Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing?

Journal name:
Nature Reviews Clinical Oncology
Year published:
Published online


The prevalence of obesity, of type 2 diabetes mellitus (T2DM), and of cancer are all increasing globally. The relationships between these diseases are complex, and thus difficult to elucidate; nevertheless, evidence supports the hypothesis that obesity increases the risks of both T2DM and certain cancers. Further complexity arises from controversial evidence that specific drugs used in the treatment of T2DM increase or decrease cancer risk or influence cancer prognosis. Herein, we review the current evidence from studies that have addressed these relationships, and summarize the methodological challenges that are frequently encountered in such research. We also outline the physiology that links obesity, T2DM, and neoplasia. Finally, we outline the practical principles relevant to the increasingly common challenge of managing patients who have been diagnosed with both diabetes and cancer.

At a glance


  1. Simplified representation of the physiological processes that might link obesity, diabetes, and neoplasia.
    Figure 1: Simplified representation of the physiological processes that might link obesity, diabetes, and neoplasia.

    When caloric intake exceeds energy expenditure insulin levels rise and excess energy is stored in adipose tissue. Insulin signals adipocytes to take up glucose and convert it to lipids as a way of storing energy to be used at times of inadequate caloric intake. Chronic excess of caloric intake over energy consumption, however, can lead to insulin resistance in insulin-target tissues, one of the consequences of which is increased hepatic gluconeogenesis — an important cause of hyperglycaemia. If the degree of hyperglycaemia surpasses a defined threshold, type 2 diabetes mellitus (T2DM) will be diagnosed. Importantly, as glucose levels rise, insulin secretion increases, which can reduce glucose levels in some patients, leading to a normoglycaemic, but hyperinsulinaemic, state; however, T2DM characterized by both hyperglycaemia and hyperinsulinaemia develops eventually. Hyperinsulinaemia is hypothesized to stimulate the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway in at least a subset of cancers or cells at risk of malignant transformation, promoting tumour growth or resulting in increased rates of carcinogenesis, respectively. This hypothesis is supported by data from animal models, but remains to be investigated rigorously in the clinic. Other metabolic features of obesity that might influence neoplasia include increased levels of inflammatory cytokines, which stimulate various processes involved in cancer development, and reduced levels of adiponectin, an adipokine that normally inhibits cell proliferation via activation of AMP-activated protein kinase (AMPK). Metformin decreases hyperglycaemia, hyperinsulinaemia, and the consequences of these conditions predominantly by decreasing hepatic gluconeogenesis. This drug might also act directly on cancers or cells at risk of transformation by inducing energy stress, which slows cell proliferation via activation of AMPK and/or other mechanisms. On the other hand, the use of inhibitors of the PI3K pathway to target this signalling cascade in cancer cells could potentially have unintended metabolic consequences, such as hyperglycaemia, owing to off-tumour effects on tissues involved in the regulation of blood glucose, such as adipocytes. mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB.

  2. Clinical vignette and putative causal relationships between obesity, diabetes, antidiabetic medications, cancer, and cancer treatments.
    Figure 2: Clinical vignette and putative causal relationships between obesity, diabetes, antidiabetic medications, cancer, and cancer treatments.

    a | A hypothetical patient with obesity, type 2 diabetes mellitus (T2DM), and breast cancer is depicted. Treatment for early stage breast cancer is commenced on the background of dual antidiabetic therapy with metformin and a sulfonylurea (SU). Further dysglycaemia leads to metformin, thiazolidinedione (TZD), and a dipeptidyl peptidase-4 inhibitor (DPP4i) triple therapy for T2DM, with continuation of adjuvant hormonal therapy for breast cancer. When liver metastases are diagnosed and hyperglycaemia worsens, metformin and TZD are withdrawn; chemotherapy and irradiation are then administered as anticancer therapy, and long-acting (LA) insulin is prescribed to achieve better glycaemic control. Following the diagnosis of brain metastases, the patient is given steroids, necessitating the addition of short-acting (SA) insulin to antidiabetic therapy (with DPPi withdrawal). b | The directed acyclic schematic depicts the possible causal relationships between obesity, T2DM, antidiabetic medications, cancer, and cancer treatments. Obesity is associated with increased mortality in general, but can also lead to T2DM and, possibly, cancer, which further increase morbidity and mortality. Cancer and cancer treatment influence the progression and treatment of T2DM, and possibly vice versa. An example of a hypothesized interaction is the reduction of breast-cancer risk associated with metformin treatment of T2DM. An example of a known clinical interaction is that steroid treatments for brain metastases or chemotherapy-induced vomiting can lead to increased insulin requirements in patients with insulin-dependent diabetes and cancer. BMI, body mass index; HbA1c, haemoglobin A1c (glycated haemoglobin).


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  1. Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Côte Ste-Catherine Road, Montreal, Quebec H3T 1E2, Canada.

    • Adi J. Klil-Drori &
    • Laurent Azoulay
  2. Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Purvis Hall, 1020 Pine Avenue West, Montreal, Quebec H3A 1A2, Canada.

    • Adi J. Klil-Drori &
    • Laurent Azoulay
  3. Departments of Oncology and Medicine, McGill University, McIntyre Medical Building, 3655 Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.

    • Laurent Azoulay &
    • Michael N. Pollak
  4. Segal Cancer Centre, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1E2, Canada.

    • Michael N. Pollak


A.J.K.-D. and M.N.P. researched data for the article and wrote the manuscript. All authors contributed to discussions of content, and reviewed and/or edited the manuscript before submission.

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The authors declare no competing interests.

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  • Adi J. Klil-Drori

    Adi J. Klil-Drori received his MD in 2007 from the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. In 2013, he completed residency and fellowship training in internal medicine and haematology at the Rambam Health Care Campus in Haifa, Israel. In 2016, Dr Klil-Drori completed a 2-year research fellowship in pharmacoepidemiology at the Centre for Clinical Epidemiology of the Jewish General Hospital, Montreal, Quebec, Canada. Currently, Dr Klil-Drori is a clinical fellow with the Clinical Research Unit at the Jewish General Hospital. He continues research in pharmacoepidemiology with a special interest in haematological malignancies and venous thrombosis. Dr Klil-Drori is a recipient of a 2016 Young Investigator Award from the Conquer Cancer Foundation of ASCO.

  • Laurent Azoulay

    Laurent Azoulay is an Associate Professor in the Department of Epidemiology, Biostatistics, and Occupational Health and in the Gerald Bronfman Department of Oncology at McGill University, Montreal, Quebec, Canada. Dr Azoulay has expertise in the design and analysis of pharmacoepidemiological studies using large patient databases. He has published extensively on the safety of antidiabetic drugs, including their effects on cancer incidence and cancer-related outcomes. To date, he has been published close to 100 papers, several of which were published in top-tier journals. His research programme is supported by provincial and national funding agencies.

  • Michael N. Pollak

    Michael N. Pollak is a professor in the Departments of Oncology and Medicine at McGill University, and holds the Alexander-Goldfarb Research Chair. His research training was conducted in the laboratory of Ron Buick at the Ontario Cancer Institute, Toronto, Ontario, Canada. He practices medical oncology at the Jewish General Hospital, and also actively involved in laboratory and clinical research. His lab includes a section that acts as a resource for the measurement of peptide hormone levels in tissue specimens from collaborative population-based research projects and clinical trials. He heads the Division of Cancer Prevention at the Department of Oncology at McGill and the Stroll Cancer Prevention Centre at the Jewish General Hospital. His interests include cancer metabolism and the roles of peptide growth factors and hormones in cancer biology. He has published more than 420 papers with a total of over 16,000 citations. He was awarded the Harold Warwick Prize by the Canadian Cancer Society Research Institute in 2012.

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