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 EMJ EUROPEAN MEDICAL JOURNAL
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 EMJ EUROPEAN MEDICAL JOURNAL
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 EMJ EUROPEAN MEDICAL JOURNAL
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 EMJ EUROPEAN MEDICAL JOURNAL
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. EMJ EUROPEAN MEDICAL JOURNAL EMJ EUROPEAN MEDICAL JOURNAL
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.
1. International Diabetes Federation Europe. Diabetologia. 2002;45:S5–12.
(IDF). IDF Diabetes Atlas, 5th ed. 5. Rydén L et al. Guidelines on diabetes, PANORAMA study. Clin Endocrinol (Oxf).
pre-diabetes, and cardiovascular disease. 2012:doi:10.1111/cen.112119. [Epub ahead of
diabetesatlas/5e/Update2012. Accessed Eur Heart J. 2007;9(Suppl C):C3–C74.
6. Alberti K et al. International Diabetes 10. Baggio L, Drucker DJ. Biology of
2. International Diabetes Federation Federation: a consensus on Type 2 incretins: GLP-1 and GIP. Gastroenterology.
(IDF). IDF Diabetes Atlas, 5th ed Available diabetes prevention. Diabet Med. 2007;132:2131–57.
11. Calara F et al. Effect of injection site
7. Del Prato S. Megatrials in type 2 on relative bioavailability of exenatide
3. International Diabetes Federation diabetes. From excitement to frustration? (synthetic exendin-4). Clin Pharm Ther.
(IDF). Federation of European Nurses in Diabetologia. 2009;52:1219–26.
Diabetes (FEND), Alliance for European 8. Inzucchi SE et al. Management of 12. Agersø H et al. The pharmacokinetics,
Diabetes Research (EURADIA) and hyperglycemia in type 2 diabetes: a pharmacodynamics, safety and
Primary Care Diabetes Europe (PCDE). patient-centered approach: position tolerability of NN2211, a new long-
Diabetes – The policy puzzle: Is Europe statement of the American Diabetes acting GLP-1 derivative, in healthy men.
Association (ADA) and the European Diabetologia. 2002;45:195–202.
Association for the Study of Diabetes 13. Drucker DJ et al. Exenatide once weekly
Diabetes-Policy-Puzzle-3rd-ed-2011.pdf. (EASD). Diabetes Care. 2012;35:1364–79.
9. de Pablos-Velasco P et al. Current type 2 diabetes: a randomised, open-
4. Jönsson B, CODE-2 Advisory Board. level of glycaemic control and its label, non-inferiority study. Lancet.
Revealing the cost of type II diabetes in associated factors in patients with type 2008;372:1240–50.
EMJ EUROPEAN MEDICAL JOURNAL EMJ EUROPEAN MEDICAL JOURNAL
14. Pratley RE et al. Liraglutide versus 27. Wenten M et al. Relative risk of acute 41. Parikh S et al. Characterisation of
sitagliptin for patients with type 2 pancreatitis in initiators of exenatide urinary tract infections in the setting of
diabetes who did not have adequate twice daily compared with other anti-
diabetic medication: a follow-up study. Presented at the 47th Annual Meeting for
the European Association for the Study of
label trial. Lancet. 2010;375:1447–56.
28. Alves C et al. A meta-analysis Diabetes, 12–16 September 2011, Lisbon,
15. Wang Y et al. Glucagon-like peptide-1 of serious adverse events reported Portugal. Poster 070.
receptor agonists versus insulin in with exenatide and liraglutide: acute 42. Dapagliflozin. Summary of Product
inadequately controlled patients with pancreatitis and cancer. Diabetes Res Clin Characteristics. Bristol-Myers Squibb/
type 2 diabetes mellitus: a meta-analysis Pract. 2012;98:271–84.
of clinical trials. Diabetes Obes Metab. 29. Monami M et al. Dipeptidyl peptidase-4 43. Johnsson K et al. Safety of dapagliflozin
inhibitors and cardiovascular risk: a meta-
16. Krentz AJ Bailey CJ. Oral antidiabetic analysis of randomized clinical trials. mellitus. Presented at the 48th Annual
agents: current role in type 2 diabetes Diabetes Obes Metab. 2013;15:112‒20.
Meeting for the European Association for
30. EMA press release. July 2013 available the Study of Diabetes, 1–5 October 2012,
17. Bydureon™ Summary of product at: http://www.ema.europa.eu/ema/ Berlin, Germany. Poster 743.
characteristics. Amylin Pharmaceuticals. index.jsp?curl=pages/news_and_events/ 44. Ptaszynska A et al. Effects of
18. Nathan DM et al. Medical management jsp&mid=WC0b01ac058004d5c1.
of hyperglycaemia in type 2 diabetes 31. Clinicaltrials.gov. Accessed Aug 2013.
initiation and adjustment of therapy: a 32. Wright EM. Renal Na(+)-glucose on complications in overweight patients
consensus statement from the American cotransporters. Am J Physiol Renal with type 2 diabetes (UKPDS 34). Lancet.
Diabetes Association and the European Physiol. 2001;280:F10–8.
Association for the Study of Diabetes. 33. Lee YJ et al. Regulatory mechanisms
of Na(+)/glucose cotransporters in renal 46. Dormandy JA et al. Secondary
19. Vilsbøll T et al. Effects of glucagon-
proximal tubule cells. Kidney Int Suppl. in patients with type 2 diabetes in
like peptide-1 receptor agonists on 2007;(106):S27–35.
34. Hummel CS et al. Glucose transport pioglitAzone Clinical Trial In
analyses of randomised controlled trials. by human renal Na+/D-glucose macroVascular Events): a randomised
cotransporters SGLT1 and SGLT2. Am J controlled trial. Lancet. 2005;366:1279–
20. Diamant M et al. Once weekly Physiol Cell Physiol. 2011;300:C14–21.
exenatide compared with insulin glargine 35. Forxiga® Summary of product 47. Yki-Järvinen H. The PROactive study:
titrated to target in patients with type 2 characteristics. Bristol-Myers Squibb/
diabetes (DURATION-3): an open-label AstraZeneca 2013.
randomised trial. Lancet. 2010;375:2234–
36. Henry RR et al. Dapagliflozin, metformin
XR, or both: initial pharmacotherapy for of intensive glucose lowering in type 2
21. Noel RA et al. Increased risk of acute type 2 diabetes, a randomised controlled diabetes. N Engl J Med. 2008;358:2545–
pancreatitis and biliary disease observed trial. Int J Clin Pract. 2012;66:446–556.
in patients with type 2 diabetes: a 37. Bailey CJ et al. Dapagliflozin add-on to
metformin in type 2 diabetes inadequately
controlled with metformin: a randomized, vascular outcomes in patients with type 2
22. Girman CJ et al. Patients with type double-blind, placebo-controlled 102-
2 diabetes mellitus have higher risk for week trial. BMC Med. 2013;11:43.
38. Jabbour S et al. Dapagliflozin as part of
type 2 diabetes treated with exenatide or
sitagliptin: a retrospective observational Scientific Sessions, 21–25 June 2013, 51. ORIGIN Trial Investigators. Basal
pharmacy claims analysis. Diabetes Care. Chicago, USA. Abstract 1176-P.
39. Häring HU et al. Empagliflozin as add-
not associated with increased acute renal for 24 weeks improves glycemic control 52. DREAM Trial Investigators et al.
failure. Presented at the 70th American in patients with Type 2 diabetes (T2DM). Effect of rosiglitazone on the frequency
Diabetes Association Scientific Sessions, Presented at the 73rd American Diabetes of diabetes in patients with impaired
June 25–29, 2010, Orlando, Florida, USA. Association Scientific Sessions, 21–25 glucose tolerance or impaired fasting
25. Dore DD et al. Use of a claims-based P.
active drug safety surveillance system 40. Rohwedder K et al. Dapagliflozin, 53. Nissen SE, Wolski K. Effect of
to assess the risk of acute pancreatitis a Sodium-Glucose Cotransporter 2 rosiglitazone on the risk of myocardial
with exenatide or sitagliptin compared Inhibitor, Has a Low Propensity To Cause infarction and death from cardiovascular
to metformin or glyburide. Curr Med Res Hypoglycemia in Patients with Type 2 causes. N Engl J Med. 2007;356:2457–71.
Diabetes. Presented at the 71st American 54. EMA. Guideline on clinical investigation
26. Dore DD et al. A cohort study of acute Diabetes Association Scientific Sessions, of medicinal products in the treatment or
pancreatitis in relation to exenatide use. 24–28 June 2011, San Diego, USA. prevention of diabetes mellitus. Available
Diabetes Obes Metab. 2011;13:559–66. EMJ EUROPEAN MEDICAL JOURNAL EMJ EUROPEAN MEDICAL JOURNAL
56. Lamanna C et al. Effect of metformin 58. Bhatt D et al. SAVOR-TIMI 53:
guideline/2012/06/WC500129256.pdf. on cardiovascular events and mortality: a Saxagliptin Assessment of Vascular
meta-analysis of randomized clinical tri-
55. Food and Drug Administration, als. Diabetes Obes Metab. 2011;13:221–28.
Diabetes Mellitus (SAVOR)-TIMI 53 Study.
2008. Available from: http://www.fda.
57. Scirica BM et al. Saxagliptin and Presented at the European Society of
Cardiovascular Outcomes in Patients with Cardiology Congress 31 August–04
Type 2 Diabetes Mellitus. N Engl J Med. September 2013, Amsterdam, The
EMJ EUROPEAN MEDICAL JOURNAL EMJ EUROPEAN MEDICAL JOURNAL
6 TEMA: HÄLSANS PSYKOLOGI OCH MATENS FYSIOLOGI ”Big Pharma“ Antidepressivum ökar självmordsrisken Gäller Hippokrates ed också för företag som gör miljonvinster på läkemedel eller är de edsvurna inför aktieägarna enbart? mycket själva föreläsningen som hans framtida risker kan undvikas ifall barnets som lider av hjärt- och kärlsjukdomar till intresse för Tobin-fallet
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