Dapagliflozin: a review on efficacy, clinical effectiveness and safety.

INTRODUCTION: The prevalence of type 2 diabetes mellitus has reached epidemic proportions. Progressive deterioration in glycaemic control and the current limitations of existing therapies such as weight gain and hypoglycaemia led us to welcome the first of a new class of drugs. Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a novel mode of therapy independent of insulin secretion or action. By blocking glucose reabsorption in the kidney they lead to an increase in urinary glucose excretion with reduction in plasma glucose levels. AREAS COVERED: In this article, we will review inhibition of SGLT2 as a novel strategy for the treatment of type 2 diabetes mellitus with dapagliflozin . PubMed and MEDLINE were searched for literature published up to July 2012, for efficacy, clinical effectiveness and safety reports of dapagliflozin. EXPERT OPINION: Improvement in glycaemic control with a low risk of hypoglycaemia, concomitant weight loss and the potential of lowering of blood pressure make SGLT2 inhibition an attractive approach using dapagliflozin therapy. Many SGLT2 inhibitors are undergoing Phase III clinical trials and more are in Phase I and II clinical trials.

Real time presence of a microbiologist in a multidisciplinary diabetes foot clinic.

Multidisciplinary foot-care teams (MDFT) are recommended in the management of severe diabetic foot disease [1]. However, even though infection is often the dominant immediate risk, it is rare to have real time input from a microbiologist. We highlight the value of a microbiologist as a MDFT member.

Small vessel remodeling and impaired endothelial-dependent dilatation in subcutaneous resistance arteries from patients with acromegaly.

CONTEXT: Patients with acromegaly have increased morbidity and mortality, predominantly from cardiovascular disease. Hypertension and diabetes are more prevalent, and both cause small vessel remodeling and endothelial dysfunction. OBJECTIVE: To understand the structure and function of small arteries in acromegaly, sc blood vessels from gluteal fat biopsies were harvested from 18 patients with active disease (AD; age, 56 +/- 15 yr; 14 males), 23 patients in remission (CD; age, 55 +/- 12 yr; 15 males), and 20 healthy controls (age, 55 +/- 11 yr; 10 males) and examined in vitro using pressure myography. DESIGN: Contractile responses to cumulative noradrenaline concentrations were recorded and followed by dose-dependent dilator responses to acetylcholine. The acetylcholine protocol was repeated after incubation with a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester) and cyclooxygenase inhibitor (indomethacin). After perfusion with Ca(2+)-free physiological saline solution, structural measurements were recorded at varying intraluminal pressures (3-180 mm Hg). RESULTS: Wall thickness and wall:lumen ratio were increased in AD, reduced with treatment but remained greater in CD than controls. Wall cross-sectional area was increased in AD vs. controls (P < 0.001), decreased with treatment (AD vs. CD, P < 0.001), but remained higher than controls (CD vs. controls, P = 0.015). Growth index was increased in AD (20%) compared to controls (CD, 9%). Contractility was similar in all groups. Endothelial-dependent dysfunction was evident in AD compared with CD (P < 0.001) and controls (P < 0.01). Dilation did not change after N-nitro-L-arginine methyl ester but was impaired after indomethacin incubation. CONCLUSION: Active acromegaly is associated with hypertrophic remodeling of the vascular wall and embarrassed endothelial function due to reduced nitric oxide and endothelium-derived hyperpolarizing factor bioavailability, both of which may contribute to the early mortality from cardiovascular disease.

Treatment of acromegaly improves quality of life, measured by AcroQol.

BACKGROUND: AcroQol is a disease-generated questionnaire, developed to assess quality of life (QOL) in patients with acromegaly. We have previously demonstrated severely impaired QOL in patients with acromegaly and the value of AcroQol in measuring QOL in a cross-sectional study compared with the non-disease-specific generic tools 'Psychological general wellbeing schedule' (PGWBS) and EuroQol (EQ-5D), and the disease-specific signs and symptoms score (SSS). AIM, SUBJECTS AND METHODS: We re-evaluated these tools in a longitudinal study of 56 of the previously reported patients (33 male, mean age 55 +/- 15 years), in order to determine change in QOL over time and the effect of different treatment modalities. Data were analysed using Spearman's correlation tests. RESULTS: Baseline median IGF-I was 354 ng/ml (range 48-899) and at re-evaluation 217 ng/ml (60-594) (P < 0.001) [median time interval 608 days (113-1136)]. Analysis of change in IGF-I levels and AcroQol scores demonstrated a significant negative correlation (i.e. a reduction in IGF-I being associated with improved overall QOL (r = -0.36, P = 0.006). Significant negative correlations were also seen in the physical (r = -0.33, P = 0.01), psychological (r = -0.37, P = 0.005) and appearance (r = -0.42, P = 0.001) AcroQol subdomains. No correlations were seen between change in IGF-I and change in overall PGWBS score or subdomains, SSS or EQ-5D. CONCLUSIONS: In summary, of the tools studied we have demonstrated AcroQol to be uniquely capable of detecting changes in QOL associated with treatment-induced improvement in the main biochemical marker of disease activity in patients with acromegaly. Further studies are required to evaluate the long-term biological significance of the changes seen in AcroQol.

Recent developments in the therapy of acromegaly.

Acromegaly, a condition due to growth hormone hypersecretion usually from a benign pituitary tumour, is associated with significant morbidity and mortality. Disease control leads to normalisation of life expectancy with a reduction in signs and symptoms. Treatment modalities include surgery, radiotherapy and medical management. Surgery is the primary treatment in most of the patients, with success rates of 61-91% reported for those with microadenomas who are operated on by a specialist pituitary surgeon; however, most patients have macroadenomas and, although benefiting from surgery, are not cured and require additional medical therapy. This review will focus on emerging concepts in the medical treatment of acromegaly.

Treatment of pituitary tumors: pegvisomant.

Pegvisomant is a pegylated analog of growth that functions as a growth hormone receptor antagonist. The drug is capable of normalizing serum IGF-I concentrations (the chief mediator of disease activity in acromegaly) in 97% of patients, and therapy is associated with significant improvements in the symptoms and signs of GH excess. Biochemical control may be achieved with pegvisomant in patients wholly or partially resistant to somatostatin analogs, and there are emerging data to suggest that the drug may be particularly suitable for patients with acromegaly and co-existent diabetes mellitus.

The place of pegvisomant in the acromegaly treatment algorithm.

The disfiguring disease acromegaly results from hypersecretion of growth hormone (GH). The main goals of treatment for acromegaly include normalisation of biochemical markers of disease activity to restore normal life expectancy, amelioration of signs and symptoms of the disease, removal of the pituitary tumour without damaging the optic chiasm and other peripituitary structures, and preservation of pituitary function. Conventional options for treatment of acromegaly include surgery, radiotherapy (RT), and medical therapy with either dopamine agonists or somatostatin (SMS) analogues. The advent of the genetically engineered growth hormone analogue pegvisomant is unlikely to alter significantly the place of surgery and RT in the treatment algorithm for acromegaly biochemical control as determined based on serum IGF-I concentrations is achievable with pegvisomant in virtually all patients, and it will clearly become the drug of choice in patients partially or completely unresponsive to SMS analogues. Preliminary studies suggest improved insulin sensitivity for a given IGF-I with pegvisomant compared with SMS analogues; if these results are confirmed by results of future studies, such a metabolic advantage may encourage the use of pegvisomant.

Pegvisomant: a novel pharmacotherapy for the treatment of acromegaly.

Pegvisomant is a pegylated analogue of growth hormone (GH) that functions as a growth hormone receptor antagonist. Clinical trials of its use in acromegaly commenced in 1997; the drug was approved in the US in March 2003 and in Europe in November 2003. In the same year, it was made available on prescription in several European countries, with further launches due in 2004. Pegvisomant is capable of normalising serum insulin-like growth factor-I concentrations (the chief mediator of disease activity in acromegaly) in 97% of patients with active acromegaly, and therapy is associated with a significant improvement in the symptoms and signs of GH excess. Disease control is achievable with pegvisomant in patients who are wholly or partially resistant or do not tolerate somatostatin analogues; preliminary data suggest that the drug may be particularly suitable for patients with acromegaly and co-existent diabetes mellitus.

The challenges of reliance on insulin-like growth factor I in monitoring disease activity in patients with acromegaly.

Serum insulin-like growth factor I (IGF-I) is an important marker of disease activity in patients with acromegaly, and epidemiological data indicate control of circulating IGF-I in patients with acromegaly restores life expectancy to normal. Improvements in the quality of, and access to, IGF-I assays has encouraged monitoring of acromegaly with IGF-I, although circulating growth hormone (GH) and IGF-I values provide different information, so ideally both should be monitored. However, the introduction of the GH receptor antagonist pegvisomant poses new challenges. Pegvisomant binds with high affinity to GH receptors, thereby blocking the action of GH at the tissue level and rendering the hormone biologically inactive. This leaves IGF-I as the principal marker of disease activity. It is conceptually possible to induce a state of functional GH deficiency (GHD) with pegvisomant with IGF-I values within the normal range. With the goal of minimizing the risk of over-treatment and GHD, we have provided preliminary guidance on the target range for IGF-I in patients receiving pegvisomant based on the gender- and decade-based percentile ranges for IGF-I of adult patients with untreated GHD enrolled in the Pfizer International Metabolic Database (KIMS).

Medical treatment in acromegaly.

Acromegaly is a rare disabling disorder that results in premature death. The excess mortality and morbidity are the result of prolonged elevation of growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels, and vigorous control of these improves well-being and restores life expectancy to normal. Recognition of the benefits of treatment has emphasised the need for optimal control of the GH/IGF-I axis. Transsphenoidal surgery is first-line therapy in the majority of patients; however, as most tumours are macroadenomas, cure rates are low. The role of radiotherapy is evolving and, although extremely effective at controlling tumour growth, it can take up to 15 years to control GH & IGF-I levels. In the interim, medical therapy is necessary. Dopamine agonists are inexpensive oral agents but, although most patients experience some benefit, GH and IGF-I levels are only normalised in around 35-40% of patients, and side effects are common. Somatostatin analogues are the gold standard of medical treatment. They can induce tumour shrinkage in a proportion of patients and can normalise the GH/IGF-I axis (at best) in approximately 65% of individuals; however, this leaves a significant cohort uncontrolled. The advent of the GH receptor antagonist pegvisomant provides the potential for IGF-I to be normalised in virtually every patient, but this novel form of therapy, which does not act on the pituitary, also raises many questions.