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Key Paper Evaluation
1.
Introduction
2.
Results from the paper
3.
Significance of the results
4.
Expert opinion
Combination therapy for patients with uncontrolled type 2 diabetes mellitus: adding empagliflozin to pioglitazone or pioglitazone plus metformin Evaluation of Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 2014;16:147-158
Thomas Blevins Texas Diabetes & Endocrinology, P.A, Austin, TX, USA
Introduction: For patients with type 2 diabetes mellitus (T2DM), there is a growing interest in sodium glucose co-transporter 2 (SGLT2) inhibitors, a class of glucose-lowering agents that act independently of insulin secretion and insulin action and also have a weight-lowering effect. Empagliflozin is an SGLT2 inhibitor that has been demonstrated to significantly reduce blood glucose levels and is well tolerated in patients with T2DM. Areas covered: Kovacs et al. have reported a randomized, placebo-controlled study of empagliflozin as add-on to pioglitazone or pioglitazone plus metformin in patients with T2DM. The study results are evaluated, and potential impact on clinical practice is considered. Expert opinion: The addition of empagliflozin to pioglitazone or pioglitazone plus metformin treatment may offer some advantages. Together, their complementary mechanisms of action result in significant reductions in glycated hemoglobin levels, weight, and blood pressure, with a low risk of hypoglycemia, but were associated with an increased risk of events consistent with genital mycotic infections. Keywords: combination therapy, empagliflozin, metformin, Phase III clinical trial, pioglitazone, SGLT2 inhibitors, type 2 diabetes mellitus Expert Opin. Drug Saf. [Early Online]
1.
Introduction
Kovacs et al. investigated the efficacy and safety of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin as add-on to pioglitazone or pioglitazone plus metformin in the EMPA-REG PIO TM study (NCT01210001) [1]. There has been significant interest in treating type 2 diabetes mellitus (T2DM) with the SGLT2 inhibitors, which work via a novel, insulin-independent mechanism of action [2]. Empagliflozin is a potent and selective SGLT2 inhibitor that reduces levels of glycated hemoglobin (HbA1c) as well as weight and blood pressure (BP). As with other members of the SGLT2 class, empagliflozin is generally well tolerated, with a risk of hypoglycemic events similar to that of placebo if used in monotherapy or in combination with other antihyperglycemic agents that by themselves do not 10.1517/14740338.2015.1020294 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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T. Blevins
Table 1. Changes in glucose control, weight, and blood pressure at week 24.
HbA1c, %
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FPG, mg/dl*
Weight, kg
SBP, mmHg
DBP, mmHg
Baseline Change from baseline Difference vs placebo (95%CI) p-value Baseline Change from baseline Difference vs placebo (95%CI) p-value Baseline Change from baseline Difference vs placebo (95%CI) p-value Baseline Change from baseline Difference vs placebo (95% CI) p-value Baseline Change from baseline Difference vs placebo (95% CI) p-value
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
8.2 ± 0.92 -0.11 ± 0.07
8.1 ± 0.89 -0.59 ± 0.07 -0.48 ± 0.09 (-0.66, -0.29) < 0.001 152.0 ± 3.0 -17.0 ± 2.6 -23.5 ± 3.7 (-30.8, -16.2) < 0.001 78.0 ± 19.1 -1.62 ± 0.21 -1.95 ± 0.30 (-2.55, -1.36) < 0.001 126.5 ± 13.7 -3.1 ± 0.9 -3.9 ± 1.2 (-6.23, -1.50) 0.001 77.2 ± 8.7 -1.5 ± 0.5 -1.8 ± 0.7 (-3.20, -0.36) 0.014
8.1 ± 0.82 -0.72 ± 0.07 -0.61 ± 0.09 (-0.79, -0.42) < 0.001 151.9 ± 2.9 -22.0 ± 2.6 -28.5 ± 3.7 (-35.7, -21.2) < 0.001 78.9 ± 19.9 -1.47 ± 0.21 -1.81 ± 0.30 (-2.41, -1.22) < 0.001 125.9 ± 13.9 -4.0 ± 0.8 -4.7 ± 1.2 (-7.08, -2.37) < 0.001 77.2 ± 8.0 -2.2 ± 0.5 -2.5 ± 0.7 (-3.92, -1.08) < 0.001
151.9 ± 3.1 6.5 ± 2.6
78.1 ± 20.1 0.34 ± 0.21
125.7 ± 12.1 0.7 ± 0.9
76.3 ± 8.7 0.3 ± 0.5
Baseline values are mean ± standard deviation. Changes from baseline at week 24 are adjusted mean ± standard error (analysis of covariance model, last observation carried forward). *FPG originally reported as mmol/L. DBP: Diastolic blood pressure; FPG: Fasting plasma glucose; HbA1c: Glycated hemoglobin; SBP: Systolic blood pressure.
increase the risk for hypoglycemia. Empagliflozin has an increased risk of genital mycotic infections [3]. Both metformin and pioglitazone are widely used therapies, having the advantage that neither is associated with an increased risk of hypoglycemia. Metformin is recommended as first-line therapy for hyperglycemia, but its glucose-lowering effects may not be sufficient alone, or sustained as T2DM progresses [4-6]. Pioglitazone reduces glucose levels primarily by increasing insulin sensitivity in muscle and is one of several options recommended for adding to metformin if additional glucose lowering is required [4,5]. Empagliflozin is a candidate for combination therapy with these agents due to its complementary mechanism of action, and no predicted increased risk of hypoglycemia [7]. 2.
Results from the paper
To assess the efficacy and safety of empagliflozin added to pioglitazone or pioglitazone plus metformin, Kovacs et al. performed a randomized, double-blind, placebo-controlled trial. Patients from eight countries were randomized to once-daily empagliflozin 10 mg (n = 165), empagliflozin 25 mg (n = 168), or placebo (n = 165) for 24 weeks, in addition to background therapy. Investigators enrolled 2
patients who had a baseline HbA1c of 7.0 -- 10.0%, inclusive, and were on a stable dose of pioglitazone (‡ 30 mg/d or maximum tolerated dose) or pioglitazone plus metformin (‡ 1500 mg/d or maximum tolerated dose). Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73 m2) were excluded. Randomization was stratified for baseline HbA1c, background therapy, and renal function, to ensure that these characteristics were evenly distributed. At baseline, 75.5% of all patients were on background pioglitazone plus metformin, and 24.5% were on pioglitazone alone. In the primary analysis, including all patients regardless of background therapy, empagliflozin 10 and 25 mg significantly lowered HbA1c compared with placebo (Table 1), and HbA1c reductions were similar in patients receiving pioglitazone alone or pioglitazone plus metformin (Figure 1). At week 24, 7.7% of patients in the placebo group versus 23.8 and 30.0% in the empagliflozin 10 and 25 mg groups, respectively, achieved HbA1c < 7%. Fasting plasma glucose was decreased in patients treated with empagliflozin and increased in those taking placebo (Table 1). Empagliflozin treatment significantly reduced weight compared with placebo (Table 1), and a higher proportion of patients exposed to empagliflozin achieved > 5% loss in weight (18.8 and 13.7% in the 10 and 25 mg groups versus
Expert Opin. Drug Saf. (2015) 14(5)
Combination therapy for patients with uncontrolled T2DM
0.2
All patients
Add-on to pio
Add-on to pio + met
Change in HbA1c, %
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0.0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2
Empagliflozin 10 mg
Placebo
Empagliflozin 25 mg
Figure 1. Changes in HbA1c after 24 weeks, by background antidiabetic therapy. Values shown are adjusted mean changes ± standard error. Analyses of sub-groups by background therapy were analyzed as part of a confirmatory sequence, and all empagliflozin groups had significant changes versus placebo. Baseline values and the number of patients in each subgroup were not reported. The analysis of all patients was undertaken using an analysis of covariance (ANCOVA) model including treatment, background therapy, and baseline estimated glomerular filtration rate (eGFR) as fixed effects and baseline HbA1c as a linear covariate. The analysis by sub-group of background therapy used an ANCOVA model including treatment and baseline eGFR as fixed effects and baseline HbA1c and background therapy as linear covariates. HbA1c: Glycated hemoglobin; met: Metformin; pio: Pioglitazone.
5.5% in the placebo group). Empagliflozin treatment also significantly lowered systolic and diastolic BP (Table 1). Compared with the placebo group, similar or lower percentages of patients treated with empagliflozin experienced adverse events (AEs) or discontinued due to AEs. Overall, hypoglycemia occurred at rates that were similarly low across all groups (1.2, 2.4, and 1.8% with empagliflozin 10 mg, 25 mg, and placebo, respectively). No instances of hypoglycemia were severe (requiring external assistance). Events consistent with urinary tract infections (UTIs) were observed in 17.0, 11.9, and 16.4% of patients in the empagliflozin 10 mg, 25 mg, and placebo groups, respectively. In 97% of cases, the event was graded as mild or moderate by the investigators (i.e., symptoms did not prevent patients from doing their usual activities). One patient each in the placebo and empagliflozin 10 mg groups experienced a severe event consistent with UTI that led to premature discontinuation. Events consistent with genital mycotic infections were reported in 8.5 and 3.6% of the empagliflozin 10 and 25 mg groups versus 2.4% of the placebo group. No patients prematurely discontinued treatment due to events consistent with genital mycotic infections. There was no increased incidence of AEs typically associated with pioglitazone in the patients receiving empagliflozin as add-on therapy versus those receiving placebo. For laboratory measurements, there were no significant changes from baseline in total cholesterol and low-density lipoprotein cholesterol (LDL-C) in the empagliflozin groups. However, an increase in high-density lipoprotein cholesterol (HDL-C) was observed in the empagliflozin 10 mg arm
(placebo-corrected mean change ± standard error [SE] 0.06 ± 0.02 mmol/l; p = 0.012). The placebo-corrected change in HDL-C in the empagliflozin 25 mg group was not statistically significant (mean ± SE 0.03 ± 0.02 mmol/l; p = 0.186). In the empagliflozin groups, there were small increases in hematocrit (mean ± standard deviation [SD] change from baseline, 2.1 ± 4.4, 2.6 ± 3.4, and -0.6 ± 3.6% with empagliflozin 10 and 25 mg, and placebo, respectively) and small decreases in uric acid. At baseline, the eGFR range for all treatment groups was 84.3 -- 87.4 ml/min/1.73 m2. Small decreases in eGFR were seen in the empagliflozin groups (mean ± SD change from baseline, 2.1 ± 14.4, -3.4 ± 15.6, and -0.5 ± 12.5 ml/min/1.73 m2 with empagliflozin 10 and 25 mg, and placebo, respectively). No significant changes in electrolyte levels were observed. 3.
Significance of the results
Kovacs et al. concluded that the addition of empagliflozin for individuals with T2DM who are on pioglitazone or pioglitazone plus metformin provided improved glycemic control without increased risk of hypoglycemia, and with the added benefits of weight loss and improvements in BP. The results in this treatment combination are consistent with previous findings of empagliflozin used as monotherapy and when added to metformin [7,8], and the AE profile also appeared consistent with previously reported studies. Empagliflozin add-on to pioglitazone or pioglitazone plus metformin was well tolerated in the study by Kovacs et al. The empagliflozin groups had a similar rate of events consistent with UTI to the placebo group, although the frequency
Expert Opin. Drug Saf. (2015) 14(5)
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T. Blevins
was higher than expected in all groups (including placebo). In other studies of empagliflozin, subjects with a history of events consistent with genital mycotic infections were more likely to develop such events [9]. As expected, empagliflozin treatment in the study by Kovacs et al. was associated with increased risk of events consistent with genital mycotic infections. No related discontinuations were observed, suggesting that this problem was effectively managed. The absence of an increase in pioglitazone-related AEs suggests empagliflozin does not affect these, but it should be noted that the patients here were a selected group who had been receiving stable doses of pioglitazone before the study. 4.
Expert opinion
These results demonstrate the efficacy and tolerability of this regimen, but what do they mean for patients in practice? For patients on stable pioglitazone (with or without metformin) who need additional glucose control, these results support the use of empagliflozin as add-on therapy. This strategy would allow patients to remain on a regimen of oral therapy and offer the possibility of weight loss. The vast majority of patients with T2DM are overweight, and treatment with many glucose-lowering agents such as insulin or pioglitazone may result in weight gain. During this trial, empagliflozin reduced weight by ~ 2 kg versus placebo, and significantly more patients achieved a loss of 5% of weight compared with placebo. Body composition analysis in patients receiving empagliflozin added to background metformin suggests that 90% of the weight reduction with empagliflozin is due to a loss of abdominal visceral adipose and abdominal subcutaneous adipose tissue [10]. The weight loss in the Kovacs study may have contributed to BP improvements seen with empagliflozin, although osmotic diuresis is thought to account for the majority of BP reductions [11]. Although the magnitude of systolic BP lowering is small, it may be attractive in patients who would benefit from a little extra BP reduction. Conversely, patients at risk of low BP (including those on diuretic medications) or orthostatic hypotension would likely be at greater risk with empagliflozin, although there were no events of volume depletion noted in the patients studied by Kovacs et al. The potential clinical impact of the effects of empagliflozin on serum lipids is unclear. There were no significant
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changes in LDL-C, and while the change in HDL-C in the empagliflozin 25 mg group was not significant, HDL-C did increase by ~ 2 mg/dl in the empagliflozin 10 mg group versus placebo--an extent consistent with changes reported in other empagliflozin studies [7,8]. The increase in HDL-C in the empagliflozin 10 mg group identified by Kovacs et al. is of interest; any potential clinical significance of lipid changes, or changes in other risk factors beyond glycemic control, is uncertain. Indeed, as yet, there are no data on macrovascular clinical outcomes for empagliflozin, but these endpoints will be evaluated in the ongoing EMPA-REG OUTCOMETM study (NCT01131676). Based on the Kovacs study, it may be reasonable to consider the option of adding empagliflozin to pioglitazone in patients likely to benefit from improvements in weight and BP, in addition to glycemic control. The empagliflozin combinations studied here--with pioglitazone or pioglitazone plus metformin--may also be of particular value in cases where a low risk of hypoglycemic events is a key driver of treatment decisions.
Declaration of interest The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The author received no direct compensation related to the development of the manuscript. Writing support was provided by Daniella A Babu, PhD of Envision Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. T Blevins reports clinical research support from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Merck, Sanofi, and Halozyme Therapeutics. He also serves on speaker bureaus for Boehringer Ingelheim, Eli Lilly, Sanofi, Merck, AstraZeneca, and Novo Nordisk, but has not been compensated for the authorship of this review. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Expert Opin. Drug Saf. (2015) 14(5)
Combination therapy for patients with uncontrolled T2DM
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Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Missouri Kansas City UMKC on 04/01/15 For personal use only.
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Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 2014;16:147-58 This paper presents the study of empagliflozin add-on therapy that is reviewed in the current discussion. Neumiller JJ. Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. Drugs Context 2014;3:212262 This is an excellent review of the mechanism of action and available clinical trial data on empagliflozin. Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 2014;16:984-93
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Affiliation Thomas Blevins MD Texas Diabetes & Endocrinology, P.A, 6500 N MoPac Expwy, Building III, Suite 200, Austin, TX 78731, USA Tel: +1 512 458 8400; E-mail:
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