Exenatide-induced Acute Pancreatitis

Exenatide-induced Acute Pancreatitis

Walaa A. Ayoub, MD, PhD; Ashok A. Kumar, MD; Hossam S. Naguib, MD; Harris C. Taylor, MD, FACP, FACE

Posted: 03/25/2010; Endocrine Practice. 2010;16(1):80-83. © 2010 American Association of Clinical Endocrinologists
Abstract and Introduction
Abstract

Objective: To report acute pancreatitis in a patient with non–insulin-dependent diabetes mellitus (NIDDM) receiving exenatide and critically review previous reports.
Methods: We describe clinical and laboratory data of a woman with probable exenatide-induced pancreatitis and apply the same criteria to previously published cases.
Results: A 64-year-old, nonalcoholic woman with NIDDM presented with a 1-month history of epigastric pain beginning 2 days after starting exenatide. Serum lipase concentration was 2700 U/L (reference range, 114–320 U/L), and serum amylase concentration was 131 U/L (reference range, 30–110 U/L). Liver function test results, lipid profile, and serum creatinine concentration were normal. Abdominal computed tomography (CT) showed changes consistent with pancreatitis, and the gallbladder was absent. Exenatide was discontinued. Conservative therapy resulted in rapid resolution of symptoms, normal lipase concentration (151 U/L), and normal findings from CT of the pancreas 90 days later. The US Food and Drug Administration has reported 36 cases of presumed pancreatitis associated with exenatide. However, none of the selection criteria were specified, two-thirds of the patients did not have CT, and 90% had at least 1 other risk factor for acute pancreatitis. A single published case report of exenatide-induced pancreatitis contains no description of the pancreas on abdominal CT, does not mention alcohol use, and does not report normal lipase values.
Conclusions: This is the most thoroughly documented example of probable exenatide-induced pancreatitis. In any diabetic patient with acute pancreatitis, exenatide must be ruled out as the cause and its use discontinued.
Introduction

Exenatide is a 39-amino acid synthetic version of exendin-4, a naturally occurring component of Gila monster saliva.[1] Similar to glucagonlike peptide 1, exenatide stimulates glucose-dependent insulin secretion, inhibits hyperglucagonemia, and delays gastric emptying.[2] The US Food and Drug Administration (FDA) approved it in 2005 as adjunctive therapy for non–insulin-dependent diabetes mellitus (NIDDM). Common adverse effects include nausea in 40% to 50% of patients and hypoglycemia in 17% to 27%.[3] Recently, the FDA described 36 patients with pancreatitis related to exenatide use reported through its Adverse Drug Events Reporting System.[4,5] However, inclusion criteria were not specified, individual patient data were not identified, approximately two-thirds of the patients did not have computed tomography (CT) of the pancreas, and most had coexisting alcohol use and/or gallbladder disease.[5] We describe, to our knowledge, the most extensively documented patient with probable exenatide-induced pancreatitis and critically review previous reports.
Case Report

A 64-year-old white woman presented with 1 month of epigastric pain aggravated by food and unrelieved by movements, melena, or rectal bleeding. Medical history included NIDDM, hypertension, hyperlipidemia, and cholecystectomy. She did not smoke cigarettes, had no history of recent trauma or endoscopic retrograde cholangiopancreatography, and did not drink alcohol. Her medications included metformin, 1000 mg twice daily; lovastatin, 40 mg daily; glipizide, 20 mg twice daily; lisinopril, 10 mg daily; furosemide, 40 mg daily; sertraline, 50 mg daily; aspirin, 325 mg daily; calcium carbonate, 1250 mg daily; multivitamin tablet, once daily; and pantoprazole, 40 mg daily. One month before hospital admission, she was prescribed exenatide, 5 mcg twice daily, because of poor glycemic control. This was stopped 10 days before admission because of symptoms that began 2 days after initiation of exenatide therapy.

On physical examination, she weighed 79 kg and was 164 cm tall (body mass index, 29.3 kg/m2). Temperature was 98.4°F, blood pressure was 119/55 mm Hg, and pulse rate was 87 beats/min. Abdominal examination revealed epigastric tenderness, but no mass or rigidity. The serum lipase concentration was 2700 U/L (reference range, 114–320 U/L), and the serum amylase concentration was 131 U/L (reference range, 30–110 U/L). Liver function test results were within normal limits. The following lipid values were documented: total cholesterol, 120 mg/dL; triglycerides, 122 mg/dL; and low-density lipoprotein cholesterol, 61 mg/dL. Serum creatinine concentrations ranged from 0.44 mg/dL to 0.8 mg/dL. A hemoglobin A1c value was 7.8% 2 weeks before hospital admission. Abdominal ultrasonography revealed generalized echogenicity of the liver suggestive of fatty infiltration, but no intrahepatic or extrahepatic biliary dilatation. Abdominal CT showed a diffusely and mildly enlarged pancreas, particularly at the head and body, with surrounding edema, consistent with pancreatitis (Fig. 1). The gallbladder was absent, and no evidence of either stones or intrahepatic or extrahepatic obstruction was noted on CT.

Figure 1. Axial image from abdominal computed tomography at hospital admission showing diffuse enlargement of the pancreas (white arrows), particularly at the head. Pancreatic head transverse diameter is 2.83 cm (white dashed line).

Conservative management included nothing by mouth, intravenous fluids, pain medications, and intravenous pantoprazole. Subsequent daily lipase determinations (U/L) were 2412, 2078, 964, 707, and 610 (Fig. 2). The abdominal pain resolved by day 4, clear fluids were begun, and the diet was advanced without difficulty. The patient was discharged home without sequelae. All medications, except glipizide and exenatide, were restarted at the same preadmission dosages. Insulin glargine, 20 units subcutaneously daily, and insulin aspart, as per sliding scale 3 times daily before meals, were added. Repeated abdominal CT 90 days after initial hospital admission showed resolution of pancreatitis, and again, no evidence of stones or intrahepatic or extrahepatic obstruction was seen (Fig. 3). Serum lipase, amylase, and creatinine concentrations remained in the reference range at 1, 4, 8, and 12 weeks after discharge.

Figure 2. Serum lipase concentrations during and after acute pancreatitis. Reference range, 114–320 U/L.

Figure 3. Axial image from follow-up abdominal computed tomography 90 days after initial hospital admission, showing complete resolution of the previous pancreatic inflammatory changes and surrounding edema (white arrows). Pancreatic head transverse diameter is 1.53 cm (white dashed line).

Discussion

The most common cause of acute pancreatitis is gallstone disease (accounting for 30% to 60% of cases), followed by alcohol (5% to 30%), and hypertriglyceridemia (1.3% to 3.8%). The serum triglyceride levels are usually greater than 1000 mg/dL when hypertriglyceridemia is the etiology.[6] Because this patient had a cholecystectomy, had no evidence of intrahepatic or extrahepatic duct obstruction, had no history of trauma or endoscopic retrograde cholangiopancreatography, did not drink alcohol, and had a normal lipid profile, we explored other etiologies. The commencement of exenatide treatment just before the onset of symptoms was striking.

The FDA has now described 36 cases of presumed pancreatitis in association with exenatide treatment.[4,5] These are based on cases reported through the Adverse Drug Events Reporting System and have resulted in the manufacturer strengthening its labeling with regard to acute pancreatitis. On the package insert, this information was moved from the "Adverse Reactions" section to the "Precautions" section.[4]

Despite these changes and the resultant publicity, none of the FDA selection criteria for inclusion are specified. The exact concentrations of serum lipase were not mentioned for individual cases, thereby making it impossible to discern whether any of these patients had lipase levels below the generally accepted value of at least 3 times the upper level of normal, which confers 99% specificity for pancreatitis.[7] Creatinine levels were not included for any of the cases; when elevated, creatinine is known to increase lipase values.[8] Moreover, 27 of the first 30 reported patients had at least 1 other risk factor known to cause acute pancreatitis. Finally, only 11 of 30 patients had ultrasonography or CT of the pancreas.[5]

To our knowledge, there is only 1 published case report of exenatide-induced pancreatitis—that of Denker and Dimarco in 2006.[9] Regrettably, the reference ranges for amylase or lipase, which vary by laboratory method, were not reported; no description of the pancreas on abdominal CT was provided; and alcohol use was not mentioned. We believe the patient we describe represents the most thoroughly documented case of probable exenatide-induced pancreatitis and is supported by a Naranjo score of 7/9, signifying a probable association.[10] The Naranjo scale consists of a 10-item, yes or no questionnaire used to estimate the probability of a change in clinical status being due to an adverse drug reaction. A score of 9 or greater indicates that an adverse drug reaction is "highly probable"; 5–8 indicates "probable"; 1–4 indicates "possible"; and 0 or less indicates "doubtful." For a quarter of a century, the Naranjo scale has been widely accepted in the pharmacologic literature to assess the probability of an adverse drug reaction.[11]

Obviously, an occult etiology for the patient's pancreatitis cannot be entirely discounted without rechallenging with exenatide, an unethical intervention in this circumstance. Although pancreatitis has been reported with furosemide, lisinopril, lovastatin, sertraline, and metformin, their protracted use in the described patient without change in dosage militates against their being the etiologic agent.[12] To our knowledge, there has been no report of glipizide causing pancreatitis, although single case reports of the association of pancreatitis and glimepiride and gliclazide do exist.[13,14] Reinstitution of these medications, with the exception of glipizide and exenatide, at the same dosages did not result in recrudescence of symptoms, abnormal serum lipase concentration, or radiographic evidence of pancreatitis in our patient. Whether the presence of these drugs may have rendered her more susceptible to exenatide is speculative in the absence of rechallenging with the drug. These pharmaceuticals are, of course, used with great frequency in patients with NIDDM.

Most recently, Dore et al published an assessment of cohorts of 27 996 exenatide initiators and 16 276 sitagliptin initiators and approximately equal numbers of matched metformin or glyburide initiators.[15] During follow-up of up to 1 year, acute pancreatitis occurred in 0.13% of patients treated with exenatide and in 0.12% of patients treated with sitagliptin. In comparison with metformin and glyburide, the relative risk was 1.0 for both drugs. Although this study may help define the magnitude of the problem, 4 points require emphasis. First, the method used, "an active drug surveillance system that applies propensity score matching methodology to a large automated health care claims data set for safety signal detection and assessment," is proprietary. We are unaware of any independent published validation of the system. Second, because pancreatitis was identified according to hospitalization claims associated with a primary International Classification ofDiseases, Ninth Revision diagnosis (577.0) of acute pancreatitis, there is no adjudication of the diagnoses. Third, the specificity of the method is, by the authors' acknowledgment only 72%.[16] Finally, even if we accept the data as valid, this does not address the possibility of a rare adverse drug reaction.

The mechanism for this adverse drug reaction is unknown. Exenatide antibodies develop in 40% to 50% of patients using the drug.[17] Exenatide's mechanism of action involves its binding to the pancreatic glucagonlike peptide 1 receptor. It is possible, therefore, but entirely speculative, that these antibodies might cross-react in susceptible patients with various pancreatic antigens, including the exenatide-glucagonlike peptide 1 receptor complex, resulting in pancreatitis.
Conclusion

The temporal relation of the symptoms to the onset and cessation of therapy, in the absence of other identifiable causes of pancreatitis, together with the normalization of clinical, laboratory, and radiographic parameters on drug withdrawal, strongly suggest exenatide as the etiology of pancreatitis in this patient. In any diabetic patient with acute pancreatitis, exenatide must be ruled out as the cause and its use discontinued.
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References

1. Dungan KM, Buse JB. Glucagon-like peptide 1-based therapies for type 2 diabetes: a focus on exenatide. ClinDiabetes. 2005;23:56–62.
2. Kolterman OG, Kim DD, Shen L, et al. Pharmoacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005;62:173–181.
3. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083–1091.
4. US Food and Drug Administration. FDA alert: Information for healthcare professionals: exenatide (marketed as Byetta). Available at: http://www.fda.gov/Drugs/DrugSafety/ostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm. Updated August 2008.
5. Cure P, Pileggi A, Alejandro R. Exenatide and rare adverse events. N Engl J Med. 2008;358:1969–1972.
6. Greenberger NJ, Toskes PP. Acute and chronic pancreatitis. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison'sPrinciples of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Professional, 2008: 2005–2027.
7. Gumaste VV, Roditis N, Mehta D, Dave PB. Serum lipase levels in nonpancreatic abdominal pain versus acute pancreatitis. Am J Gastroenterol. 1993;88:2051–2055.
8. Lin XZ, Chen TW, Wang SS, et al. Pancreatic enzymes in uremic patients with or without dialysis. Clin Biochem. 1988;21:189–192.
9. Denker PS, Dimarco PE. Exenatide (exendin-4)-induced pancreatitis: A case report. Diabetes Care. 2006;29:471.
10. Naranjo CA, Busto U, Seller EM, et al. A method for estimating the probability of adverse drug reactions. ClinPharmacol Ther. 1981;30:239–245.
11. Doherty MJ. Algorithms for assessing the probability of an adverse drug reaction. Respir Med. 2009;2:63–67.
12. Kaurich T. Drug-induced acute pancreatitis: Proc (BaylUniv Med Cent). 2008;21:77–81.
13. Duboeuf T, De Widerspach-Thor A, Scotto B, Bacq Y. Acute glimepiride-induced pancreatitis [article in French]. Gastroenterol Clin Biol. 2004;28:409–410.
14. Roblin X, Abinader Y, Baziz A. Acute pancreatitis induced by gliclazide [article in French]. Gastroenterol ClinBiol. 1992;16:96.
15. Dore DD, Seeger JD, Arnold Chan K. Use of a claimsbased active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin. 2009;25:1019–1027.
16. Yadav D. How accurate are ICD codes-9 for acute (AP) and chronic pancreatitis (CP)? A large VA hospital experience. Pancreas. 2006;33:508.
17. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092–1100.

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Authors and Disclosures

Walaa A. Ayoub, MD, PhD; Ashok A. Kumar, MD; Hossam S. Naguib, MD; Harris C. Taylor, MD, FACP, FACE

Department of Internal Medicine, Fairview General Hospital, Cleveland Clinic Health System, Westlake, Ohio.

Address correspondence and reprint requests to
Dr. Walaa A. Ayoub, Department of Internal Medicine, Fairview General Hospital, Cleveland Clinic Health System, 28283 Center Ridge Rd, Suite E-23, Westlake, OH 44145. E-mail: w_gabra@yahoo.com

Disclosure
The authors have no multiplicity of interest to disclose.

Abbreviations
CT = computed tomography; FDA = US Food and Drug Administration; NIDDM = non–insulin-dependent diabetes mellitus

Acknowledgment
This case report was presented as a poster at The Endocrine Society's Annual Meeting, Washington, DC, June 10–13, 2009.

Endocrine Practice. 2010;16(1):80-83. © 2010 American Association of Clinical Endocrinologists

RECEITA DE PÁSCOA PARA PACEINTES COM DIABETES

No site da SBD, receitas para páscoa dos pacientes com diabetes. Vale a pena conferir
http://www.diabetes.org.br/component/content/article/45-noticias-em-destaque/224-pascoa

Encontro Da Liga de Endocrinologia de Maringá

Clique aqui para ver as fotos do Primeiro Encontro da Liga de Endocrinologia Pediátrica de Maringá. O Evento ocorreu agora, dia 20 de março e contou com a participação de 170 participantes. Muitas discussões e alta produtividade no bem organizado evento.

http://bit.ly/crH323

Todas as pesquisas que acontecem nesse momento com células tronco

Clique no link para ler sobre todas as pesquisas em andamento no mundo sobre células tronco e o diabetes. Boa leitura

http://www.clinicaltrials.gov/ct2/results?term=stem+cell+diabetes

An Endocrine Society Statement to Providers on Study Findings Related to Treatment of Hypertension in Patients with Diabetes

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An Endocrine Society Statement to Providers on Study Findings Related to Treatment of Hypertension in Patients with Diabetes
March 18, 2010

On March 14, three studies presented at an American College of Cardiology meeting raised questions about whether normalization of blood pressure in hypertensive patients with diabetes or those with impaired glucose tolerance and cardiovascular risk factors could lead to a reduction in the rate of cardiovascular events. Two of these papers, covering findings from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial (ACCORD BP) and Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, were simultaneously published on-line in the New England Journal of Medicine.

These studies do not advise against the treatment of hypertension in patients with diabetes; the controversy concerns the target level to which blood pressure should be reduced in these patients. The conclusions of the ACCORD BP study suggest that achieving a systolic blood pressure of 120 mm Hg compared to 140 mm Hg does not reduce the rate of major cardiovascular events. Furthermore, systolic blood pressure levels in the intensive treatment arm of the study were associated with more adverse events, including higher rates of hypokalemia and elevations of serum creatinine. The NAVIGATOR study similarly concludes that the addition of Valsartan to the treatment regimen for patients with impaired glucose tolerance did not reduce the rate of cardiovascular events. The final study, INVEST, evaluated a control group compared to a moderate blood pressure group and an intensive blood pressure group in hypertensive diabetic patients with heart disease. While the greatest morbidity and mortality was seen in the control group, there was an increase in mortality in the intensively treated group compared to the moderate blood pressure control group, though this finding was restricted to those who achieved systolic blood pressure less than 115 mm Hg.

In interpreting these findings, The Endocrine Society recommends that practitioners consider several points. First, the INVEST study has only been presented in abstract form and has not yet been through the formal peer review process leading to publication. Second, the ACCORD BP and NAVIGATOR studies evaluated patients with modest degrees of hyperglycemia and hypertension, so extrapolating the results from the latter two papers to patients with more significant hyperglycemia and hypertension could be problematic. Moreover, in the NAVIGATOR trial, the achieved difference in blood pressure between the group that received Valsartan and the control group was only 2.8/1.4 mm Hg, a difference that may be too small to lead to differences in cardiovascular outcomes.

It should also be noted that the ACCORD BP study found some significant improvements in secondary outcome measures. Total strokes were reduced by 41% in the intensively managed group compared to controls (from 0.53% to 0.32%).

The Endocrine Society continues to support the treatment of hypertension in patients with diabetes and recommends that patients should not modify or discontinue antihypertensive medications without consulting their physicians. While a systolic blood pressure target below 140 mm Hg in hypertensive patients with diabetes remains a reasonable goal and seems consistent with the findings of these new studies, reductions in blood pressure below this level might not afford much additional cardiovascular benefit. Furthermore, aggressive systolic blood pressure targets below 120 mm Hg may be detrimental. In light of these studies, the current Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) and American Diabetes Association recommendations (less than 130/80 mm Hg for patients with diabetes) seem prudent for many, but not all patients. In patients with significantly higher blood pressure and blood sugar than the subjects in these studies, the optimum blood pressure goal remains to be defined.

Cardiologia diabetológica por Dr. Pimazoni

CARDIOLOGIA DIABETOLÓGICA E PREVENÇÃO DO DIABETES: NOVOS ESTUDOS CONTESTAM CONCEITOS TRADICIONAIS

Dr. Augusto Pimazoni Netto

Coordenador dos Grupos de Educação e Controle do Diabetes do
Hospital do Rim e Hipertensão da Universidade Federal de São Paulo – UNIFESP e do

Centro de Diabetes do Hospital Alemão Oswaldo Cruz.

A edição Online First do New England Journal Medicine (NEJM) de hoje, 14 de março de 2010, nos traz os resultados de dois grandes estudos (ACCORD e NAVIGATOR), cujos resultados contestam conceitos tradicionais nas áreas de cardiologia diabetológica e prevenção do diabetes.

Resultados preliminares do estudo ACCORD mostraram que uma estratégia muito intensificada de controle glicêmico aumentou o risco de morte em pacientes diabéticos, muito embora essa conclusão tenha sido recentemente contestada por uma metanálise publicada no Lancet [1]. Agora, a publicação do NEJM traz os resultados do braço do estudo ACCORD que avaliou o impacto do controle intensivo da pressão arterial [2], bem como a eficácia da terapia de combinação para o controle de lípides no paciente diabético [3].

Até agora, não havia evidência de estudos randomizados para se adotar metas abaixo de 135 a 140 mmHg para a pressão sistólica em portadores de diabetes tipo 2 (DM-2), muito embora a meta de 120 mmHg já estivesse sendo adotada há algum tempo pelas sociedades médicas. O braço do estudo ACCORD que tentou comprovar a validade dessa recomendação investigou se uma meta de pressão sistólica menor que 120 mmHg conseguiria efetivamente reduzir a incidência de eventos cardiovasculares em pacientes com DM-2 de maior risco. O resultado foi decepcionante: em pacientes com DM-2 e com alto risco para eventos cardiovasculares, a utilização da meta de 120 mmHg para a pressão sistólica não reduziu as taxas de desfecho composto para os principais eventos cardiovasculares fatais e não fatais [2].

Outro braço do estudo ACCORD avaliou se os efeitos da terapia de combinação com sinvastatina mais fibrato, em comparação com a monoterapia com sinvastatina, poderia reduzir o risco cardiovascular em pacientes com DM-2 já em risco aumentado para essas complicações. Mais uma vez os resultados foram decepcionantes: a combinação de fenofibrato mais sinvastatina não reduziu a taxa de eventos cardiovasculares fatais, de infarto do miocárdio não fatal e de acidente vascular cerebral não fatal, em comparação à monoterapia com sinvastatina, ou seja, os resultados do estudo não suportaram o uso rotineiro da terapia de combinação com fenofibrato e sinvastatina para reduzir o risco cardiovascular na maioria dos pacientes com diabetes tipo 2 de maior risco [3].

O estudo NAVIGATOR avaliou estratégias de prevenção do DM-2 e também mostrou resultados frustrantes. Diante do conceito tradicional de que alguns fármacos poderiam promover a prevenção adequada do DM-2, um braço do estudo NAVIGATOR avaliou o potencial da nateglinida, um secretagogo de insulina de curta duração, de reduzir o risco de diabetes ou de eventos cardiovasculares em pessoas com tolerância diminuída à glicose. Os dados desse braço do estudo mostraram que o tratamento com nateglinida por cinco anos não reduziu a incidência de diabetes ou os desfechos cardiovasculares nesses pacientes [4].

Um segundo braço do estudo NAVIGATOR avaliou os efeitos da valsartana, em comparação com placebo, associados a modificações do estilo de vida em indivíduos com tolerância diminuída à glicose e com doença cardiovascular estabelecida ou com fatores de risco cardiovascular. Os resultados mostraram que, nesses pacientes, o uso da valsartana por cinco anos, em comparação ao placebo, ambos associados a modificações do estilo de vida, levou a uma redução relativa de 14% na incidência de diabetes, mas não conseguiu reduzir a taxa de eventos cardiovasculares [5].

Resumo da ópera: a cada novo estudo publicado, aumentam nossas incertezas quanto ao que se deve ou não se deve fazer na prática clínica, principalmente em função dos resultados quase que frequentemente contraditórios entre os vários estudos. E como superar as incertezas decorrentes dessas controvérsias? O acompanhamento atento da literatura internacional, aliado à experiência clínica de cada um em seus respectivos setores de atividade, talvez seja a forma mais segura de fazer frente à transitoriedade das verdades médicas.

Referências Bibliográficas:

1. Ray, K.K. et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis os randomised controlled trials. Lancet 2009;373:1765-72.
2. The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 10.1056/NEJMoa1001286. Publicado online em 14 de março de 2010.
3. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 10.1056/NEJMoa1001282. Publicado online em 14 de março de 2010.
4. The NAVIGATOR Study Group. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 10.1056/NEJMoa1001122. Publicado online em 14 de março de 2010.
5. The NAVIGATOR Study Group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 10.1056/NEJMoa1001121. Publicado online em 14 de março de 2010.

Calendário para vacina H1N1 no Brasil. Diabéticos terão suas vacinas de 22/03 a 02/04