Not so critical appraisal of dapagliflozin

Autor: Doggrell, Sheila A, Brooks, Amie D
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: Patient preference and adherence
ISSN: 1177-889X
Popis: Dear editor A recent review by Salvo et al published in Patient Preference and Adherence concerned dapagliflozin, and was titled “Patient considerations in the management of type 2 diabetes – critical appraisal of dapagliflozin”.1 Having read the article, I do not consider it to be a critical appraisal of dapagliflozin. Thus, after comparing dapagliflozin with other oral antidiabetic medications, the authors concluded that “Dapagliflozin’s noted blood pressure reduction, weight loss, and low potential to cause hypoglycemia are advantageous, when compared with currently available oral medications”.1 This statement is not supported by the content of the review and/or the literature. In their review of the efficacy of dapagliflozin, Salvo et al have provided little or no evidence that dapagliflozin reduces blood pressure. Dapagliflozin monotherapy was initially suggested to reduce blood pressure by a small amount at 24 weeks.2 However, the ability of dapagliflozin to reduce blood pressure is small, and is not always statistically significant.3,4 Thus, the reduction of blood pressure with dapagliflozin cannot be considered to be notable, and is unlikely to have any clinical significance. Secondly, Salvo et al do provide some evidence of weight loss with dapagliflozin, of up to 4.65 kg,1 but do not critically appraise the significance of this. Although it is well established that being overweight or obese is a risk factor for diabetes and cardiovascular disease, it has not been shown that reducing weight in subjects with diabetes reduces long term cardiovascular outcomes. Thus, the Look AHEAD (Action for Health In Diabetes) trial in overweight or obese subjects with type 2 diabetes, compared an intensive lifestyle intervention to promote weight loss to diabetes support and education (control group). This trial was abandoned after 9.6 years, on the basis of a futility analysis for the primary outcome, which was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina.5 The futility in Look AHEAD was shown despite an initial 8.6% body weight loss (from a baseline of approximately 101 kg) and reduction in glycated hemoglobin of approximately 0.6% (from a baseline of about 7.3%) in the intensive lifestyle intervention group.5 Given the findings of Look AHEAD, it is unlikely that a reduction in body weight of up to 4.65 kg with dapagliflozin is alone going to be beneficial in type 2 diabetes. Also, Salvo et al suggest that the weight loss with dapagliflozin is an advantage over other oral medications in treating subjects with type 2 diabetes.1 Weight gain is observed with the sulfonylureas and the thiazolidinediones (eg, rosiglitazone). Thus, the weight loss with dapagliflozin may be an advantage over these medicines. However, the dipeptidylpeptidase inhibitors (gliptins) do not cause weight gain, and usually cause weight loss eg, saxagliptin.6 Glucagon-like peptide 1 receptor (GLP-1R) agonists, which are administered subcutaneously, also cause weight loss eg, exenatide.7 It seems to me, that these groups of anti-diabetic drugs, and their ability to cause weight loss, should have been part of any critical appraisal of dapagliflozin. Thirdly, Salvo et al have suggested that dapagliflozin has a lesser ability to cause hypoglycemia than other oral anti-diabetes medicines, and provided evidence that dapagliflozin has a low potential to cause hypoglycemia compared to the sulfonylureas (glipazide, glimepride),1 but not to other oral anti-diabetic medications. Thus, there is no evidence available to support dapagliflozin having lower hypoglycemia potential than metformin or GLP-1R agonists/gliptins, all of which have a lesser propensity to cause hypoglycemia than the sulfonylureas, eg, exenatide,7 saxagliptin.6 Also, definitive evidence for any low potential to cause hypoglycemia can only be obtained from comparative trials, and (at present) there are no published studies comparing metformin or the GLP-1R agonists/gliptins to dapagliflozin, let alone comparing their potential to cause hypoglycemia. The authors did conclude that “long-term clinical trials and post-marketing studies are needed to further investigate dapagliflozin’s cardiovascular profile, and its impact on morbidity and mortality”,1 but this seems somewhat understated to me. To date, cardiovascular events with dapagliflozin have only been evaluated in subjects with type 2 diabetes, not having major cardiovascular disease. In their submission to the US Food and Drug Administration (FDA) about dapagliflozin, Bristol-Myers Squibb included a meta-analysis of cardiovascular events in their clinical program, in which only 37% of subjects had a history of cardiovascular disease (excluding hypertension).8 In this group, the cardiovascular events (cardiovascular death, stroke, myocardial infarction, hospitalization of unstable angina) were low; probably because the enrolled population was not high risk.8 In this low risk group, cardiovascular events occurred in 1.99% of the comparator group, compared to 1.64% per subject year in the dapagliflozin, and this was not significantly different.8 The multicenter trial that will eventually be able to evaluate the cardiovascular safety of dapagliflozin, is the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58).9 DECLARE-TIMI58 is a Phase III trial recruiting 22,200 subjects with type 2 diabetes and high cardiovascular risk subjects.9 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.9 DECLARE-TIMI58 is due to be completed in April 2019.9 By this time, it will be about 5 years since the FDA approved dapagliflozin for use in subjects with type 2 diabetes. Thus, dapagliflozin will be available for 5 years without proven cardiovascular efficacy or safety. It seems to me, that dapagliflozin should not have been registered, until DECLARE-TIMI58 was complete, and cardiovascular safety established. This point should have been considered by Salvo et al in a critical appraisal of dapagliflozin. In conclusion, dapagliflozin does not have a noted ability to reduce blood pressure. However, dapagliflozin does cause weight loss and have a low potential to cause hypoglycemia, but this is not necessarily an advantage, as other medicines available for the treatment of type 2 diabetes also cause weight loss and have a low propensity to cause hypoglycemia. Most importantly, the cardiovascular clinical outcome study DECLARE-TIMI58 being undertaken with dapagliflozin will not report for 5 years, and thus dapagliflozin will be available for the treatment of type 2 diabetes for 5 years without proven cardiovascular efficacy or safety.
Databáze: OpenAIRE
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