8 research outputs found
Dapagliflozin: a sodium glucose cotransporter 2 inhibitor in development for type 2 diabetes
Type 2 diabetes mellitus (T2DM) is a growing worldwide epidemic. Patients face lifelong therapy to control hyperglycemia and prevent the associated complications. There are many medications, with varying mechanisms, available for the treatment of T2DM, but almost all target the declining insulin sensitivity and secretion that are associated with disease progression. Medications with such insulin-dependent mechanisms of action often lose efficacy over time, and there is increasing interest in the development of new antidiabetes medications that are not dependent upon insulin. One such approach is through the inhibition of renal glucose reuptake. Dapagliflozin, the first of a class of selective sodium glucose cotransporter 2 inhibitors, reduces renal glucose reabsorption and is currently under development for the treatment of T2DM. Here, we review the literature relating to the preclinical and clinical development of dapagliflozin
Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes
There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80–90 g [300–400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances
Dapagliflozin and cardiovascular outcomes in type 2 diabetes
BACKGROUND
The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium–
glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes,
is undefined.
METHODS
We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE),
defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite
(≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per
1.73 m2
of body-surface area, new end-stage renal disease, or death from renal or
cardiovascular causes) and death from any cause.
RESULTS
We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular
disease, who were followed for a median of 4.2 years. In the primary safety outcome
analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with
respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001
for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result
in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo
group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate
of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard
ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no
between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to
1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the
placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause
occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3%
vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the
regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).
CONCLUSIONS
In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate
of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization
for heart failure. (Funded by AstraZeneca; DECLARE–TIMI 58 ClinicalTrials.gov
number, NCT01730534.
Hypothalamic neuropeptide Y in the control of normal abnormal food intake and metabolism
SIGLEAvailable from British Library Document Supply Centre-DSC:DX190112 / BLDSC - British Library Document Supply CentreGBUnited Kingdo
Dapagliflozin: A Once-Daily Oral Therapy Sodium-Glucose Cotransporter-2 Inhibitor for the Treatment of Adult Patients with Type 2 Diabetes
Selecting Core Outcomes for Randomised Effectiveness trials In Type 2 diabetes (SCORE- IT): A patient and healthcare professional consensus on a core outcome set for type 2 diabetes
Objectives
Heterogeneity in outcomes measured across trials of glucose-lowering
interventions for people with type 2 diabetes impacts on the ability to
compare findings and may mean that the results have little importance to
healthcare professionals and the patients that they care for. The
SCORE-IT study (Selecting Core Outcomes for Randomised Effectiveness
trials In Type 2 diabetes) has addressed this issue by establishing
consensus on the most important outcomes for non-surgical interventions
for hyperglycemia in type 2 diabetes.Research design and methods
A comprehensive list of outcomes was developed from registered clinical
trials, online patient resources, qualitative literature and long-term
studies in the field. This list was then scored in a two-round online
Delphi survey completed by healthcare professionals, people with type 2
diabetes, researchers in the field and healthcare policymakers. The
results of this online Delphi were discussed and ratified at a
face-to-face consensus meeting.Results
173 people completed both rounds of the online survey (116 people with
type 2 diabetes, 37 healthcare professionals, 14 researchers and 6
policymakers), 20 of these attended the consensus meeting (13 people
with type 2 diabetes and 7 healthcare professionals). Consensus was
reached on 18 core outcomes across five domains, which include outcomes
related to diabetes care, quality of life and long-term diabetes-related
complications.Conclusions
Implementation of the core outcome set in future trials will ensure
that outcomes of importance to all stakeholders are measured and
reported, enhancing the relevance of trial findings and facilitating the
comparison of results across trials