8 genital infections, 2 urinary tract infections, 2 abdominal pain, 5 polyuria, 1 asthenia, and 1 reduction of GFR <30 mL/min/1.73 m2). No cases of ketoacidosis, fractures, or amputations were reported.
Duration of Diabetes: <10 Years Versus >10 Years
Duration was <10 years in 74 patients (40.8%) and >10 years in 107 patients (59.1%). Baseline characteristics differed between groups, with a lower
Table II.
age, less insulin use, a lower level of serum creatinine, higher total cholesterol, and a higher LDL level in the short-duration group. Despite these differences, the evolution and outcomes of the groups were comparable.
Initiation of the Combination Treatment: Sequential Versus Simultaneous Both groups of patients were comparable in all their baseline parameters, with the exception of basal serum glucose level and the use of insulin. Fasting glycemia was lower in the sequential group (9.6 [2.9] mmol/L) than in the simultaneous group (10.9 [3.1] mmol/L), with a p value close to statistical significance (p ¼ 0.053). The use of insulin was significantly higher in the sequential group than in the simultaneous group (45.4% vs 21.1%; p ¼ 0.06).
Evolution of anthropometric and metabolic parameters during follow-up. Results are expressed as mean (SD) (quantitative variables) and as percentages (qualitative variables).
Parameter
Initial Visit First Visit Precombination After Combination (V1) (V2)
Final Visit (V3)
V1 to V2, p V1 to V3, p
V2 to V3, p
Weight, kg BMI, kg/m2 SBP, mm Hg DBP, mm Hg Basal glycemia, mmol/L HbA1c, mmol/mol HbA1c, % % patients with HbA1c <53 mmol/mol (<7%) Uric acid, mmol/L Total cholesterol, mmol/L LDL-C, mmol/L HDL-C, mmol/L Triglycerides, mmol/L GGT, mkat/L ALT, mkat/L AST, mkat/L ALP, mkat/L
99.4 (18.4) 37.7 (8.1) 137.4 (17.9) 78.0 (9.2) 9.8 (3) 68.3 (13.1) 8.4 (1.2) 10.4
96.5 (17.3) 36.6 (7.6) 138.6 (13.6) 78.0 (8.5) 7.7 (2.1) 56.3 (9.8) 7.3 (0.9) 41.3
95.2 (18.4) 35.6 (7.5) 134.9 (13.6) 78.4 (12.0) 7.6 (1.7) 56.3 (9.8) 7.3 (0.9) 41.9
<0.001* <0.001* 0.99 0.662 <0.001* <0.001*
<0.001* <0.001* 0.97 0.420 <0.001* <0.001*
0.229 0.310 0.534 10,92 0.96 0.561
<0.001*
0.087
<0.001*
309.4 (88.3) 4.3 (0.9) 2.2 (0.7) 1.1 (0.3) 2.1 (1.1) 0.8 (0.9) 0.6 (0.4) 0.5 (0.3) 2.7 (0.9)
303.5 (125) 4.1 (0.9) 2.1 (0.6) 1.1 (0.4) 1.9 (0.9) 0.6 (0.7) 0.5 (0.2) 0.4 (0.2) 2.7 (0.9)
285.6 (89.3) 4.2 (0.8) 2.3 (0.6) 1 (0.3) 2 (1.3) 0.7 (0.8) 0.5 (0.2) 0.4 (0.2) 2.8 (0.9)
0.98 0.162 0.97 1.1 0.040* 0.003* <0.001* <0.001* 0.136
0.116 0.327 0.98 0.022* 0.087 0.016* <0.001* <0.001* 0.99
0.793 10.99 0.99 0.166 0.96 0.95 0.95 0.97 0.794
ALP ¼ alkaline phosphatase; ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; BMI ¼ body mass index; DBP ¼ diastolic blood pressure; GGT ¼ gamma-glutamyl transferase; HbA1c ¼ glycosylated hemoglobin; SBP ¼ systolic blood pressure; *¼ p <0.05
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Clinical Therapeutics
Figure 1. Percentage of patients who achieved the main goals of glycosylated hemoglobin and/or weight loss during the follow-up period. V2 ¼ first visit after combination therapy; V3 ¼ final visit.
During the study period, the achievement of the goals differed between groups (Table III). Simultaneous initiation seemed to achieve faster and better glycemic and weight control than sequential initiation (a higher proportion of patients with HbA1c values <53 mmol/mol [<7%] and/or weight loss >5%). However, at the end of follow-up, the differences regarding HbA1c values in both groups had disappeared. The rest of the parameters studied (analytical measurements, adverse events, renal outcomes, and the need for new antidiabetic therapies) were comparable between groups. We also analyzed the results in patients with sequential treatment according to the drug used second, the SGT2 inhibitor or the GLP1RA. At the end of the follow-up, no relevant differences were observed between groups.
DISCUSSION The findings of this retrospective real-life study in patients with type 2 diabetes support the combination of an SGLT2 inhibitor with a GLP1RA as an effective therapeutic option in clinical practice. Combination therapy has shown benefits in
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metabolic parameters (a significant reduction in HbA1c values, fasting plasma glucose level, weight, and transaminase levels) and an improvement in renal outcomes, even in patients with a long duration of diabetes. The benefits of the combination of these 2 drugs have been shown in 3 randomized clinical trials and in several observational reports. The DURATION-8 (Efficacy and Safety of Once-Weekly Exenatide Plus Once-Daily Dapagliflozin vs Exenatide or Dapagliflozin Alone) trial studied the co-initiation of exenatide long-acting release and dapagliflozin, whereas AWARD-10 (Study of Dulaglutide [LY2189265] in Participants With Type 2 Diabetes Mellitus) and SUSTAIN-9 (SGLT-2i in Subjects With Type 2 Diabetes Mellitus) examined the addition of dulaglutide and semaglutide, respectively, to ongoing treatment with an SGLT2 inhibitor versus placebo. All of these studies found that combination therapy significantly reduced HbA1c level, weight, and systolic blood pressure, proving superior to either drug alone or to placebo. Furthermore, combination therapy achieved a higher proportion of patients with HbA1c values <53 mmol/mol (<7%) or a weight loss 5%. These results are in line with the results observed in other studies.18e24 In our real-world study, the metabolic results of the combination therapy were similar to those reported in the clinical trials, particularly the AWARD-10 trial. The HbA1c<53 mmol/mol (<7%) target was achieved in 42% of our patients, proving similar to the DURATION-8 result, and was slightly higher than in other studies.20 Nevertheless, taking into consideration the fact that the HbA1c<53 mmol/mol (<7%) goal is not valid for all patients and that it should be individualized, we also considered the level of HbA1cthe patients' physicians selected as appropriate during follow-up. More than 70% of our sample achieved their individualized HbA1ctargets with the combination therapy, thereby confirming its usefulness in terms of glycemic control. The mean weight loss in the current study was −3.5 kg, with almost 40% of the patients attaining the weight loss goal of 5% by the end of the study. This weight reduction was similar to that found in clinical trials18,19,21 and real-world studies.20,22,23,25e27 In their study, Goncalves and Bell24 reported greater weight loss (approximately −9.1% to −9.2%),
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O. Díaz-Trastoy et al.
Figure 2.
Evaluation of albuminuria during the study period.
independently of the simultaneous or sequential initiation of the combination therapy (−9.5 kg vs −10.3 kg, respectively). Some explanations for this greater weight loss could be this population's longer follow-up period, the use of maximum doses of the drugs, and the selection of liraglutide as the GLP1RA, which has a marked effect on weight loss compared with other GLP1RAs. As far as HbA1c values and weight loss goals (5%) are concerned, nearly one third of our patients exhibited an excellent response to the combination therapy. Similar data can be found in the literature supporting the combined use of a GLP1RA and SGLT2 inhibitor to achieve a good metabolic response in patients with diabetes and obesity.23,28
The benefits of the combination therapy were observed in patients with a short (<10 years) and a long (>10 years) evolution of their diabetes, including those treated with insulin. Therefore, the combination of a GLP1RA and SGLT2 inhibitor is an appropriate option even for patients with advanced type 2 diabetes (ie, a greater impairment of beta-cell function).20,29 Furthermore, with the combination therapy, a reduction in insulin needs may occur. At the end of the study, although it was not statistically significant, there was a tendency toward a reduction in insulin doses, in line with other studies, such as that conducted by Saroka et al.25 It is noteworthy that the combination therapy's main metabolic effects, in terms of reduction of weight, fasting plasma glucose, and HbA1c, were observed in the first visit after initiating combination therapy and remained stable until the final visit. This result supports the idea of the combined treatment's rapid and durable benefits, even with a mean follow-up time of 16.4 months (from the initiation of the combined treatment to the final registered visit), much longer than that of other studies and clinical trials. However, long-term clinical trials with dapagliflozin found some attenuation of HbA1creduction during follow-up, which may reflect progressive beta-cell failure.26 In terms of the patients' lipid profiles, no significant changes were found in LDL-C or HDL-C levels. Triglyceride levels had decreased by the first visit, but differences had disappeared at the end of the followup period. These results are consistent with those observed in Phase III clinical trials and some
Table III. Differences in achievement of goals between the sequential and simultaneous therapy groups. Study Group % of patients with HbA1c <53 mmol/mol (<7%) at V2 % of patients with HbA1c <53 mmol/mol (<7%) at V3 Weight loss 5% at V2 Weight loss 5% at V3 HbA1c <53 mmol/mol (<7%) + weight loss 5% at V2 HbA1c <53 mmol/mol (<7%) + weight loss 5% at V3 HbA1c at individualized goal weight loss 5% at V2 HbA1c at individualized goal weight loss 5% at V3
Sequential Group (%) (n ¼ 174) 37.4 40.9 26.1 34.3 11.9 17.3 21.9 29.5
Simultaneous Group (%) (n ¼ 38) 60 47.6 45.5 70.6 29 23.5 38.7 47.1
p 0.015 0.634 0.035 0.007 0.023 0.511 0.066 0.168
V2 ¼ first visit after combination therapy; V3 ¼ final visit.
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Clinical Therapeutics observational studies.18e21,26 However, a small elevation in HDL-C has been reported in the literature.25 This apparent absence of effect on the combination therapy's lipid profile could be due to the addition of the SGLT2 inhibitor, which may neutralize the benefits observed with the GLP1RA alone.20 Contrary to clinical trials and previous studies,18e21 no significant changes in systolic and diastolic blood pressures were found in our study population. However, SGLT2 inhibitors have osmotic diuretic and natriuretic effects, which are associated with a small reduction in blood pressure. In addition, multiple pathways have been suggested for the effect of GLP1RAs on blood pressure, including vasodilation and natriuresis.18 These discrepancies may be explained by our study's retrospective design and the limited data regarding blood pressure values registered in the computer records, restricting the relevance of our findings. Levels of transaminases (aspartate aminotransferase, ALT, and gamma-glutamyl transferase) decreased significantly from baseline in the present study, as in other studies.29 NAFLD, a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease and is frequently associated with type 2 diabetes and obesity. SGLT2 inhibitors seem to have a variety of functions, including the amelioration of insulin resistance and anti-inflammatory and antioxidative effects.30 In a meta-analysis, the administration of GLP1RA substantially decreased the marker of hepatic inflammation (serum ALT), thus improving ultrasound imaging and reducing steatosis, inflammation, and fibrosis in liver biopsy samples. The combination of these 2 drugs is expected to substantially improve NAFLD in patients with type 2 diabetes, a clinically relevant result due to the fact that NAFLD has severe consequences for all previously mentioned aspects, in addition to its potential as a cardiovascular risk factor.7 The renal benefits of GP1RAs and SGLT2 inhibitors have clearly been individually established,12e15 but little is known about their combined effect on kidney disease. Several GLP1RA cardiovascular trials have noted a decrease in the risk of the prespecified composite renal outcome (progression to macroalbuminuria, doubling of serum creatinine, end-stage kidney disease, or kidney death). However, this effect was mainly due to a reduction in
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macroalbuminuria, rather than more clinically relevant renal end points.10,11,31 Findings from the analysis with SGLT2 inhibitors support the hypothesis that they have the potential to provide nephroprotection, perhaps via their direct effect on renal hypertension and hyperfiltration and on renal tubular inflammation and hypertrophy, as well as via indirect effects on glycemic control, weight, and reductions in systolic blood pressure, improved insulin sensitivity, and lowering of serum uric acid levels.28 Although the results from cardiovascular SGLT2 inhibitor trials have suggested a positive effect on diabetic kidney disease,12e15 the CREDENCE (Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation) study was the first trial primarily designed to evaluate the effects of SGLT2 inhibitors on patients with diabetes and chronic kidney disease. This trial showed that canagliflozin, added to optimal nephroprotective therapy, reduced the risk of the primary end point (composite of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular disease) by 30%, in addition to a significant reduction in albuminuria.32 Our results showed that after an initial decrease, GFR remained stable during the study period. As far as albuminuria is concerned, we detected significant changes during the study period, with an increase in the rate of normoalbuminuria and a decrease in microalbuminuria. The albuminuria data have not been related to blood pressure or antihypertensive medication due to the fact that this is a real-life practice study, and there was insufficient information regarding the blood pressure values of the patients recorded in medical records to draw any conclusions. In summary, a wide swath of evidence supports the idea of renal benefits using both an SGLT2 inhibitor and GLP1RA, and our results seem to be in agreement with published data. However, clinical trials with the combination treatment are needed to confirm these results. No clinical trial has previously been conducted, to the best of our knowledge, to determine whether different results are produced with sequential or simultaneous initiation of the SGLT2 inhibitor and GLP1RA combination. In our study, 38 patients initiated the combined treatment simultaneously, whereas 174 patients began sequentially. Our data suggest that co-initiation of a GLP1RA and SGLT2 inhibitor leads to faster weight loss and decrease in
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O. Díaz-Trastoy et al. HbA1c values than a sequential initiation of the drugs. A simultaneous start seems to lead to a higher proportion of patients with HbA1c <53 mmol/mol (<7%) and greater weight loss at the first visit, but, in the long term, these differences in metabolic control were not observed. In a prospective study with 113 patients in clinical practice, Carretero G omez et al23 analyzed 3 groups according to the sequential order of treatment (ie, the addition of a GLP1RA before an SGLT2 inhibitor, an SGLT2 inhibitor before a GLP1RA, or both agents initiated simultaneously). After 6 months, the greatest reduction in HbA1c levels and weight was observed in patients who had initiated both drugs simultaneously (P < 0.0001). The second greatest reduction was seen when GLP1RA was added to previous treatment with an SGLT2 inhibitor (P < 0.0001). Goncalves and Bell24 found that simultaneous initiation with combination therapy achieved a greater decrease in HbA1c levels than in the case of sequential initiation (75.9 mmol/mol [9.1%] to 54.1 mmol/mol [7.1%] and 73.8 mmol/ mol [8.9%] to 59.6 mmol/mol [7.6%], respectively). The group treated sequentially had been treated with a GLP1RA for a median of 141 weeks when the SGLT2 inhibitor was added to the therapy, thereby explaining the lower total HbA1creduction compared with that of the group which initiated the combination simultaneously. Total weight loss was comparable between groups, and a plateauing of the weight effect after ~1 year was observed, as the weight loss was similar at 62 and 217 weeks. Previous weight loss with a GLP1RA may make further weight reduction more difficult due to compensatory mechanisms, which tend to return body weight to its former steady state.18 In the present sample, the patients who initiated the combination therapy simultaneously had worse initial metabolic control, which may justify the choice of coinitiation of both drugs, although sequential combination was the most frequent option. It is well known that abrupt reductions in HbA1c levels can worsen microvascular complications, such as retinopathy or neuropathy. In clinical practice, the stepwise approach is the most common, introducing a new drug when the previous ones are not capable of maintaining adequate control, not only for
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economic reasons but also to achieve adequate adherence to treatment. Adverse events were analyzed from the beginning of the combined treatment until the end of the follow-up and were reported in 9.9% of the patients in our sample, although no serious adverse events were noted during the study. Therefore, the combination of an SGLT2 inhibitor with a GLP1RA seems to be effective and reasonably well tolerated (91% of patients had no adverse events). Similar results were seen in a randomized, double-blind, parallel-group, Phase IV Japanese trial evaluating the safety and effectiveness of empagliflozin added to liraglutide treatment.33 The main adverse events were genital mycotic infections and polyuria. No amputations, pancreatitis, or acute kidney injury events were reported. In addition, no cases of diabetic ketoacidosis were noted in our population, as was the case in the 3 main combination therapy trials.18,19,21 Overall, the safety findings were consistent with results of previous studies, and no new safety concerns were identified. In our cohort, 41% of patients were taking insulin, and no episodes of severe hypoglycemia were reported. The main limitations of this study include its retrospective and observational design. Furthermore, the lack of a comparative group did not allow for stronger conclusions to be drawn. Because there were no data on antihypertensive treatment received by patients before the combined treatment and during follow-up, causality cannot be associated between the improvement of albuminuria and exclusively antidiabetic treatment. However, our study also has certain strengths, such as the size of the sample, which included all the patients in the health area undertaking the combination therapy, thus avoiding the risk of inclusion bias, and the long follow-up period (16.4 months), greater than that of other studies. This analysis was a real-life clinical practice study, which makes the results easier to extrapolate to other scenarios compared with those of clinical trials.
CONCLUSIONS This study's findings support the effectiveness and safety of combination therapy with a GLP1RA and SGLT2 inhibitor in obese patients with inadequately controlled type 2 diabetes. This combination therapy
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Clinical Therapeutics improved metabolic parameters such as HbA1c levels and weight loss, with a low risk of hypoglycemia. A reduction in transaminase levels and improvement of renal parameters were also observed. These benefits were maintained over time and were independent of the years of evolution of diabetes. Although with the simultaneous initiation of both drugs, the effect was more intense at the beginning, the differences were equalized with time, showing that sequential initiation may also be effective. Our data provide real-world evidence and support the combined benefits of a GLP1RA and SGLT2 inhibitor in clinical practice.
CONFLICTS OF INTEREST ODT declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, Sanofi, RVT declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, Sanofi, Boehringer Ingelheim, Janssen. JMCA declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen and advisory board membership from Novo Nordisk. VML declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, Sanofi, Boehringer Ingelheim, AstraZeneca. RPG declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, AstraZeneca. AMS declares speaker’s bureau honoraria from Novo Nordisk.
ACKNOWLEDGMENTS The authors are grateful to Dr. Araújo Vilar for his collaboration in the study. Drs. Díaz-Trastoy and Sifontes-Dub on were responsible for conceptualization, methodology, investigation, and writing of the original draft; Dr. Villar-Taibo was responsible for conceptualization, methodology, formal analysis, investigation, writing of the original draft, and resources; and Drs. MozoPe~ nalver, Bernabeu-Mor on, Cabezas-Agrícola, Mu~ noz-Leira, Pein o-García, Martís-Sueiro, GarcíaL opez, and Martínez-Olmos were responsible for resources, and writing review and editing. No funding has been received for the study.
REFERENCES 1. De Block C. SGLT2 inhibitors and GLP-1 receptor agonists: a sound combination. Lancet Diabetes Endocrinol. 2018;6: 349e352. https://doi.org/10.1016/S2213-8587(18) 30031-7.
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2. Stein SA, Lamos EM, Davis SN. A review of the efficacy and safety of oral antidiabetic drugs. Expert Opin Drug Saf. 2013;12:153e175. https://doi.org/10.1517/ 14740338.2013.752813. 3. Kaul S. Mitigating cardiovascular risk in type 2 diabetes with antidiabetes drugs: a review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 Trials. Diabetes Care. 2017;40:821e831. https://doi.org/10.2337/dc17-0291. 4. Goncalves E, Bell DSH. Combination treatment of SGLT2 inhibitors and GLP-1 receptor agonists: symbiotic effects on metabolism and cardiorenal risk. Diabetes Ther. 2018;9: 919e926. https://doi.org/10.1007/s13300-018-0420-6. 5. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773e795. https:// doi.org/10.2337/db09-9028. 6. Chan WB. Clinical use of sodium-glucose co-transporter-2 inhibitors in Chinese patients with type 2 diabetes mellitus. Singapore Med J. 2019;60:309e313. https://doi.org/ 10.11622/smedj.2018139. 7. Doumas M, Imprialos K, Stavropoulos K, Reklou A, Sachinidis A, Athyros VG. Combination of SGLT-2 inhibitors and GLP-1 receptor agonists: potential benefits in surrogate and hard endpoints. Curr Pharm Des. 2018;24: 1879. https://doi.org/10.2174/ 1381612824666180604113653. 8. Packer M. Should we be combining GLP-1 receptor agonists and SGLT2 inhibitors in treating diabetes? Am J Med. 2018;131:461e463. https://doi.org/10.1016/ j.amjmed.2017.11.052. 9. Gorgojo-Martínez JJ. Nuevos f armacos para la reducci on del riesgo cardiovascular en pacientes con diabetes mellitus tipo 2. Hipertension y Riesgo Vasc. 2019;36:145e161. https:// doi.org/10.1016/j.hipert.2019.03.005. 10. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311e322. https://doi.org/10.1056/ NEJMoa1603827. 11. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834e1844. https://doi.org/ 10.1056/NEJMoa1607141. 12. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019 Jul 13;394(10193): 121e130. https://doi.org/10.1016/S0140-6736(19) 31149-3. 13. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117e2128. https://doi.org/ 10.1056/NEJMoa1504720.
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O. Díaz-Trastoy et al. 14. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644e657. https://doi.org/ 10.1056/NEJMoa1611925. 15. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347e357. https:// doi.org/10.1056/NEJMoa1812389. 16. Memoria. Sistema Público de Saúde de Galicia (electronic publication). Edici on; 2018. https://www.sergas. es/A-nosa-organizacion/Documents/ 832/MemoriaActividade2018.pdf. Accessed April 3, 2018. 17. Glycemic targets: standards of medical care in diabetesd2019. Diabetes Care. 2019;42(Supplement 1):S61eS70. https://doi.org/ 10.2337/dc19-S006. 18. Frías JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4:1004 e1016. https://doi.org/10.1016/ S2213-8587(16)30267-4. 19. Ludvik B, Frías JP, Tinahones FJ, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebocontrolled trial. Lancet Diabetes Endocrinol. 2018;6:370e381. https:// doi.org/10.1016/S2213-8587(18) 30023-8. 20. Fulcher G, Matthews DR, Perkovic V, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic
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dapagliflozin therapy added to a GLP1 receptor agonist in patients with type 2 diabetes. Nutr Metab Cardiovasc Dis. 2017;27:129e137. https://doi.org/10.1016/ j.numecd.2016.11.007. Harashima S, Inagaki N, Kondo K, et al. Efficacy and safety of canagliflozin as add-on therapy to a glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: a 52-week, open-label, phase IV study. Diabetes Obes Metab. 2018;20:1770e1775. https://doi.org/10.1111/ dom.13267. Pratley RE, Cersosimo E. Use of canagliflozin in combination with and compared to incretin-based therapies in type 2 diabetes. Clin Diabetes. 2017;35:141e153. https:// doi:10.2337/cd16-0063. Seino Y, Yabe D, Sasaki T, et al. Sodium-glucose cotransporter-2 inhibitor luseogliflozin added to glucagon-like peptide 1 receptor agonist liraglutide improves glycemic control with bodyweight and fat mass reductions in Japanese patients with type 2 diabetes: a 52-week, open-label, single-arm study. J Diabetes Invest. 2018;9:332e340. https://doi.org/ 10.1111/jdi.12694. Sumida Y, Seko Y, Yoneda M, NAFLD (JSG-NAFLD) JSG. Novel antidiabetic medications for non-alcoholic fatty liver disease with type 2 diabetes mellitus. Hepatol Res. 2017;47:266 e280. https://doi.org/10.1111/ hepr.12856. Muskiet M, Wheeler D, Heerspink H. New pharmacological strategies for protecting kidney function in type 2 diabetes. Lancet Diabetes Endocrinol. 2019;7:397e412. https://doi.org/ 10.1016/S2213-8587(18)30263-8. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in
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Address for correspondence: Rocío Villar-Taibo, MD, PhD, Complejo Hospitalario Universitario de Santiago, Rúa Choupana s/n, 15706, Santiago de Compostela, Spain. E-mail: [email protected]
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GLP1 receptor agonist and SGLT2 inhibitor combination: An effective approach in real-life clinical practice Olaia Díaz-Trastoy, MD1; Rocío Villar-Taibo, MD, PhD2; Mildred Sifontes-Dub on, MD3; Hector Mozo-Pe~ nalver, PharmD4; Ignacio Bernabeu-Mor on, MD, PhD2; Jose M. Cabezas-Agrícola, MD2; Virginia Mu~ noz-Leira, MD2; Roberto Pein o-García, MD, PhD2; Aurelio Martís-Sueiro, MD2; Jose M. García-L opez, MD, PhD2; and Miguel A. Martínez-Olmos, MD, PhD2 1
Endocrinology and Nutrition Department, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain; 2Endocrinology and Nutrition Department, Complejo Hospitalario Universitario de Santiago de Compostela, A Coru~na, Spain; 3Clinical Nutrition and Dietetics Unit, Endocrinology and Nutrition Department, Hospital General Mateu Orfila, Menorca, Spain; and 4Hospital Pharmacy Department, Hospital da Barbanza, Ribeira, Spain ABSTRACT Purpose: The aim of this study was to evaluate the effectiveness and safety of combination therapy with a sodium-glucose cotransporter-2 (SGLT2) inhibitor and a glucagon-like peptide-1 receptor agonist (GLP1RA) in patients with inadequately controlled type 2 diabetes. Methods: A retrospective search of electronic prescriptions of patients undergoing GLP1RA and SGLT2 inhibitor combination therapy was conducted. Once the patients had been identified, demographic data, blood and urine analyses (glycosylated hemoglobin [HbA1c], glucose, renal function, albuminuria, lipid profile, liver enzymes, and uric acid), physical examination (weight, body mass index, and blood pressure), and adverse effects were obtained from their electronic clinical records according to each of the following 3 periods: before the initiation of the combination, the first visit after initiation, and the last available visit. The influence of the duration of diabetes and the drug combination sequence on the effectiveness of the treatment was also analyzed. Statistical analysis was performed with SPSS version 21.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). Quantitative variables are presented as mean and SD and were compared by using the Student t test, one-way ANOVA, or repeated measures ANOVA with
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Bonferroni correction. Categorical variables are expressed as percentages and were compared by using the c2 test. Results: A total of 212 patients were included, with women accounting for 52.4%. The mean age (SD) of the population was 61.5 (9.6) years. A significant reduction in HbA1c (−12 mmol/mol [e1.1%]) was observed with combined therapy (P < 0.001). The target of HbA1c <53 mmol/mol (<7%) was achieved in 42% of the participants. Mean weight loss was −3.5 kg, and almost 40% of the patients attained the weight loss goal of 5% (P < 0.001 in all analyses). Transaminase levels and renal parameters also improved. These benefits persisted over time and bore no relation to the evolution of diabetes. Simultaneous initiation of a combination of a GLP1RA and SGLT2 inhibitor led to faster weight loss and a greater decrease in HbA1c than when they are used sequentially; however, the long-term benefits in terms of metabolic control were similar. Adverse events were rare, and a tendency for a reduced insulin dose was observed. Implications: The findings of this study reveal the combined benefits of a GLP1RA and SGLT2 Accepted for publication December 30, 2019 https://doi.org/10.1016/j.clinthera.2019.12.012 0149-2918/$ - see front matter © 2020 Elsevier Inc. All rights reserved.
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Clinical Therapeutics inhibitor in real-life clinical practice. In general, the combined treatment was well tolerated, and few adverse events were detected. (Clin Ther. xxxx;xxx:xxx) © 2020 Elsevier Inc. All rights reserved. Key words: GLP1 receptor agonist, SGLT-2 inhibitor, type 2 diabetes, clinical practice.
INTRODUCTION Management of type 2 diabetes has evolved from a glucocentric to a cardiometabolic approach. This new attitude toward type 2 diabetes treatment seeks a decrease in glycosylated hemoglobin (HbA1c) levels, which should be accompanied by an improvement in other risk factors (eg, weight or blood pressure), with a low rate of hypoglycemia and a reduction in cardiovascular morbidity and mortality.1 Classical antidiabetic medications, such as secretagogues, glitazones, and even insulin, can be associated with considerable weight gain or a high risk of hypoglycemia.2 On the contrary, glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodiumglucose cotransporter-2 (SGLT2) inhibitors have become more suitable due to their beneficial effects: weight loss, decreased blood pressure, low risk of hypoglycemia, and their relevant cardiorenal protection.3 GLP1RAs and SGLT2 inhibitors have different mechanisms of action, and their effects are additive. They therefore seem to be an ideal duo for combination therapy.4 GLP1RAs enhance insulin secretion, inhibit glucagon secretion, reduce hepatic glucose production, suppress appetite due to a central effect, and promote weight loss, enhancing peripheral insulin sensitivity. SGLT2 inhibitors inhibit renal glucose reabsorption, improving glucotoxicity and insulin sensitivity and increasing beta-cell function. They also cause weight loss, increasing the excretion of calories in urine. However, the effect of an SGLT2 inhibitor on appetite remains unclear; both an increase in calorie intake and a decrease in appetite are described in the literature.5,6 GLP1RAs and SGLT2 inhibitors both reduce visceral fat. Researchers have found that treatment of type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) with SGLT2 inhibitors and GLP1RAs substantially decreases the marker of hepatic inflammation (serum alanine aminotransferase
2
[ALT]), improving ultrasound imaging and reducing steatosis, inflammation, and fibrosis in liver biopsy samples.7 Regarding blood pressure, SGLT2 inhibitors induce natriuresis, favoring a reduction in intravascular volume, thus leading to a decrease in blood pressure. GLP1RAs can contribute to this effect with vasodilation and mild natriuresis.8 Furthermore, the effects of both drugs on cardiac and renal disease are highly relevant. On the one hand, GLP1RAs have a cardioprotective effect at the level of the smooth vascular muscle cells of the coronary arteries, the stimulation of which induces vasodilation, anti-inflammatory and antioxidant effects, increased endothelial function, inhibition of smooth muscle proliferation, stabilization of atheroma plaque, and greater tolerance to ischemia.9 All of these factors can explain their cardioprotection and the reduction in myocardial infarction, stroke, and cardiovascular mortality observed in the LEADER (Liraglutide Effect and Action in Diabetes), SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes), and REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) studies.10e13 Several hypotheses attempt to explain cardioprotection with SGLT2 inhibitors: metabolic effects with a reduction in cardiovascular risk factors such as glucotoxicity, perivisceral fat, or uric acid; and hemodynamic effects (osmotic diuresis reduces preload [volemia] and afterload and improves tubuloglomerular balance). Reducing preload decreases myocardial wall tension and can potentially contribute to reducing the risk of ventricular arrhythmias. Hemoconcentration caused by the SGLT2 inhibitor increases hematocrit, which can facilitate the release of oxygen to ischemic tissues. These drugs directly affect the myocardium due to increased plasma levels of betahydroxybutyrate (a source of energy for the diseased myocardium). Finally, there is a direct inhibitory effect on sodium-hydrogen exchanger type 1 of the myocardium, inhibition of cardiac fibrosis, and reduction of proinflammatory adipokines derived from epicardial and perivascular fat.9 This cardiovascular improvement was observed in the EMPA-REG OUTCOME, CANVAS (Canagliflozin Cardiovascular Assessment Study), and DECLARE (Dapagliflozin Effect on Cardiovascular Events) trials and may be additive to the benefit of GLP1RAs.13e15
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O. Díaz-Trastoy et al. The aim of the present study was to investigate the usefulness of the GP1RA/SGLT2 inhibitor combination therapy in our area, evaluating its effectiveness and safety in a real-life practice setting.
PATIENTS AND METHODS This retrospective study was performed in the health care area of Santiago de Compostela (Galicia, Spain), with a total population of 446,798 patients.16 In May 2018, we completed a retrospective search of the electronic prescriptions of the patients in our health area (comprising primary, specialized, and sociosanitary care) with the aim of identifying individuals with type 2 diabetes receiving combination therapy with a GLP1RA (liraglutide, dulaglutide, exenatide, exenatide long-acting release, or lixisenatide) and an SGLT2 inhibitor (dapagliflozin, empagliflozin, or canagliflozin). The hospital's Ethics and Clinical Research Committee approved the study protocol, and patient anonymity was preserved. We identified 212 patients receiving this treatment, and the clinical records of each case were reviewed. According to reimbursement restrictions by the Spanish public health system, all patients treated with a GLP1RA had a body mass index >30 kg/m2 before initiating this therapy. Three clinical visits were selected to evaluate their evolution: the visit before initiating the combination of a GLP1RA and SGLT2 inhibitor (V1), the first visit after starting the therapy (V2), and the last available visit (V3). Study parameters included baseline demographic variables (age, sex, duration of diabetes, and macrovascular and microvascular complications registered on the clinical record and concurrent use of antidiabetic therapies). The characteristics of the combination therapy were also registered, including the type of GLP1RA and SGLT2 inhibitor, the combination sequence, and the prescribing physician. At each visit, certain clinical and analytical variables were recorded: weight, body mass index, blood pressure, basal glycemia, HbA1c value, uric acid, lipid profile (total cholesterol, LDL, HDL, and triglycerides), liver enzymes (aspartate aminotransferase, ALT, gamma-glutamyl transferase, and alkaline phosphatase), and renal parameters (creatinine, glomerular filtration rate [GFR], and albuminuria). We also recorded whether the patients met the HbA1c goal considered appropriate by their physician according to the recommendations of the
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American Diabetes Association.17 Changes in diabetes therapy and adverse events during follow-up were also enumerated. The primary outcome was evaluation of the effectiveness of the combination therapy in terms of glycemic control (reduction in HbA1c level and percentage of patients with HbA1c on target), weight loss (defining relevant weight loss as 5%), and renal benefit (changes in albuminuria). Secondary outcomes included the safety assessment (frequency of adverse events), variation of the type 2 diabetes treatment (the need for new antidiabetic drugs and changes in insulin dose), and the effect on other analytical parameters (lipid profile, liver enzymes, and uric acid) or on blood pressure. Finally, we attempted to determine the influence of long versus short duration of diabetes on the effectiveness of the treatment and the differences in results according to the drug combination sequence. Statistical analysis was performed with SPSS version 21.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). Quantitative variables are presented as mean and SD and were compared by using the Student t test, one-way ANOVA, or repeated measures ANOVA with Bonferroni correction. Categorical variables are expressed as percentages and were compared by using the c2 test. A p value <0.05 was considered statistically significant.
RESULTS Epidemiologic Characteristics of the Sample The baseline (V1) demographic parameters and the background of diabetic drugs are described in Table I. Of the 87 patients treated with insulin, 58 received only basal insulin (66.6%), 16 were on a basal bolus regimen (18.3%), 9 received mixed insulins (10.3%), and 4 received basal and mixed insulins (4.5%). The mean (SD) insulin dose before starting the combination treatment with a GLP1RA and SGT2 inhibitor was 59.3 (38.7) IU. The combination sequence and the frequency of use of any individual drug are also described in Table I. The combination therapy was prescribed in 81.1% of the cases by endocrinologists, followed by primary care physicians (16.5%) and internists (2.4%).
Follow-up and Patients' Evolution For the first follow-up visit (V2), we registered a mean of 5.5 (2.6) months after initiating combination
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Clinical Therapeutics
Table I.
Epidemiologic characteristics of the patients and their treatments. Values are given as mean (SD) unless otherwise indicated.
Characteristic Age, y Female sex Duration of diabetes, y Hypertension Diabetes complications Retinopathy Nephropathy Peripheral neuropathy Autonomic neuropathy Cardiovascular disease Cerebrovascular disease Heart failure Pulmonary edema Use of concomitant diabetes drugs Metformin Sulfonylureas DPP-4 inhibitors Pioglitazone Repaglinide Insulin Combination sequence First drug SGTL2 inhibitor and second drug GLP1RA First drug GLP1RA and second drug SGLT2 inhibitor Simultaneous addition Type of SGLT2 inhibitor Dapagliflozin Empagliflozin Canagliflozin Type of GLP1RA Dulaglutide Liraglutide Exenatide LAR Lixisenatide
Value 61.5 (9.6) 52.4% 12.3 (7.0) 51.1% 14.6% 10.4% 3.3% 1.9% 11.8% 1.4% 0.5% 0.9% 184 (86.8%) 23 (10.8%) 4 (1.9%) 2 (0.9%) 2 (0.9%) 87 (41%) 85 (40.0%) 89 (41.9%) 38 (17.9%) 97 (45.8%) 76 (35.8%) 39 (18.4%) 111 (52.4%) 57 (26.9%) 36 (17%) 8 (3.8%)
DDP-4 ¼ dipeptidyl peptidase-4; GLP1RA ¼ glucagonlike peptide-1 receptor agonist; LAR ¼ longacting release; SGLT2 ¼ sodium-glucose cotransporter-2.
4
therapy. The final visit (V3) was performed after 16.4 (6.5) months. The evolution of the patients' anthropometric and metabolic outcomes is summarized in Table II. Figure 1 shows the percentage of our sample who reached the metabolic and weight loss objectives with the combination therapy. More than 70% of the patients achieved a level of HbA1c considered appropriate by their physicians at the time of the follow-up. The mean weight loss was −3.45% (3.75%) at V2 and e3.49% (5.22%) at V3. However, almost 40% of the patients attained the weight loss goal of 5% by the end of the study. Nearly one third of the patients exhibited an excellent response to the combination therapy, reaching the HbA1c and weight loss goals. The univariate analysis did not reveal any association between the desired response to the treatment and the patients' basal characteristics or their parameters at the initial visit. A slight nonsignificant reduction in insulin dose was observed at the end of the study, from 59.3 (38.7) IU at V1 to 54.9 (40.1) IU at V3 (p ¼ 0.341). Of the total sample, 188 patients (88%) did not need any new diabetes treatment. Only 19 patients (9%) required a new antidiabetic drug or insulin during the study period. In terms of renal parameters, serum creatinine levels remained stable during the study period (mean in V1, 61.9 [8.8] mmol/L; mean in V2, 61.9 [8.8] mmol/L; mean in V3, 61.9 [8.8] mmol/L [p¼1]). The mean GFR decreased from 89.4 (10.4) mL/min/1.73 m2 at V1 to 74.3 (12.1) mL/min/1.73 m2 at V2 (p ¼ 0.310). However, at V3, it had stabilized, with a mean value of 75.4 (17.1) mL/min/1.73 m2, and no significant change emerged in V1 (p ¼ 0.889) or V2 (p¼1). Data were available regarding albuminuria at baseline and during follow-up for 127 of the 212 patients. In this subset of patients with available data, significant differences were found with an increase in the rate of normoalbuminuria and a decrease in microalbuminuria (Figure 2). Several patients experienced relevant changes in their albuminuria status. Ten patients experienced progression: 7 progressed from normoalbuminuria to microalbuminuria, 1 patient from normoalbuminuria to macroalbuminuria, and 2 patients from microalbuminuria to macroalbuminuria. Conversely, 13 patients experienced regression: 10 regressed from
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O. Díaz-Trastoy et al. microalbuminuria to normoalbuminuria, 2 from macroalbuminuria to microalbuminuria, and 1 from macroalbuminuria to normoalbuminuria.
Adverse Events of the Combination Therapy The adverse events registered in the clinical records were infrequent and mild. Nineteen patients reported side effects with the combination therapy (8 genital infections, 2 urinary tract infections, 2 abdominal pain, 5 polyuria, 1 asthenia, and 1 reduction of GFR <30 mL/min/1.73 m2). No cases of ketoacidosis, fractures, or amputations were reported.
Duration of Diabetes: <10 Years Versus >10 Years
Duration was <10 years in 74 patients (40.8%) and >10 years in 107 patients (59.1%). Baseline characteristics differed between groups, with a lower
Table II.
age, less insulin use, a lower level of serum creatinine, higher total cholesterol, and a higher LDL level in the short-duration group. Despite these differences, the evolution and outcomes of the groups were comparable.
Initiation of the Combination Treatment: Sequential Versus Simultaneous Both groups of patients were comparable in all their baseline parameters, with the exception of basal serum glucose level and the use of insulin. Fasting glycemia was lower in the sequential group (9.6 [2.9] mmol/L) than in the simultaneous group (10.9 [3.1] mmol/L), with a p value close to statistical significance (p ¼ 0.053). The use of insulin was significantly higher in the sequential group than in the simultaneous group (45.4% vs 21.1%; p ¼ 0.06).
Evolution of anthropometric and metabolic parameters during follow-up. Results are expressed as mean (SD) (quantitative variables) and as percentages (qualitative variables).
Parameter
Initial Visit First Visit Precombination After Combination (V1) (V2)
Final Visit (V3)
V1 to V2, p V1 to V3, p
V2 to V3, p
Weight, kg BMI, kg/m2 SBP, mm Hg DBP, mm Hg Basal glycemia, mmol/L HbA1c, mmol/mol HbA1c, % % patients with HbA1c <53 mmol/mol (<7%) Uric acid, mmol/L Total cholesterol, mmol/L LDL-C, mmol/L HDL-C, mmol/L Triglycerides, mmol/L GGT, mkat/L ALT, mkat/L AST, mkat/L ALP, mkat/L
99.4 (18.4) 37.7 (8.1) 137.4 (17.9) 78.0 (9.2) 9.8 (3) 68.3 (13.1) 8.4 (1.2) 10.4
96.5 (17.3) 36.6 (7.6) 138.6 (13.6) 78.0 (8.5) 7.7 (2.1) 56.3 (9.8) 7.3 (0.9) 41.3
95.2 (18.4) 35.6 (7.5) 134.9 (13.6) 78.4 (12.0) 7.6 (1.7) 56.3 (9.8) 7.3 (0.9) 41.9
<0.001* <0.001* 0.99 0.662 <0.001* <0.001*
<0.001* <0.001* 0.97 0.420 <0.001* <0.001*
0.229 0.310 0.534 10,92 0.96 0.561
<0.001*
0.087
<0.001*
309.4 (88.3) 4.3 (0.9) 2.2 (0.7) 1.1 (0.3) 2.1 (1.1) 0.8 (0.9) 0.6 (0.4) 0.5 (0.3) 2.7 (0.9)
303.5 (125) 4.1 (0.9) 2.1 (0.6) 1.1 (0.4) 1.9 (0.9) 0.6 (0.7) 0.5 (0.2) 0.4 (0.2) 2.7 (0.9)
285.6 (89.3) 4.2 (0.8) 2.3 (0.6) 1 (0.3) 2 (1.3) 0.7 (0.8) 0.5 (0.2) 0.4 (0.2) 2.8 (0.9)
0.98 0.162 0.97 1.1 0.040* 0.003* <0.001* <0.001* 0.136
0.116 0.327 0.98 0.022* 0.087 0.016* <0.001* <0.001* 0.99
0.793 10.99 0.99 0.166 0.96 0.95 0.95 0.97 0.794
ALP ¼ alkaline phosphatase; ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; BMI ¼ body mass index; DBP ¼ diastolic blood pressure; GGT ¼ gamma-glutamyl transferase; HbA1c ¼ glycosylated hemoglobin; SBP ¼ systolic blood pressure; *¼ p <0.05
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Clinical Therapeutics
Figure 1. Percentage of patients who achieved the main goals of glycosylated hemoglobin and/or weight loss during the follow-up period. V2 ¼ first visit after combination therapy; V3 ¼ final visit.
During the study period, the achievement of the goals differed between groups (Table III). Simultaneous initiation seemed to achieve faster and better glycemic and weight control than sequential initiation (a higher proportion of patients with HbA1c values <53 mmol/mol [<7%] and/or weight loss >5%). However, at the end of follow-up, the differences regarding HbA1c values in both groups had disappeared. The rest of the parameters studied (analytical measurements, adverse events, renal outcomes, and the need for new antidiabetic therapies) were comparable between groups. We also analyzed the results in patients with sequential treatment according to the drug used second, the SGT2 inhibitor or the GLP1RA. At the end of the follow-up, no relevant differences were observed between groups.
DISCUSSION The findings of this retrospective real-life study in patients with type 2 diabetes support the combination of an SGLT2 inhibitor with a GLP1RA as an effective therapeutic option in clinical practice. Combination therapy has shown benefits in
6
metabolic parameters (a significant reduction in HbA1c values, fasting plasma glucose level, weight, and transaminase levels) and an improvement in renal outcomes, even in patients with a long duration of diabetes. The benefits of the combination of these 2 drugs have been shown in 3 randomized clinical trials and in several observational reports. The DURATION-8 (Efficacy and Safety of Once-Weekly Exenatide Plus Once-Daily Dapagliflozin vs Exenatide or Dapagliflozin Alone) trial studied the co-initiation of exenatide long-acting release and dapagliflozin, whereas AWARD-10 (Study of Dulaglutide [LY2189265] in Participants With Type 2 Diabetes Mellitus) and SUSTAIN-9 (SGLT-2i in Subjects With Type 2 Diabetes Mellitus) examined the addition of dulaglutide and semaglutide, respectively, to ongoing treatment with an SGLT2 inhibitor versus placebo. All of these studies found that combination therapy significantly reduced HbA1c level, weight, and systolic blood pressure, proving superior to either drug alone or to placebo. Furthermore, combination therapy achieved a higher proportion of patients with HbA1c values <53 mmol/mol (<7%) or a weight loss 5%. These results are in line with the results observed in other studies.18e24 In our real-world study, the metabolic results of the combination therapy were similar to those reported in the clinical trials, particularly the AWARD-10 trial. The HbA1c<53 mmol/mol (<7%) target was achieved in 42% of our patients, proving similar to the DURATION-8 result, and was slightly higher than in other studies.20 Nevertheless, taking into consideration the fact that the HbA1c<53 mmol/mol (<7%) goal is not valid for all patients and that it should be individualized, we also considered the level of HbA1cthe patients' physicians selected as appropriate during follow-up. More than 70% of our sample achieved their individualized HbA1ctargets with the combination therapy, thereby confirming its usefulness in terms of glycemic control. The mean weight loss in the current study was −3.5 kg, with almost 40% of the patients attaining the weight loss goal of 5% by the end of the study. This weight reduction was similar to that found in clinical trials18,19,21 and real-world studies.20,22,23,25e27 In their study, Goncalves and Bell24 reported greater weight loss (approximately −9.1% to −9.2%),
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O. Díaz-Trastoy et al.
Figure 2.
Evaluation of albuminuria during the study period.
independently of the simultaneous or sequential initiation of the combination therapy (−9.5 kg vs −10.3 kg, respectively). Some explanations for this greater weight loss could be this population's longer follow-up period, the use of maximum doses of the drugs, and the selection of liraglutide as the GLP1RA, which has a marked effect on weight loss compared with other GLP1RAs. As far as HbA1c values and weight loss goals (5%) are concerned, nearly one third of our patients exhibited an excellent response to the combination therapy. Similar data can be found in the literature supporting the combined use of a GLP1RA and SGLT2 inhibitor to achieve a good metabolic response in patients with diabetes and obesity.23,28
The benefits of the combination therapy were observed in patients with a short (<10 years) and a long (>10 years) evolution of their diabetes, including those treated with insulin. Therefore, the combination of a GLP1RA and SGLT2 inhibitor is an appropriate option even for patients with advanced type 2 diabetes (ie, a greater impairment of beta-cell function).20,29 Furthermore, with the combination therapy, a reduction in insulin needs may occur. At the end of the study, although it was not statistically significant, there was a tendency toward a reduction in insulin doses, in line with other studies, such as that conducted by Saroka et al.25 It is noteworthy that the combination therapy's main metabolic effects, in terms of reduction of weight, fasting plasma glucose, and HbA1c, were observed in the first visit after initiating combination therapy and remained stable until the final visit. This result supports the idea of the combined treatment's rapid and durable benefits, even with a mean follow-up time of 16.4 months (from the initiation of the combined treatment to the final registered visit), much longer than that of other studies and clinical trials. However, long-term clinical trials with dapagliflozin found some attenuation of HbA1creduction during follow-up, which may reflect progressive beta-cell failure.26 In terms of the patients' lipid profiles, no significant changes were found in LDL-C or HDL-C levels. Triglyceride levels had decreased by the first visit, but differences had disappeared at the end of the followup period. These results are consistent with those observed in Phase III clinical trials and some
Table III. Differences in achievement of goals between the sequential and simultaneous therapy groups. Study Group % of patients with HbA1c <53 mmol/mol (<7%) at V2 % of patients with HbA1c <53 mmol/mol (<7%) at V3 Weight loss 5% at V2 Weight loss 5% at V3 HbA1c <53 mmol/mol (<7%) + weight loss 5% at V2 HbA1c <53 mmol/mol (<7%) + weight loss 5% at V3 HbA1c at individualized goal weight loss 5% at V2 HbA1c at individualized goal weight loss 5% at V3
Sequential Group (%) (n ¼ 174) 37.4 40.9 26.1 34.3 11.9 17.3 21.9 29.5
Simultaneous Group (%) (n ¼ 38) 60 47.6 45.5 70.6 29 23.5 38.7 47.1
p 0.015 0.634 0.035 0.007 0.023 0.511 0.066 0.168
V2 ¼ first visit after combination therapy; V3 ¼ final visit.
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Clinical Therapeutics observational studies.18e21,26 However, a small elevation in HDL-C has been reported in the literature.25 This apparent absence of effect on the combination therapy's lipid profile could be due to the addition of the SGLT2 inhibitor, which may neutralize the benefits observed with the GLP1RA alone.20 Contrary to clinical trials and previous studies,18e21 no significant changes in systolic and diastolic blood pressures were found in our study population. However, SGLT2 inhibitors have osmotic diuretic and natriuretic effects, which are associated with a small reduction in blood pressure. In addition, multiple pathways have been suggested for the effect of GLP1RAs on blood pressure, including vasodilation and natriuresis.18 These discrepancies may be explained by our study's retrospective design and the limited data regarding blood pressure values registered in the computer records, restricting the relevance of our findings. Levels of transaminases (aspartate aminotransferase, ALT, and gamma-glutamyl transferase) decreased significantly from baseline in the present study, as in other studies.29 NAFLD, a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease and is frequently associated with type 2 diabetes and obesity. SGLT2 inhibitors seem to have a variety of functions, including the amelioration of insulin resistance and anti-inflammatory and antioxidative effects.30 In a meta-analysis, the administration of GLP1RA substantially decreased the marker of hepatic inflammation (serum ALT), thus improving ultrasound imaging and reducing steatosis, inflammation, and fibrosis in liver biopsy samples. The combination of these 2 drugs is expected to substantially improve NAFLD in patients with type 2 diabetes, a clinically relevant result due to the fact that NAFLD has severe consequences for all previously mentioned aspects, in addition to its potential as a cardiovascular risk factor.7 The renal benefits of GP1RAs and SGLT2 inhibitors have clearly been individually established,12e15 but little is known about their combined effect on kidney disease. Several GLP1RA cardiovascular trials have noted a decrease in the risk of the prespecified composite renal outcome (progression to macroalbuminuria, doubling of serum creatinine, end-stage kidney disease, or kidney death). However, this effect was mainly due to a reduction in
8
macroalbuminuria, rather than more clinically relevant renal end points.10,11,31 Findings from the analysis with SGLT2 inhibitors support the hypothesis that they have the potential to provide nephroprotection, perhaps via their direct effect on renal hypertension and hyperfiltration and on renal tubular inflammation and hypertrophy, as well as via indirect effects on glycemic control, weight, and reductions in systolic blood pressure, improved insulin sensitivity, and lowering of serum uric acid levels.28 Although the results from cardiovascular SGLT2 inhibitor trials have suggested a positive effect on diabetic kidney disease,12e15 the CREDENCE (Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation) study was the first trial primarily designed to evaluate the effects of SGLT2 inhibitors on patients with diabetes and chronic kidney disease. This trial showed that canagliflozin, added to optimal nephroprotective therapy, reduced the risk of the primary end point (composite of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular disease) by 30%, in addition to a significant reduction in albuminuria.32 Our results showed that after an initial decrease, GFR remained stable during the study period. As far as albuminuria is concerned, we detected significant changes during the study period, with an increase in the rate of normoalbuminuria and a decrease in microalbuminuria. The albuminuria data have not been related to blood pressure or antihypertensive medication due to the fact that this is a real-life practice study, and there was insufficient information regarding the blood pressure values of the patients recorded in medical records to draw any conclusions. In summary, a wide swath of evidence supports the idea of renal benefits using both an SGLT2 inhibitor and GLP1RA, and our results seem to be in agreement with published data. However, clinical trials with the combination treatment are needed to confirm these results. No clinical trial has previously been conducted, to the best of our knowledge, to determine whether different results are produced with sequential or simultaneous initiation of the SGLT2 inhibitor and GLP1RA combination. In our study, 38 patients initiated the combined treatment simultaneously, whereas 174 patients began sequentially. Our data suggest that co-initiation of a GLP1RA and SGLT2 inhibitor leads to faster weight loss and decrease in
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O. Díaz-Trastoy et al. HbA1c values than a sequential initiation of the drugs. A simultaneous start seems to lead to a higher proportion of patients with HbA1c <53 mmol/mol (<7%) and greater weight loss at the first visit, but, in the long term, these differences in metabolic control were not observed. In a prospective study with 113 patients in clinical practice, Carretero G omez et al23 analyzed 3 groups according to the sequential order of treatment (ie, the addition of a GLP1RA before an SGLT2 inhibitor, an SGLT2 inhibitor before a GLP1RA, or both agents initiated simultaneously). After 6 months, the greatest reduction in HbA1c levels and weight was observed in patients who had initiated both drugs simultaneously (P < 0.0001). The second greatest reduction was seen when GLP1RA was added to previous treatment with an SGLT2 inhibitor (P < 0.0001). Goncalves and Bell24 found that simultaneous initiation with combination therapy achieved a greater decrease in HbA1c levels than in the case of sequential initiation (75.9 mmol/mol [9.1%] to 54.1 mmol/mol [7.1%] and 73.8 mmol/ mol [8.9%] to 59.6 mmol/mol [7.6%], respectively). The group treated sequentially had been treated with a GLP1RA for a median of 141 weeks when the SGLT2 inhibitor was added to the therapy, thereby explaining the lower total HbA1creduction compared with that of the group which initiated the combination simultaneously. Total weight loss was comparable between groups, and a plateauing of the weight effect after ~1 year was observed, as the weight loss was similar at 62 and 217 weeks. Previous weight loss with a GLP1RA may make further weight reduction more difficult due to compensatory mechanisms, which tend to return body weight to its former steady state.18 In the present sample, the patients who initiated the combination therapy simultaneously had worse initial metabolic control, which may justify the choice of coinitiation of both drugs, although sequential combination was the most frequent option. It is well known that abrupt reductions in HbA1c levels can worsen microvascular complications, such as retinopathy or neuropathy. In clinical practice, the stepwise approach is the most common, introducing a new drug when the previous ones are not capable of maintaining adequate control, not only for
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economic reasons but also to achieve adequate adherence to treatment. Adverse events were analyzed from the beginning of the combined treatment until the end of the follow-up and were reported in 9.9% of the patients in our sample, although no serious adverse events were noted during the study. Therefore, the combination of an SGLT2 inhibitor with a GLP1RA seems to be effective and reasonably well tolerated (91% of patients had no adverse events). Similar results were seen in a randomized, double-blind, parallel-group, Phase IV Japanese trial evaluating the safety and effectiveness of empagliflozin added to liraglutide treatment.33 The main adverse events were genital mycotic infections and polyuria. No amputations, pancreatitis, or acute kidney injury events were reported. In addition, no cases of diabetic ketoacidosis were noted in our population, as was the case in the 3 main combination therapy trials.18,19,21 Overall, the safety findings were consistent with results of previous studies, and no new safety concerns were identified. In our cohort, 41% of patients were taking insulin, and no episodes of severe hypoglycemia were reported. The main limitations of this study include its retrospective and observational design. Furthermore, the lack of a comparative group did not allow for stronger conclusions to be drawn. Because there were no data on antihypertensive treatment received by patients before the combined treatment and during follow-up, causality cannot be associated between the improvement of albuminuria and exclusively antidiabetic treatment. However, our study also has certain strengths, such as the size of the sample, which included all the patients in the health area undertaking the combination therapy, thus avoiding the risk of inclusion bias, and the long follow-up period (16.4 months), greater than that of other studies. This analysis was a real-life clinical practice study, which makes the results easier to extrapolate to other scenarios compared with those of clinical trials.
CONCLUSIONS This study's findings support the effectiveness and safety of combination therapy with a GLP1RA and SGLT2 inhibitor in obese patients with inadequately controlled type 2 diabetes. This combination therapy
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Clinical Therapeutics improved metabolic parameters such as HbA1c levels and weight loss, with a low risk of hypoglycemia. A reduction in transaminase levels and improvement of renal parameters were also observed. These benefits were maintained over time and were independent of the years of evolution of diabetes. Although with the simultaneous initiation of both drugs, the effect was more intense at the beginning, the differences were equalized with time, showing that sequential initiation may also be effective. Our data provide real-world evidence and support the combined benefits of a GLP1RA and SGLT2 inhibitor in clinical practice.
CONFLICTS OF INTEREST ODT declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, Sanofi, RVT declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, Sanofi, Boehringer Ingelheim, Janssen. JMCA declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen and advisory board membership from Novo Nordisk. VML declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, Sanofi, Boehringer Ingelheim, AstraZeneca. RPG declares speaker’s bureau honoraria from Eli Lilly, Novo Nordisk, AstraZeneca. AMS declares speaker’s bureau honoraria from Novo Nordisk.
ACKNOWLEDGMENTS The authors are grateful to Dr. Araújo Vilar for his collaboration in the study. Drs. Díaz-Trastoy and Sifontes-Dub on were responsible for conceptualization, methodology, investigation, and writing of the original draft; Dr. Villar-Taibo was responsible for conceptualization, methodology, formal analysis, investigation, writing of the original draft, and resources; and Drs. MozoPe~ nalver, Bernabeu-Mor on, Cabezas-Agrícola, Mu~ noz-Leira, Pein o-García, Martís-Sueiro, GarcíaL opez, and Martínez-Olmos were responsible for resources, and writing review and editing. No funding has been received for the study.
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Address for correspondence: Rocío Villar-Taibo, MD, PhD, Complejo Hospitalario Universitario de Santiago, Rúa Choupana s/n, 15706, Santiago de Compostela, Spain. E-mail: [email protected]
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