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Summary of Presentations from the Bristol Myers Squibb/ AstraZeneca Alliance Symposium, European Association for the Study of Diabetes (EASD) 49th Annual Congress, Barcelona, Spain, 23rd September 2013.
Michael Nauck,1 Dídac Mauricio,2 Anthony Barnett3 Tina Vilsbøll,4 Samy Hadjadj,5 Peter Rossing,6 Edoardo Mannucci,7 Harald 1. Head, Diabeteszentrium Bad Lauterberg, Harz, Germany 2. Chief Physician, Department of Endocrinology & Nutrition, Germans Trias i Pujol 3. Professor of Medicine, University of Birmingham, UK 4. Professor of Medicine, Head of the Diabetes Research Division, Gentofte Hospital, 5. Department of Diabetology, Poitiers University Hospital, France 6. Head of Research, Steno Diabetes Centre, Professor of Diabetic Angiopathy, Aarus University, 7. Director, Diabetes Agency of Careggi Teaching Hospital, Florence, Italy 8. Director, Department of Cardiology, Vascular Medicine and Intensive Care Medicines, Vivantes Neukölln Medical Centre, Berlin, Germany 9. Professor of Medicine, Katholieke University, Leuven, Belgium Disclosure: Speakers participating in this symposium received honorarium from Bristol-Myers Squibb.
Acknowledgements: Writing assistance provided by Dr Jonathan Viney.
Support: The publication of this article was funded by Bristol-Myers Squibb. The views and opinions expressed are those of the authors and not necessarily of Bristol-Myers Squibb. Citation: EMJ Diabet. 2013;1:22-29.
This meeting comprised two sessions: the morning session centred around glucagon-like peptide-1 receptor (GLP-1R) agonists and SGLT-2 inhibitors, a new class of glucose-lowering compounds, while the afternoon session focused on new results of cardiovascular safety studies with diabetes medications, with special attention to the SAVOR-TIMI trial of saxagliptin.
Morning Session – Catalysts for Change? How Can GLP-1 Receptor Agonists and SGLT-2 Inhibitors Help Us Reshape Individualised Diabetes Care? EMJ EUROPEAN MEDICAL JOURNAL
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Prof Nauck started his presentation by giving an Prof Mauricio began by highlighting the disease overview of the mechanism of action of GLP-1 burden of type 2 diabetes (T2D) and indicated that receptor (GLP-1R) agonists. GLP-1 affects gastric previous predictions on prevalence of burden are motility and metabolism and reduces appetite; far behind the reality of the situation. By 2030, activation/stimulation of GLP-1Rs with GLP-1 there will be more than 500 million people around agonists could provide a potential avenue for the world affected by T2D.1,2 In recent years, treatment of T2D. Endogenous GLP-1 has a short diabetes has been estimated to account for 4–13% half-life (<2 minutes) due to degradation and of national healthcare budgets in Europe,3 with the inactivation by DPP-4, requiring GLP-1 analogues estimated average yearly cost per patient at €2,834.4 to have a longer half-life to be effective.10 A number of GLP-1R agonists are available, which The progressive nature of the disease also mainly differ in terms of their pharmacokinetic profile. Exenatide achieves peak plasma complications develop that ultimately require concentration 2 hours after injection, while additional treatment resources. Examples liraglutide maintains high concentrations even include macrovascular complications such as cardiovascular (CV) disease, and microvascular Prof Nauck presented results from the complications such as nephropathy, neuropathy DURATION-1 study where long-acting once- and retinopathy.5 Patients with T2D have a 2 to weekly exenatide was more effective at lowering 4-fold higher risk of coronary heart disease than HbA1c and fasting glycaemia than the short- those without the condition, and 75–80% die due acting twice-daily formulation, but not at lowering body weight.13 A comparison of the DPP-4 Prof Mauricio discussed the benefit of early therapy inhibitor sitagliptin and injectable GLP-1R agonist in newly diagnosed T2D in reducing long-term liraglutide showed that the injectable liraglutide complications. In the UK Prospective Diabetes was more potent in reducing glycaemia and body Study (UKPDS), newly diagnosed patients weight when compared to sitagliptin.14were randomised to receive either conventional Prof Nauck highlighted that the results of therapy (dietary restriction) or intensive therapy meta-analyses have shown that there is a higher (sulphonylurea or insulin, or metformin if >120% likelihood of achieving target HbA1c levels with ideal body weight). Early intensive intervention a GLP-1R agonist when compared to insulin, even provided benefits not only for microvascular more so when a longer-acting preparation is disease but also for myocardial infarction (MI).7 used, as was shown with exenatide once weekly The American Diabetes Association (ADA) and in DURATION-3 study up to 3 years.15 It was European Association for the Study of Diabetes Prof Nauck’s opinion that the short-acting GLP- (EASD) now recommend early, patient-centred 1R agonists should be used in combination with treatment in order to manage hyperglycaemia.8 long-acting insulin because they show a beneficial effect on postprandial glucose excursions.
Prof Mauricio presented recent European data concerning glycaemic control showing that conventional therapy is suboptimal, and patients receiving more complex treatments are less likely to achieve their target glycated haemoglobin (HbA1c).9 He stressed that glycaemic control is treating T2D; a multifactorial approach is essential, and comorbidities, efficacy, hypoglycaemia, Prof Vilsbøll discussed the treatment options for weight, and cost have to be taken into account.
diabetes available in her practice. When she first EMJ EUROPEAN MEDICAL JOURNAL
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decides on a treatment, she has to consider its Prof Hadjadj presented data comparing efficacy with respect to change in HbA1c, change dapagliflozin to current therapies. Dapagliflozin in body weight and risk of hypoglycaemia. Prof combined with metformin XR in drug naïve Vilsbøll noted that compared to sulphonylureas, patients provided an even greater reduction up to thiazolidinedione and insulin, GLP-1R agonists 2% in HbA1c and body weight compared to have favourable efficacy outcomes since they metformin alone. In patients with background reduce both HbA1c and body weight, with low metformin therapy, these reductions were sustained well beyond the primary endpoint of 24 weeks; at 102 weeks patients treated with Prof Vilsbøll asked how GLP-1R agonists could the combination therapy had a 0.78% reduction improve daily life. She first looked at their effect in HbA1c.36,37 When dapagliflozin is used as part on HbA1c, citing a meta-analysis performed in of triple-combination therapy it helps to reduce her lab that compared exenatide once-weekly, HbA1c and body weight in patients with T2D.38 exenatide twice-daily and liraglutide to all the Other combinations of medications, such as non-GLP-1R agonists given for more than 20 empagliflozin in combination with metformin and weeks in clinically-relevant doses. The GLP-1R sulphonylurea produce similar effects.39 agonists provided a sustained 0.6% difference HbA1c after 20 weeks.19 GLP-1R agonists Prof Hadjadj highlighted that SGLT-2 inhibitors have a low propensity to cause hypoglycaemia. level of hypoglycaemia compared to insulin Dapagliflozin in particular is no different to placebo glargine, especially when on a non-sulphonylurea in this respect.40 Side-effects, such as genital and background,17,20 and therefore may represent urinary tract infections, are manageable.35,41,42 an improvement in treatment in this respect.
Professor Hadjadj noted that the incidence for bladder cancer was slightly raised in patients Patients with T2D have a 2 to 3-fold increase in treated with dapagliflozin. He commented that risk of pancreatitis, and GLP-1R agonist therapies this might be explained by a better opportunity to do not change this risk.21-29 The European more efficiently diagnose bladder cancer, because Medicines Association concluded that there are the mechanism of action on urine outflow makes no new concerns for GLP-1 therapies based on it easier to observe haematuria.43 A meta-analysis the available evidence,30 and Prof Vilsbøll was of for major adverse CV events showed no warning the view that the side-effect profile is acceptable considering the sustained effect GLP-1R agonists have on glycaemic control, body weight, and hypoglycaemia.
Prof Rossing outlined the current problems with diabetes disease progression and treatment. It has been shown that progressive loss of glycaemic control occurs in T2D patients, irrespective of treatment.45 SGLT-2 inhibitors may provide some Prof Hadjadj started his presentation by introducing of the features that are necessary for obtaining the sodium glucose co-transporter-2 (SGLT-2) good control of glucose and some of the other inhibitors for the treatment of T2D. Currently, there risk factors. SGLT-2 inhibitors act on glucose, body are many of these drugs in clinical development, weight and blood pressure, and have a very low-risk with the first-in-class dapagliflozin approved in of hypoglycaemia.42 The SGLT-2 inhibitor the EU and canagliflozin approved in the USA.31 dapagliflozin is indicated to improve glycaemic SGLT-2 is expressed in the renal proximal tubule, control as both a combination and monotherapy.42 and causes reabsorption of glucose back into the bloodstream. An SGLT-2 inhibitor such Prof Rossing presented case studies. The first case as dapagliflozin inhibits this reabsorption, leading was Anna, a 42-year-old female diagnosed with to an increase in glucose excretion and caloric diabetes. After two years her HbA1c started to rise loss. This mechanism is specific to the kidney due and her body weight increased. The patient was to the localisation of SGLT-2 receptors.32-35 prescribed dapagliflozin, since she had normal EMJ EUROPEAN MEDICAL JOURNAL
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liver function, preserved renal function, and did patient was prescribed dapagliflozin since other not want to risk hypoglycaemia due to her active prescribing considerations such as liver function lifestyle. The patient responded very well to and infection history were normal. Dapagliflozin treatment and was happy with the results.
treatment led to a reduction in body weight John, a 55-year-old male, who was severely obese and a heavy smoker, did not drastically Prof Rossing concluded that better treatment for improve his lifestyle after diagnosis. After glycaemia is needed. SGLT-2 inhibitors work in metformin administration he lost weight and had the kidneys and complement the action of a large reduction in HbA1c, but like Anna this metformin and other anti-diabetic drugs. Blocking control waned after time. Treatment with DPP-4 SGLT-2 reduces blood glucose and has other inhibitors, GLP-1R agonists and insulin were not beneficial effects on body weight and BP, with a low-effective. Despite his slightly lowered GFR, the How May the Largest DPP-4 Inhibitor CV Safety Study Influence Day-to-Day Clinical Practice? studies.48,49 The VADT and ORIGIN study also showed similar results, that glycaemic control had From UKPDS to SAVOR: The Evolving a neutral effect on CV outcomes.50,51 Prof Barnett asked what we can conclude from these studies. His suggestion was that there is no one-for-all approach to glycaemic control, and that by increasing risk and rates of hypoglycaemia Prof Barnett presented the results of CV risk the benefits of tight glycaemic control may factor intervention trials from a glycaemia be negated. The current ADA and EASD Joint perspective. The UKPDS remains the first large- Position Statement, therefore, recommends an scale study of intensive versus conventional individualised approach to treatment targets.8 As glucose control in T2D. In this study, over a mean of 10 years the difference in favour of tight a result of causing more CV events, an increase control was 0.9% HbA1c, which was associated in heart failure and MI risk, the thiazolidinedione with a 25% risk reduction for microvascular rosiglitazone was withdrawn in the EU, and the complications.45 After a further 10 years, patients EMA stated that ‘a new glucose-lowering agent from the UKPDS were followed-up; despite the should preferably show a neutral or beneficial fact that during the interim period there was no effect on parameters associated with CV risk’.52-54effort to maintain treatment and that HbA1c levels were the same between both groups, the intensively-treated patients had significantly Prof Barnett then presented the PROactive study, the conclusions of which are still hotly debated. This study showed that oral pioglitazone reduced Prof Mannucci started his presentation by discussing the composite endpoint of all-cause mortality, the case of rosiglitazone. In 2007, a meta-analysis non-fatal MI and stroke in patients with T2D but of rosiglitazone studies suggested that its use with increased side-effects, particularly of heart could be associated with a relevant increase in failure.46,47 Other confounding CV outcomes were the incidence of MI and also possibly CV mortality.53 also shown in the ACCORD and ADVANCE As a result of these findings, the Food and Drug EMJ EUROPEAN MEDICAL JOURNAL
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Administration (FDA) imposed new rules for the saxagliptin and 6.5% for placebo, which again approval of newly-developed glucose-lowering satisfied FDA requirements.57 In terms of glycaemic agents; in particular, drugs must demonstrate CV control, Prof Darius noted that saxagliptin safety, specifically by showing that they do not treatment led to a significant reduction in HbA1c increase CV events by more than 30%.55 compared to placebo: 7.5% versus 7.8% at year 2. The proportion of patients achieving a Since the FDA regulations only apply to drugs HbA1c of less than 7% was also increased in marketed after 2009, many older drugs that the treatment group. Fewer patients in the are currently used for treatment would not get saxagliptin group required the addition or approved if developed today. Only two current increase of any new anti-diabetic therapies, drugs have shown reliable data from large-scale or initiation of insulin therapy for more than CV outcome trials: pioglitazone and insulin were 3 months.57,58 shown to be safe in the PROactive and ORIGIN trials, respectively.46,51 There are a lack of good Saxagliptin neither reduced nor increased the risk quality data for the CV safety of metformin, of the primary composite endpoint of CV however a meta-analysis of all metformin trials death, MI, or ischaemic stroke in comparison to showed that the drug is associated with a placebo, in patients with a very high CV risk. In significant reduction in the incidence of major addition, the saxagliptin group experienced an CV events,56 and from this it can be concluded improved glycaemic control, an increased rate that under current FDA guidelines metformin of hypoglycaemic events but not hospitalisation would likely be approved. Similar results were for hypoglycaemia, a higher rate of hospitalisation shown for sulphonylureas and DPP-4 inhibitors.29 for heart failure, a reduced requirement for insulin or other diabetes medications, a favourable Prof Mannucci asked the audience about their effect on microalbuminuria, and no increased risk experience with DDP-4 inhibitors; 10% of the of pancreatitis or pancreatic cancer.
audience’s patients were receiving these drugs as secondary prevention after a major CV event. Prof Mannucci concluded by discussing the characteristics of the patients entered into these trials, specifically that those enrolled into large CV outcome trials are not representative of the general population. As such, when considering treatment options, the results of Prof Mathieu presented her views on the trials such as EXAMINE and SAVOR must be SAVOR trial. A major positive from the trial was placed into context of the patient population.
that it met its primary safety endpoint, namely no increased risk of CV death, non-fatal MI, and non-fatal stroke. Thus, indicating there was no difference between the treatment and placebo groups (hazard ratio=1.0).57,58 Another positive outcome was that the trial also met its secondary endpoint (composite primary endpoint plus hospitalisation for heart failure), and in Prof Mathieu’s opinion this was an important result, SAVOR study of the DPP-4 inhibitor saxagliptin, and based on these data she would recommend conducted in T2D patients with CV risk. The saxagliptin as a safe drug to use in T2D treatment.
primary endpoint of the trial was namely CV death, non-fatal MI, and non-fatal ischaemic Prof Mathieu suggested that the 0.3% HbA1c stroke. The study met this endpoint, meaning difference observed between the treatment and that CV risk increase could definitely be ruled out placebo groups may diverge after additional with a very high statistical power.57 Saxagliptin time beyond the current 2-year measurement, was not shown to be superior to placebo in terms since other studies only saw differences after several years of treatment. Prof Mathieu expressed a positive opinion about the safety profile of The secondary endpoint, which included saxagliptin, in particular regarding pancreatitis and hospitalisations, came to a rate of 6.6% for pancreatic cancer.
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Prof Mathieu concluded that SAVOR provides were also important findings. She ended her an important set of data on the safety and presentation by polling the audience on whether efficacy of this DPP-4 inhibitor, and that the lack they were reassured about the use of DPP-4 of increase in CV risk was a major finding. inhibitors. Two-thirds of the audience were increase in pancreatitis and pancreatic cancer How Could We Transform Treatment in Type 2 Diabetes: A broader panel discussion then took place involving speakers from both sessions of the meeting. Discussion began by examining the evidence for metformin in the treatment of early stages of diabetes. Prof Mannucci stated that we cannot be sure that metformin is superior to other drugs, despite its effectiveness and safety, and that if another drug was developed that showed clear superiority it would replace metformin as first-line therapy.
The panel then discussed how recent trials such as SAVOR may change treatment strategies. Regarding the concept of treatment individualisation, Prof Barnett stressed that the whole package of treatment must be considered, not just pharmacotherapy. Adherence rates to therapy are very low, and as such, patient needs, lifestyle and attitude must be considered in addition to clinical factors. Prof Mathieu added that cost must be considered as part of this treatment package, since in her opinion sulphonylureas would not be used if they are more expensive.
One question asked whether the results of the SAVOR and EXAMINE trials could be used to generalise for the DPP-4 inhibitors and GLP-1R agonists. It was Prof Vilsbøll’s opinion that it is unlikely we will get any surprises in patients having CV heart failure with DPP-4 inhibitor trials.
Prof Mauricio asked the panel for their opinion on the best method for treatment individualisation since phenotyping for patients is currently lacking. Prof Nauck concluded the panel discussion by suggesting that the best method of individualisation is to take into account all of a patient’s characteristics, such as obesity and previous efforts at weight loss, since these will inform choices of medication.
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