Key Paper Evaluation
Dapagliflozin -- do we need it registered for type 2 diabetes? 1.
Introduction
2.
Dapagliflozin as add-on therapy to sitagliptin with or without metformin
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
3.
Expert opinion
Evaluation of Jabbour SA, Hardy E, Sugg J, Parikh S. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomised, double-blind, placebo-controlled study. Diabetes Care 2014;37:740-50
Sheila A Doggrell† & Rinku Tuli Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, Brisbane, Australia
Introduction: Inhibitors of the sodium--glucose co-transporter 2 (SGLT2) promote the excretion of glucose to reduce glycated hemoglobin (HbA1c) levels. Canagliflozin was the first SGLT2 inhibitor to be approved by the US FDA for use in the treatment of type 2 diabetes, and recently dapagliflozin has also been approved. Areas covered: We evaluated a recent Phase III clinical trial with dapagliflozin. Expert opinion: Dapagliflozin was studied as add-on therapy to sitagliptin with or without metformin, and was shown to lower HbA1c levels and body weight. The incidence of hypoglycaemia was low with dapagliflozin, but it did increase the incidence of urogenital infections. As no clear benefits have been identified for dapagliflozin over canagliflozin, which was the first gliflozin registered by the FDA, we do not fully understand why it was necessary to register dapagliflozin. Given that there are no completed cardiovascular/ clinical outcome studies with dapagliflozin, and therefore no evidence of beneficial effect, it also seems premature to be using it extensively or considering it as an alternative to the clinically proven metformin. Keywords: dapagliflozin, HbA1c, metformin, sodium glucose co-transporter 2 inhibitors, sitagliptin, type 2 diabetes Expert Opin. Pharmacother. (2014) 15(11):1631-1635
1.
Introduction
According to the World Health Organisation, 347 million people worldwide have diabetes and, of this diabetes, 90% is type 2. Over 3 million people die each year from diabetes, and 50% of subjects with diabetes die of cardiovascular disease (primarily heart disease and stroke). Subjects with prolonged diabetes are more likely to have neuropathy, diabetic retinopathy and kidney failure than their non-diabetic peers [1]. This mortality and morbidity occur despite having a range of medicines available to treat type 2 diabetes, including metformin, sulphonylureas, thiazolidinediones, incretins and injectable insulin. This suggests that new medicines are needed to be used alone or in combination with the presently available agents to reduce the effects of diabetes. Some recent physiological discoveries have opened up a new paradigm in the treatment of diabetes. The sodium--glucose co-transporters (SGLTs) control the transport of glucose across the intestinal epithelium and proximal kidney tubules (reviewed in [2]). SGLT2 in the kidney accounts for 90% of the re-absorption of glucose [2]. Inhibition of SGLT2 causes glucosuria, and ultimately a reduction in glycated hemoglobin (HbA1c) levels, which may be beneficial in the treatment 10.1517/14656566.2014.930438 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1631
S. A. Doggrell & R. Tuli
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
of type 2 diabetes [2]. Examples of SGLT2 inhibitors are canagliflozin and dapagliflozin, and both have been approved by the US FDA for treatment of type 2 diabetes. Canagliflozin was approved in March 2013 [3], and recently, dapagliflozin (Farxiga) has been approved (8 January, 2014 [4]). This evaluation is of a trial of dapagliflozin as add-on treatment to sitagliptin with or without metformin in subjects with type 2 diabetes, and confirms dapagliflozin decreases HbA1c levels.
2. Dapagliflozin as add-on therapy to sitagliptin with or without metformin
Methods and results The methods and results of the multicenter, randomised, double-blind, placebo-controlled, parallel-group, Phase III trial of dapagliflozin as add-on therapy to sitagliptin, with or without metformin [5] are combined and pre´cised in this section. The parallel groups were with or without metformin immediate release (‡ 1500 mg/day) bid with meals. Subjects with poor kidney function or high blood pressure were excluded. The 447 subjects enrolled had a mean age of ~ 55 years, there were slightly more males than females, and those enrolled were predominantly White (~ 74%). As sitagliptin monotherapy is restricted in European countries, the parallel groups were not matched for body weight. All subjects with type 2 diabetes were initially stabilised over 10 weeks on sitagliptin 100 mg/day, and then subsequently randomised to dapagliflozin 10 mg or placebo for 24 weeks with a further 24 weeks extension. The primary efficacy end point was change in HbA1c from baseline at 24 weeks. In the 221 subjects taking sitagliptin only (no metformin), baseline HbA1c was 8.0%, and this was reduced by 0.5% with dapagliflozin, whereas the placebo group gained 0.1%. In the 226 subjects taking sitagliptin and metformin, the baseline HbA1c was 7.9%, and this was reduced by 0.4% with dapagliflozin, with no change in the placebo group. These reductions in HbA1c with dapagliflozin were maintained after 48 weeks. One of the secondary end points was change in body weight. In subjects taking sitagliptin only, the baseline body weight was ~ 86 kg, and this decreased by 1.9 kg in the dapagliflozin group, compared to 0.1 kg in the placebo group. In the subjects taking sitagliptin and metformin, the baseline body weight was higher at 94 kg, probably because more of this population were White (88%) than in the population not taking metformin (59%). Body weight was reduced by 2.4 kg in the dapagliflozin group, compared to no change in the control group. These reductions in body weight with dapagliflozin were maintained after 48 weeks. Dapagliflozin caused small increases in total cholesterol (3.6%), low density lipoprotein cholesterol (3.6%) and high density lipoprotein cholesterol (4.6%), and a small decrease in triglycerides (1.9%) at 24 and 48 weeks. 2.1
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The incidence of many adverse effects (hypoglycaemia, hypotension/dehydration/hypovolaemia, kidney infection) was similar in the dapagliflozin and placebo groups. However, there was more renal impairment with dapagliflozin (3.6%) than in the placebo group (1.8%) due to a more decreased creatinine clearance with dapagliflozin. Vulvovaginitis/balanitis infection (signs, symptoms and events suggestive) was greater in the dapagliflozin group (24 weeks, 8.4%; 48 weeks, 9.8%) than in the placebo group (0.4% at 24 and 48 weeks). Most of the subjects (75%) who had these genital infections were women, with one women discontinuing dapagliflozin due to vulvovaginal mycotic infection. Urinary tract infections were diagnosed to a greater extent with dapagliflozin (24 weeks, 3.6%; 48 weeks, 5.8%) than placebo (1.3 and 3.5%). One event of prostate neoplasm and one of thyroid neoplasm were reported with dapagliflozin.
Discussion In their discussion, the authors point out that this is the first published study evaluating triple oral combination therapy that includes dapagliflozin, and demonstrates that dapagliflozin add-on reduces HbA1c and body weight [5]. The authors consider the small changes in lipids with dapagliflozin to have no clinical significance [5]. The authors do not give importance to the increased renal impairment in this study with dapagliflozin, as previous studies with dapagliflozin have not demonstrated this [5]. 2.2
3.
Expert opinion
Urogenital infections with gliflozins The increased glucose excretion with the SGLT2 inhibitors leads to increased urogenital infections with the gliflozins, in subjects with type 2 diabetes taking these inhibitors, and these are more common in women than men. Thus, a study combining 4545 subjects enrolled in Phase IIb/III studies showed a greater percentage of women (1.5, 5.8, 8.4 and 6.9%) were diagnosed with genital infections than men (0.3, 2.4, 2.8 and 2.7%) in all the placebo, dapagliflozin 2.5, 5 and 10 mg groups, respectively [6]. Additionally, recurrent infections occurred frequently in the dapagliflozin group (18.1%) rather than the placebo group (8.3%) [6]. Similar findings were observed with respect to urinary tract infections, which were more common in women (6.6, 5.8, 9.6 and 7.7%) than men (1.0, 1.4, 1.6 and 0.8%) in the placebo, dapagliflozin 2.5, 5 and 10 groups, respectively [7]. Canagliflozin is another SGLT2 inhibitor used in type 2 diabetes mellitus, which has shown to cause urogenital infections. Similar to dapagliflozin, the occurrence of incidence was higher in females than in males with canagliflozin [8]. As more urogenital adverse effects with the gliflozins (SGLT2 inhibitors) appear in women than men, the gliflozins may be preferred for use by men over women. 3.1
Expert Opin. Pharmacother. (2014) 15(11)
Dapagliflozin -- do we need it registered for type 2 diabetes?
Was the dapagliflozin add-on therapy to sitagliptin with or without metformin the most suitable trial?
3.2
It seems to us that the rationale for the add-on trial, discussed in this evaluation, is not fully justified, and the reasons for this are discussed below. Why would you use dapagliflozin prior to metformin?
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
3.2.1
In most countries, metformin is the first medication introduced for the treatment of type 2 diabetes. However, in the add-on study with dapagliflozin, all the 447 subjects with type 2 diabetes are taking sitagliptin, but only some of them (226) are taking metformin, and the reason why the other 221 subjects are not taking metformin is not given [5]. For metformin, improved cardiovascular outcomes were shown in the UK Prospective Diabetes Study 34 [9]. Clinical outcome studies with dapagliflozin have not been undertaken to date. Thus, it would seem preferential to us, to use the clinically proven metformin, prior to adding on dapagliflozin, and that dapagliflozin should only be considered in subjects with type 2 diabetes who are unable to take or tolerate metformin. Is sitagliptin generally accepted as add-on therapy to metformin?
3.2.2
When glycaemic control cannot be achieved with metformin alone, in subjects with type 2 diabetes, add-on oral treatment with the sulphonylureas is the classical treatment, but other add-on treatments have also been considered, for example, insulin. Thus, before considering whether dapagliflozin is an appropriate add-on therapy to sitagliptin and metformin, it seems to us that it is necessary to consider whether sitagliptin is an appropriate/best add-on therapy, when diabetes cannot be controlled with metformin alone. In a study comparing sitagliptin with the sulphonylurea glimepiride in subjects with type 2 diabetes inadequately controlled with metformin, HbA1c levels were lowered by 0.47% with sitagliptin and 0.54% with glimepiride [10]. There was less hypoglycaemia with sitagliptin than glimepiride, and a weight loss with sitagliptin versus a weight loss with glimepiride [10]. As no clinical outcomes have been published from this comparison, we cannot be sure that sitagliptin is superior to glimepiride as add-on therapy to metformin. However, the results from this comparison do suggest considering sitagliptin as an appropriate option for add-on therapy, compared to glimepiride, in subjects with type 2 diabetes not controlled with metformin. However, this does not establish sitagliptin as the best add-on therapy when type 2 diabetes is not controlled by metformin alone, as other add-ons may be better than sitagliptin or glimepiride, for example, insulin. Another approach to glycaemic control, when it cannot be controlled with metformin alone, is to add-on insulin. Thus, it is necessary to compare sitagliptin with insulin as add-on
treatment, before accepting sitagliptin as the best add-on treatment to metformin. This was not the finding of the EASIE (Evaluation of insulin glargine versus Sitagliptin in Insulin-naı¨ve patients) trial [11]. EASIE compared insulin glargine and sitagliptin in 515 subjects with type 2 diabetes, uncontrolled with metformin, and a baseline HbA1c of 8.5% [11]. HbA1c was reduced by 1.7% by insulin glargine, compared to 1.1% with sitagliptin [11]. The incidence of severe hypoglycaemia was low, and occurred in three subjects on insulin glargine and one on sitagliptin [11]. The authors of EASIE suggest that the achievement of better glycaemic control with insulin glargine than sitagliptin may lead to better outcomes [11], although this has not been tested. Without good evidence that sitagliptin is a good add-on therapy to metformin, it seems to us that it may be premature to be considering dapagliflozin as add-on therapy to sitagliptin and metformin in subjects with type 2 diabetes. Dapagliflozin as add-on therapy to sitagliptin and metformin
3.2.3
In the rationale for the study using dapagliflozin as add-on therapy to sitagliptin and metformin, the authors state that when two oral anti-diabetic medicines are not enough to control HbA1c levels, insulin is usually added [5]. However, they consider a third oral medication, for example, dapagliflozin, should be considered before introducing insulin [5]. As dapagliflozin has a different mechanism of action, it is not surprising that it reduces HbA1c in the presence of metformin and sitagliptin [5], but the additional effect was relatively modest, ~ 0.5%. A much more important question is whether the combination of metformin, sitagliptin and dapagliflozin is superior to metformin, sitagliptin and insulin in reducing HbA1c levels and clinical outcomes in subjects with type 2 diabetes, and this was not tested in the add-on study, and should be tested in the future. Dapagliflozin does not reduce HbA1c in subjects with impaired kidney function
3.3
In both of the studies evaluated here, subjects with type 2 diabetes and impaired kidney function were excluded. Thus, neither study considers whether dapagliflozin can be used in subjects with impaired kidney function. This is an important consideration, as kidney disease is very common in subjects with long-standing type 2 diabetes. In subjects with type 2 diabetes, improvements with SGLT2 inhibitors, such as dapagliflozin, will depend on the kidney’s ability to filter glucose. Recently, it has been shown that human plasma levels of dapagliflozin are incrementally increased with declining renal function, and the ability of dapagliflozin to increase the renal clearance of glucose is also reduced in renal impairment in subjects with type 2 diabetes [12]. Dapagliflozin has also been tested in 252 subjects with inadequately controlled type 2 diabetes, and moderate renal impairment, and shown not to significantly decrease HbA1c, compared to placebo [13].
Expert Opin. Pharmacother. (2014) 15(11)
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S. A. Doggrell & R. Tuli
Thus, dapagliflozin may not be suitable for long-term treatment in subjects with type 2 diabetes as it progresses and kidney impairment develops, and this requires testing.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
3.4
Do we need dapagliflozin registered for type 2 diabetes?
3.5
Clinical outcome studies
In their submission to the FDA about dapagliflozin, Bristol Myers Squibb included a meta-analysis of cardiovascular events in their clinical programme, in which only 37% of subjects had a history of cardiovascular disease (excluding hypertension) [14]. In this group, the cardiovascular events (cardiovascular death, stroke, myocardial infarction, hospitalisation of unstable angina) were low; 1.99% in the comparator group, compared to 1.64% per subject year in the dapagliflozin [14]. In our opinion, one of the major limitations to the studies to date with dapagliflozin is that no clinically beneficial outcomes (e.g., cardiovascular mortality or morbidity) have been undertaken in subjects at high cardiovascular risk. In approving dapagliflozin for use in the treatment of type 2 diabetes, the FDA asked for six post-marketing trials with dapagliflozin [14]. Only one of these is to investigate any beneficial effects of dapagliflozin, and this is a cardiovascular outcomes trial to evaluate the cardiovascular risk of dapagliflozin in subjects with high baseline risk of cardiovascular disease [15]. This multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58) is a Phase III trial recruiting high cardiovascular risk subjects with type 2 diabetes [15]. In this trial, dapagliflozin or placebo will be added to the subjects’ current anti-diabetes medicines, and the primary outcome measure is the composite of cardiovascular death, myocardial infarction or ischemic stroke in subjects with type 2 diabetes [15]. DECLARE-TIMI58 is due to be completed in April 2019 [15]. This suggests that dapagliflozin will be available for use for 5 years before its cardiovascular efficacy and safety are established. This seems inappropriate to us, and we would prefer anti-diabetic medicines to have established benefits on cardiovascular outcomes before approval from the FDA for wide use. The obvious precedent for this is rosiglitazone, which effectively lowers HbA1c, and
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was approved by the FDA, but has no benefit or may increase cardiovascular outcomes [16].
At the present time, several countries have two gliflozins approved for use. In the USA, canagliflozin was approved prior to dapagliflozin. In Europe and Australia, dapagliflozin was approved prior to canagliflozin. To our knowledge, there are no major differences between the pharmacology, efficacy and most of the adverse effects with these gliflozins. Pooled evidence suggests that there is not an increased incidence of bladder or breast cancers with canagliflozin, but this matter is unresolved for dapagliflozin. Thus, nine cases of bladder cancer and nine cases of breast cancer have occurred in 5000 subject-years of dapagliflozin use, and although this pooling does not have enough power to give significance, it does raise safety concerns about dapagliflozin [17]. No cases of bladder or breast cancer were observed in the relative small and short term of the studies we evaluated. Given that there is no present clinical outcome evidence (discussed in previous section) and unresolved safety issues for dapagliflozin, we are not sure why dapagliflozin has been approved by the FDA. It seems to us that drugs should be required to show significant differences to those already approved for use (for the FDA, this would be canagliflozin), that are beneficial in some subjects with type 2 diabetes, prior to approval.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organisation 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. Pharmacother. (2014) 15(11)
Dapagliflozin -- do we need it registered for type 2 diabetes?
Bibliography
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
WHO/Diabetes. Available from: http:// www.who.int/mediacentre/factsheets/ fs312/en/ [Last accessed 18 March 2014]
2.
Bakris GL, Fonseca VA, Sharma K, Wright EM. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int 2009;75:1272-7
3.
FDA news release: FDA approves Invokana to treat type 2 diabetes. Available from: http://www.fda.gov/ NewsEvents/Newsroom/ PressAnnouncements/ucm345848.htm [Accessed 31 March 2014]
4.
5.
.
FDA news release: FDA approves Farxiga to treat type 2 diabetes. Available from: http://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ ucm380829.htm [Accessed 31 March 2014] Jabbour SA, Hardy E, Sugg J, Parikh S. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicentre, randomized, double-blind, placebocontrolled study. Diabetes Care 2014;37:740-50 Evaluation of triple combination therapy of dapagliflozin, sitagliptin and metformin.
6.
Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013;27:479-84
7.
Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013;27:473-8
8.
Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:372-82
14.
Dapagliflozin (Forxiga): Summary of product characteristics. Bristol-Myers Squibb, Uxbridge, UK; 2014. Available from: http://www. medicines.org.uk/EMC/medicine/27188 [Accessed 31 March 2014]
9.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65
15.
10.
Arechevaleta R, Seck T, Chen Y, et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, not inferiority trial. Diabetes Obes Metab 2011;13:160-8
ClinicalTrials.gov Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). Available from: http://clinicaltrials.gov/ct2/show/ NCT01944618?term=dapagliflozin& rank=33 [Accessed 31 March 2014]
16.
Doggrell SA. Clinical trials with thiazolidinediones in subjects with type 2 diabetes -- is pioglitazone any different from rosiglitazone. Expert Opin Pharmacother 2008;9:405-20
17.
11.
Aschner P, Chan J, Owens DR, et al. Insulin glargine versus sitagliptin in insulin-naı¨ve patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial. Lancet 2012;379:2262-9
Vasilakou S, Karagiannis T, Athanasiadou E, et al. Sodium-glucose contransporter 2 inhibitors for type 2 diabetes; a systematic review and meta-analysis. Ann Intern Med 2013;159:262-74
Affiliation
12.
Kasichayanula S, Liu X, Pe Benito M, et al. The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol 2013;76:432-44
13.
Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014;85(4):962-71
Expert Opin. Pharmacother. (2014) 15(11)
Sheila A Doggrell†1 PhD DSc & Rinku Tuli2 PhD † Author for correspondence 1 Senior Lecturer, Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, GPO 2434, QLD 4002, Brisbane, Australia Tel: +61 7 3138 2015; Fax: +61 7 3138 1534; E-mail: [email protected] 2 Associate Lecturer, Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, GPO 2434, QLD 4002, Brisbane, Australia
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Dapagliflozin -- do we need it registered for type 2 diabetes? 1.
Introduction
2.
Dapagliflozin as add-on therapy to sitagliptin with or without metformin
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
3.
Expert opinion
Evaluation of Jabbour SA, Hardy E, Sugg J, Parikh S. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomised, double-blind, placebo-controlled study. Diabetes Care 2014;37:740-50
Sheila A Doggrell† & Rinku Tuli Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, Brisbane, Australia
Introduction: Inhibitors of the sodium--glucose co-transporter 2 (SGLT2) promote the excretion of glucose to reduce glycated hemoglobin (HbA1c) levels. Canagliflozin was the first SGLT2 inhibitor to be approved by the US FDA for use in the treatment of type 2 diabetes, and recently dapagliflozin has also been approved. Areas covered: We evaluated a recent Phase III clinical trial with dapagliflozin. Expert opinion: Dapagliflozin was studied as add-on therapy to sitagliptin with or without metformin, and was shown to lower HbA1c levels and body weight. The incidence of hypoglycaemia was low with dapagliflozin, but it did increase the incidence of urogenital infections. As no clear benefits have been identified for dapagliflozin over canagliflozin, which was the first gliflozin registered by the FDA, we do not fully understand why it was necessary to register dapagliflozin. Given that there are no completed cardiovascular/ clinical outcome studies with dapagliflozin, and therefore no evidence of beneficial effect, it also seems premature to be using it extensively or considering it as an alternative to the clinically proven metformin. Keywords: dapagliflozin, HbA1c, metformin, sodium glucose co-transporter 2 inhibitors, sitagliptin, type 2 diabetes Expert Opin. Pharmacother. (2014) 15(11):1631-1635
1.
Introduction
According to the World Health Organisation, 347 million people worldwide have diabetes and, of this diabetes, 90% is type 2. Over 3 million people die each year from diabetes, and 50% of subjects with diabetes die of cardiovascular disease (primarily heart disease and stroke). Subjects with prolonged diabetes are more likely to have neuropathy, diabetic retinopathy and kidney failure than their non-diabetic peers [1]. This mortality and morbidity occur despite having a range of medicines available to treat type 2 diabetes, including metformin, sulphonylureas, thiazolidinediones, incretins and injectable insulin. This suggests that new medicines are needed to be used alone or in combination with the presently available agents to reduce the effects of diabetes. Some recent physiological discoveries have opened up a new paradigm in the treatment of diabetes. The sodium--glucose co-transporters (SGLTs) control the transport of glucose across the intestinal epithelium and proximal kidney tubules (reviewed in [2]). SGLT2 in the kidney accounts for 90% of the re-absorption of glucose [2]. Inhibition of SGLT2 causes glucosuria, and ultimately a reduction in glycated hemoglobin (HbA1c) levels, which may be beneficial in the treatment 10.1517/14656566.2014.930438 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1631
S. A. Doggrell & R. Tuli
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
of type 2 diabetes [2]. Examples of SGLT2 inhibitors are canagliflozin and dapagliflozin, and both have been approved by the US FDA for treatment of type 2 diabetes. Canagliflozin was approved in March 2013 [3], and recently, dapagliflozin (Farxiga) has been approved (8 January, 2014 [4]). This evaluation is of a trial of dapagliflozin as add-on treatment to sitagliptin with or without metformin in subjects with type 2 diabetes, and confirms dapagliflozin decreases HbA1c levels.
2. Dapagliflozin as add-on therapy to sitagliptin with or without metformin
Methods and results The methods and results of the multicenter, randomised, double-blind, placebo-controlled, parallel-group, Phase III trial of dapagliflozin as add-on therapy to sitagliptin, with or without metformin [5] are combined and pre´cised in this section. The parallel groups were with or without metformin immediate release (‡ 1500 mg/day) bid with meals. Subjects with poor kidney function or high blood pressure were excluded. The 447 subjects enrolled had a mean age of ~ 55 years, there were slightly more males than females, and those enrolled were predominantly White (~ 74%). As sitagliptin monotherapy is restricted in European countries, the parallel groups were not matched for body weight. All subjects with type 2 diabetes were initially stabilised over 10 weeks on sitagliptin 100 mg/day, and then subsequently randomised to dapagliflozin 10 mg or placebo for 24 weeks with a further 24 weeks extension. The primary efficacy end point was change in HbA1c from baseline at 24 weeks. In the 221 subjects taking sitagliptin only (no metformin), baseline HbA1c was 8.0%, and this was reduced by 0.5% with dapagliflozin, whereas the placebo group gained 0.1%. In the 226 subjects taking sitagliptin and metformin, the baseline HbA1c was 7.9%, and this was reduced by 0.4% with dapagliflozin, with no change in the placebo group. These reductions in HbA1c with dapagliflozin were maintained after 48 weeks. One of the secondary end points was change in body weight. In subjects taking sitagliptin only, the baseline body weight was ~ 86 kg, and this decreased by 1.9 kg in the dapagliflozin group, compared to 0.1 kg in the placebo group. In the subjects taking sitagliptin and metformin, the baseline body weight was higher at 94 kg, probably because more of this population were White (88%) than in the population not taking metformin (59%). Body weight was reduced by 2.4 kg in the dapagliflozin group, compared to no change in the control group. These reductions in body weight with dapagliflozin were maintained after 48 weeks. Dapagliflozin caused small increases in total cholesterol (3.6%), low density lipoprotein cholesterol (3.6%) and high density lipoprotein cholesterol (4.6%), and a small decrease in triglycerides (1.9%) at 24 and 48 weeks. 2.1
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The incidence of many adverse effects (hypoglycaemia, hypotension/dehydration/hypovolaemia, kidney infection) was similar in the dapagliflozin and placebo groups. However, there was more renal impairment with dapagliflozin (3.6%) than in the placebo group (1.8%) due to a more decreased creatinine clearance with dapagliflozin. Vulvovaginitis/balanitis infection (signs, symptoms and events suggestive) was greater in the dapagliflozin group (24 weeks, 8.4%; 48 weeks, 9.8%) than in the placebo group (0.4% at 24 and 48 weeks). Most of the subjects (75%) who had these genital infections were women, with one women discontinuing dapagliflozin due to vulvovaginal mycotic infection. Urinary tract infections were diagnosed to a greater extent with dapagliflozin (24 weeks, 3.6%; 48 weeks, 5.8%) than placebo (1.3 and 3.5%). One event of prostate neoplasm and one of thyroid neoplasm were reported with dapagliflozin.
Discussion In their discussion, the authors point out that this is the first published study evaluating triple oral combination therapy that includes dapagliflozin, and demonstrates that dapagliflozin add-on reduces HbA1c and body weight [5]. The authors consider the small changes in lipids with dapagliflozin to have no clinical significance [5]. The authors do not give importance to the increased renal impairment in this study with dapagliflozin, as previous studies with dapagliflozin have not demonstrated this [5]. 2.2
3.
Expert opinion
Urogenital infections with gliflozins The increased glucose excretion with the SGLT2 inhibitors leads to increased urogenital infections with the gliflozins, in subjects with type 2 diabetes taking these inhibitors, and these are more common in women than men. Thus, a study combining 4545 subjects enrolled in Phase IIb/III studies showed a greater percentage of women (1.5, 5.8, 8.4 and 6.9%) were diagnosed with genital infections than men (0.3, 2.4, 2.8 and 2.7%) in all the placebo, dapagliflozin 2.5, 5 and 10 mg groups, respectively [6]. Additionally, recurrent infections occurred frequently in the dapagliflozin group (18.1%) rather than the placebo group (8.3%) [6]. Similar findings were observed with respect to urinary tract infections, which were more common in women (6.6, 5.8, 9.6 and 7.7%) than men (1.0, 1.4, 1.6 and 0.8%) in the placebo, dapagliflozin 2.5, 5 and 10 groups, respectively [7]. Canagliflozin is another SGLT2 inhibitor used in type 2 diabetes mellitus, which has shown to cause urogenital infections. Similar to dapagliflozin, the occurrence of incidence was higher in females than in males with canagliflozin [8]. As more urogenital adverse effects with the gliflozins (SGLT2 inhibitors) appear in women than men, the gliflozins may be preferred for use by men over women. 3.1
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Dapagliflozin -- do we need it registered for type 2 diabetes?
Was the dapagliflozin add-on therapy to sitagliptin with or without metformin the most suitable trial?
3.2
It seems to us that the rationale for the add-on trial, discussed in this evaluation, is not fully justified, and the reasons for this are discussed below. Why would you use dapagliflozin prior to metformin?
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3.2.1
In most countries, metformin is the first medication introduced for the treatment of type 2 diabetes. However, in the add-on study with dapagliflozin, all the 447 subjects with type 2 diabetes are taking sitagliptin, but only some of them (226) are taking metformin, and the reason why the other 221 subjects are not taking metformin is not given [5]. For metformin, improved cardiovascular outcomes were shown in the UK Prospective Diabetes Study 34 [9]. Clinical outcome studies with dapagliflozin have not been undertaken to date. Thus, it would seem preferential to us, to use the clinically proven metformin, prior to adding on dapagliflozin, and that dapagliflozin should only be considered in subjects with type 2 diabetes who are unable to take or tolerate metformin. Is sitagliptin generally accepted as add-on therapy to metformin?
3.2.2
When glycaemic control cannot be achieved with metformin alone, in subjects with type 2 diabetes, add-on oral treatment with the sulphonylureas is the classical treatment, but other add-on treatments have also been considered, for example, insulin. Thus, before considering whether dapagliflozin is an appropriate add-on therapy to sitagliptin and metformin, it seems to us that it is necessary to consider whether sitagliptin is an appropriate/best add-on therapy, when diabetes cannot be controlled with metformin alone. In a study comparing sitagliptin with the sulphonylurea glimepiride in subjects with type 2 diabetes inadequately controlled with metformin, HbA1c levels were lowered by 0.47% with sitagliptin and 0.54% with glimepiride [10]. There was less hypoglycaemia with sitagliptin than glimepiride, and a weight loss with sitagliptin versus a weight loss with glimepiride [10]. As no clinical outcomes have been published from this comparison, we cannot be sure that sitagliptin is superior to glimepiride as add-on therapy to metformin. However, the results from this comparison do suggest considering sitagliptin as an appropriate option for add-on therapy, compared to glimepiride, in subjects with type 2 diabetes not controlled with metformin. However, this does not establish sitagliptin as the best add-on therapy when type 2 diabetes is not controlled by metformin alone, as other add-ons may be better than sitagliptin or glimepiride, for example, insulin. Another approach to glycaemic control, when it cannot be controlled with metformin alone, is to add-on insulin. Thus, it is necessary to compare sitagliptin with insulin as add-on
treatment, before accepting sitagliptin as the best add-on treatment to metformin. This was not the finding of the EASIE (Evaluation of insulin glargine versus Sitagliptin in Insulin-naı¨ve patients) trial [11]. EASIE compared insulin glargine and sitagliptin in 515 subjects with type 2 diabetes, uncontrolled with metformin, and a baseline HbA1c of 8.5% [11]. HbA1c was reduced by 1.7% by insulin glargine, compared to 1.1% with sitagliptin [11]. The incidence of severe hypoglycaemia was low, and occurred in three subjects on insulin glargine and one on sitagliptin [11]. The authors of EASIE suggest that the achievement of better glycaemic control with insulin glargine than sitagliptin may lead to better outcomes [11], although this has not been tested. Without good evidence that sitagliptin is a good add-on therapy to metformin, it seems to us that it may be premature to be considering dapagliflozin as add-on therapy to sitagliptin and metformin in subjects with type 2 diabetes. Dapagliflozin as add-on therapy to sitagliptin and metformin
3.2.3
In the rationale for the study using dapagliflozin as add-on therapy to sitagliptin and metformin, the authors state that when two oral anti-diabetic medicines are not enough to control HbA1c levels, insulin is usually added [5]. However, they consider a third oral medication, for example, dapagliflozin, should be considered before introducing insulin [5]. As dapagliflozin has a different mechanism of action, it is not surprising that it reduces HbA1c in the presence of metformin and sitagliptin [5], but the additional effect was relatively modest, ~ 0.5%. A much more important question is whether the combination of metformin, sitagliptin and dapagliflozin is superior to metformin, sitagliptin and insulin in reducing HbA1c levels and clinical outcomes in subjects with type 2 diabetes, and this was not tested in the add-on study, and should be tested in the future. Dapagliflozin does not reduce HbA1c in subjects with impaired kidney function
3.3
In both of the studies evaluated here, subjects with type 2 diabetes and impaired kidney function were excluded. Thus, neither study considers whether dapagliflozin can be used in subjects with impaired kidney function. This is an important consideration, as kidney disease is very common in subjects with long-standing type 2 diabetes. In subjects with type 2 diabetes, improvements with SGLT2 inhibitors, such as dapagliflozin, will depend on the kidney’s ability to filter glucose. Recently, it has been shown that human plasma levels of dapagliflozin are incrementally increased with declining renal function, and the ability of dapagliflozin to increase the renal clearance of glucose is also reduced in renal impairment in subjects with type 2 diabetes [12]. Dapagliflozin has also been tested in 252 subjects with inadequately controlled type 2 diabetes, and moderate renal impairment, and shown not to significantly decrease HbA1c, compared to placebo [13].
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Thus, dapagliflozin may not be suitable for long-term treatment in subjects with type 2 diabetes as it progresses and kidney impairment develops, and this requires testing.
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3.4
Do we need dapagliflozin registered for type 2 diabetes?
3.5
Clinical outcome studies
In their submission to the FDA about dapagliflozin, Bristol Myers Squibb included a meta-analysis of cardiovascular events in their clinical programme, in which only 37% of subjects had a history of cardiovascular disease (excluding hypertension) [14]. In this group, the cardiovascular events (cardiovascular death, stroke, myocardial infarction, hospitalisation of unstable angina) were low; 1.99% in the comparator group, compared to 1.64% per subject year in the dapagliflozin [14]. In our opinion, one of the major limitations to the studies to date with dapagliflozin is that no clinically beneficial outcomes (e.g., cardiovascular mortality or morbidity) have been undertaken in subjects at high cardiovascular risk. In approving dapagliflozin for use in the treatment of type 2 diabetes, the FDA asked for six post-marketing trials with dapagliflozin [14]. Only one of these is to investigate any beneficial effects of dapagliflozin, and this is a cardiovascular outcomes trial to evaluate the cardiovascular risk of dapagliflozin in subjects with high baseline risk of cardiovascular disease [15]. This multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58) is a Phase III trial recruiting high cardiovascular risk subjects with type 2 diabetes [15]. In this trial, dapagliflozin or placebo will be added to the subjects’ current anti-diabetes medicines, and the primary outcome measure is the composite of cardiovascular death, myocardial infarction or ischemic stroke in subjects with type 2 diabetes [15]. DECLARE-TIMI58 is due to be completed in April 2019 [15]. This suggests that dapagliflozin will be available for use for 5 years before its cardiovascular efficacy and safety are established. This seems inappropriate to us, and we would prefer anti-diabetic medicines to have established benefits on cardiovascular outcomes before approval from the FDA for wide use. The obvious precedent for this is rosiglitazone, which effectively lowers HbA1c, and
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was approved by the FDA, but has no benefit or may increase cardiovascular outcomes [16].
At the present time, several countries have two gliflozins approved for use. In the USA, canagliflozin was approved prior to dapagliflozin. In Europe and Australia, dapagliflozin was approved prior to canagliflozin. To our knowledge, there are no major differences between the pharmacology, efficacy and most of the adverse effects with these gliflozins. Pooled evidence suggests that there is not an increased incidence of bladder or breast cancers with canagliflozin, but this matter is unresolved for dapagliflozin. Thus, nine cases of bladder cancer and nine cases of breast cancer have occurred in 5000 subject-years of dapagliflozin use, and although this pooling does not have enough power to give significance, it does raise safety concerns about dapagliflozin [17]. No cases of bladder or breast cancer were observed in the relative small and short term of the studies we evaluated. Given that there is no present clinical outcome evidence (discussed in previous section) and unresolved safety issues for dapagliflozin, we are not sure why dapagliflozin has been approved by the FDA. It seems to us that drugs should be required to show significant differences to those already approved for use (for the FDA, this would be canagliflozin), that are beneficial in some subjects with type 2 diabetes, prior to approval.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organisation 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. Pharmacother. (2014) 15(11)
Dapagliflozin -- do we need it registered for type 2 diabetes?
Bibliography
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
WHO/Diabetes. Available from: http:// www.who.int/mediacentre/factsheets/ fs312/en/ [Last accessed 18 March 2014]
2.
Bakris GL, Fonseca VA, Sharma K, Wright EM. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int 2009;75:1272-7
3.
FDA news release: FDA approves Invokana to treat type 2 diabetes. Available from: http://www.fda.gov/ NewsEvents/Newsroom/ PressAnnouncements/ucm345848.htm [Accessed 31 March 2014]
4.
5.
.
FDA news release: FDA approves Farxiga to treat type 2 diabetes. Available from: http://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ ucm380829.htm [Accessed 31 March 2014] Jabbour SA, Hardy E, Sugg J, Parikh S. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicentre, randomized, double-blind, placebocontrolled study. Diabetes Care 2014;37:740-50 Evaluation of triple combination therapy of dapagliflozin, sitagliptin and metformin.
6.
Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013;27:479-84
7.
Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013;27:473-8
8.
Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:372-82
14.
Dapagliflozin (Forxiga): Summary of product characteristics. Bristol-Myers Squibb, Uxbridge, UK; 2014. Available from: http://www. medicines.org.uk/EMC/medicine/27188 [Accessed 31 March 2014]
9.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65
15.
10.
Arechevaleta R, Seck T, Chen Y, et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, not inferiority trial. Diabetes Obes Metab 2011;13:160-8
ClinicalTrials.gov Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). Available from: http://clinicaltrials.gov/ct2/show/ NCT01944618?term=dapagliflozin& rank=33 [Accessed 31 March 2014]
16.
Doggrell SA. Clinical trials with thiazolidinediones in subjects with type 2 diabetes -- is pioglitazone any different from rosiglitazone. Expert Opin Pharmacother 2008;9:405-20
17.
11.
Aschner P, Chan J, Owens DR, et al. Insulin glargine versus sitagliptin in insulin-naı¨ve patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial. Lancet 2012;379:2262-9
Vasilakou S, Karagiannis T, Athanasiadou E, et al. Sodium-glucose contransporter 2 inhibitors for type 2 diabetes; a systematic review and meta-analysis. Ann Intern Med 2013;159:262-74
Affiliation
12.
Kasichayanula S, Liu X, Pe Benito M, et al. The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol 2013;76:432-44
13.
Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014;85(4):962-71
Expert Opin. Pharmacother. (2014) 15(11)
Sheila A Doggrell†1 PhD DSc & Rinku Tuli2 PhD † Author for correspondence 1 Senior Lecturer, Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, GPO 2434, QLD 4002, Brisbane, Australia Tel: +61 7 3138 2015; Fax: +61 7 3138 1534; E-mail: [email protected] 2 Associate Lecturer, Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, GPO 2434, QLD 4002, Brisbane, Australia
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