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Cancer Research: Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality.

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Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality.

Physiol Rev. 2015 Jul;95(3):727-48

Authors: Gallagher EJ, LeRoith D

Obesity and type 2 diabetes are becoming increasingly prevalent worldwide, and both are associated with an increased incidence and mortality from many cancers. The metabolic abnormalities associated with type 2 diabetes develop many years before the onset of diabetes and, therefore, may be contributing to cancer risk before individuals are aware that they are at risk. Multiple factors potentially contribute to the progression of cancer in obesity and type 2 diabetes, including hyperinsulinemia and insulin-like growth factor I, hyperglycemia, dyslipidemia, adipokines and cytokines, and the gut microbiome. These metabolic changes may contribute directly or indirectly to cancer progression. Intentional weight loss may protect against cancer development, and therapies for diabetes may prove to be effective adjuvant agents in reducing cancer progression. In this review we discuss the current epidemiology, basic science, and clinical data that link obesity, diabetes, and cancer and how treating obesity and type 2 diabetes could also reduce cancer risk and improve outcomes.

PMID: 26084689 [PubMed – indexed for MEDLINE]

pubmed: clinical cancer rese…

Cancer Research: Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.

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Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.

N Engl J Med. 2015 Jul 16;373(3):232-42

Authors: Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR, TECOS Study Group

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease.
METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.
RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).
CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS number, NCT00790205.).

PMID: 26052984 [PubMed – indexed for MEDLINE]

pubmed: clinical cancer rese…

Cancer Research: Stratified medicine for the use of antidiabetic medication in treatment of type II diabetes and cancer: where do we go from here?

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Stratified medicine for the use of antidiabetic medication in treatment of type II diabetes and cancer: where do we go from here?

J Intern Med. 2015 Feb;277(2):235-47

Authors: Emami-Riedmaier A, Schaeffeler E, Nies AT, Mörike K, Schwab M

At present, the global diabetes epidemic is affecting 347 million individuals, 90% of whom are diagnosed with type II diabetes mellitus (T2DM). T2DM is commonly treated with more than one type of therapy, including oral antidiabetic drugs (OADs) and agents used in the treatment of diabetic complications. Several pharmacological classes of OADs are currently available for the treatment of T2DM, of which insulin secretagogues (i.e. sulphonylureas and meglitinides), insulin sensitizers [thiazolidinediones (TZDs)] and biguanides are the most commonly prescribed. Although many of these OADs have been used for more than half a century in the treatment of T2DM, the pharmacogenomic characteristics of these compounds have only recently been investigated, primarily in retrospective studies. Recent advances in pharmacogenomics have led to the identification of polymorphisms that affect the expression and function of drug-metabolizing enzymes and drug transporters, as well as drug targets and receptors. These polymorphisms have been shown to affect the therapeutic response to and side effects associated with OADs. The aim of this review was to provide an up-to-date summary of some of the pharmacogenomic data obtained from studies of T2DM treatment, with a focus on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly prescribed OADs. In addition, the implications of pharmacogenomics in the use of the OAD metformin in cancer will be briefly discussed. Finally, we will focus on recent advances in novel ‘omics’ technologies and discuss how these might aid in the personalized management of T2DM.

PMID: 25418285 [PubMed – indexed for MEDLINE]

pubmed: clinical cancer rese…

Cancer Research: Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality.

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Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality.

JAMA. 2015 Jan 6;313(1):45-53

Authors: Writing Group for the DCCT/EDIC Research Group, Orchard TJ, Nathan DM, Zinman B, Cleary P, Brillon D, Backlund JY, Lachin JM

IMPORTANCE: Whether mortality in type 1 diabetes mellitus is affected following intensive glycemic therapy has not been established.
OBJECTIVE: To determine whether mortality differed between the original intensive and conventional treatment groups in the long-term follow-up of the Diabetes Control and Complications Trial (DCCT) cohort.
DESIGN, SETTING, AND PARTICIPANTS: After the DCCT (1983-1993) ended, participants were followed up in a multisite (27 US and Canadian academic clinical centers) observational study (Epidemiology of Diabetes Control and Complications [EDIC]) until December 31, 2012. Participants were 1441 healthy volunteers with diabetes mellitus who, at baseline, were 13 to 39 years of age with 1 to 15 years of diabetes duration and no or early microvascular complications, and without hypertension, preexisting cardiovascular disease, or other potentially life-threatening disease.
INTERVENTIONS AND EXPOSURES: During the clinical trial, participants were randomly assigned to receive intensive therapy (n = 711) aimed at achieving glycemia as close to the nondiabetic range as safely possible, or conventional therapy (n = 730) with the goal of avoiding symptomatic hypoglycemia and hyperglycemia. At the end of the DCCT, after a mean of 6.5 years, intensive therapy was taught and recommended to all participants and diabetes care was returned to personal physicians.
MAIN OUTCOMES AND MEASURES: Total and cause-specific mortality was assessed through annual contact with family and friends and through records over 27 years’ mean follow-up.
RESULTS: Vital status was ascertained for 1429 (99.2%) participants. There were 107 deaths, 64 in the conventional and 43 in the intensive group. The absolute risk difference was -109 per 100,000 patient-years (95% CI, -218 to -1), with lower all-cause mortality risk in the intensive therapy group (hazard ratio [HR] = 0.67 [95% CI, 0.46-0.99]; P = .045). Primary causes of death were cardiovascular disease (24 deaths; 22.4%), cancer (21 deaths; 19.6%), acute diabetes complications (19 deaths; 17.8%), and accidents or suicide (18 deaths; 16.8%). Higher levels of glycated hemoglobin (HbA1c) were associated with all-cause mortality (HR = 1.56 [95% CI, 1.35-1.81 per 10% relative increase in HbA1c]; P < .001), as well as the development of albuminuria (HR = 2.20 [95% CI, 1.46-3.31]; P < .001).
CONCLUSIONS AND RELEVANCE: After a mean of 27 years’ follow-up of patients with type 1 diabetes, 6.5 years of initial intensive diabetes therapy was associated with a modestly lower all-cause mortality rate when compared with conventional therapy.
TRIAL REGISTRATION: Identifiers: NCT00360815 and NCT00360893.

PMID: 25562265 [PubMed – indexed for MEDLINE]

pubmed: clinical cancer rese…

Cancer Research: Diabetes and cancer: 5 years into the recent controversy.

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Diabetes and cancer: 5 years into the recent controversy.

Eur J Cancer. 2014 Aug;50(12):2119-25

Authors: Badrick E, Renehan AG

Diabetes and cancer are common chronic disorders. The literature has long recognised that type 2 diabetes (T2D) is associated with an increased incident risk of several cancer types, independent of the mutual risk factor, obesity. However, in June 2009, four papers were published simultaneously in Diabetologia, the official journal of the European Association for the Study of Diabetes, raising questions of a link between diabetes therapies, notably the long-acting insulin analogue, glargine, and increased cancer risk. These papers awakened an unprecedented debate in the diabetes community, drawing in cancer experts and bringing together representatives from these two large, traditionally non-intersecting, biomedical communities. This Current Perspective summarises the events that followed the ‘breaking news’ from summer 2009: the pitfalls encountered; the increased mutual understanding between diabetes and cancer researchers; and the direction of current research. Much of the debate on the clinical impact of this controversy has been played out in the diabetes literature: here, we update the oncology readership.

PMID: 24930060 [PubMed – indexed for MEDLINE]

pubmed: clinical cancer rese…