Immune checkpoint inhibitor‐related hypophysitis and endocrine dysfunction: clinical review

Immune checkpoint inhibitors are a new and effective class of cancer therapy, with ipilimumab being the most established drug in this category. The drugs’ mechanism of action includes promoting the effector T cell response to tumours and therefore increased autoimmunity is a predictable side effect. The endocrine effects of these drugs include hypophysitis and thyroid dysfunction, with rare reports of adrenalitis. The overall incidence of hypophysitis with these medications is up to 9%. Primary thyroid dysfunction occurs in up to 15% of patients, with adrenalitis reported in approximately 1%. The mean onset of endocrine side effects is 9 weeks after initiation (range 5–36 weeks). Investigation and/or screening for hypophysitis requires biochemical and radiological assessment. Hypopituitarism is treated with replacement doses of deficient hormones. Since the endocrine effects of immune checkpoint inhibitors are classed as toxic adverse events, most authors recommend both discontinuation of the immune checkpoint inhibiting medication and ‘high‐dose’ glucocorticoid treatment. However, this has been challenged by some authors, particularly if the endocrine effects can be managed (e.g. pituitary hormone deficiency), and the therapy is proving effective as an anticancer agent. This review describes the mechanism of action of immune checkpoint inhibitors and details the key clinical endocrine‐related consequences of this novel class of immunotherapies.     

Glucocorticoid‐induced hyperglycaemia in respiratory disease: a systematic review and meta‐analysis

The relative risk of glucocorticoid‐induced hyperglycaemia is poorly quantified. We undertook a meta‐analysis to estimate the association between glucocorticoid treatment and hyperglycaemia, overall and separately in individuals with and without diabetes and underlying respiratory disease. We searched electronic databases for clinical trials of adults randomized to either glucocorticoid treatment or placebo. Eight articles comprising 2121 participants were identified. We performed a random effects meta‐analysis to determine relative risks for the associations between glucocorticoid use and both hyperglycaemia and starting hypoglycaemic therapy. In all individuals, the relative risk of hyperglycaemia comparing glucocorticoid treatment with placebo was 1.72 [95% confidence interval (CI) 1.50‐2.04; p < .001]. The relative risks in individuals with and those without diabetes were 2.10 (95% CI 0.92‐5.02; p = .079) and 1.50 (95% CI 0.79‐2.86; p = .22), respectively. In all individuals, the relative risk of hyperglycaemia requiring initiation of hypoglycaemic therapy, comparing glucocorticoid treatment with placebo, was 1.73 (95% CI 1.40‐2.14; p < .001). In conclusion, glucocorticoid therapy increases the risk of hyperglycaemia in all individuals with underlying respiratory disease but not when diabetic status is analysed separately.     

Longitudinal associations between depression and diabetes complications: a systematic review and meta‐analysis

To conduct a systematic review and meta‐analysis of longitudinal studies assessing the bi‐directional association between depression and diabetes macrovascular and microvascular complications. Embase, Medline and PsycINFO databases were searched from inception through 27 November 2017. A total of 4592 abstracts were screened for eligibility. Meta‐analyses used multilevel random/mixed‐effects models. Quality was assessed using the Newcastle‐Ottawa scale. Twenty‐two studies were included in the systematic review. Sixteen studies examined the relationship between baseline depression and incident diabetes complications, of which nine studies involving over one million participants were suitable for meta‐analysis. Depression was associated with an increased risk of incident macrovascular (HR = 1.38; 95% CI: 1.30–1.47) and microvascular disease (HR = 1.33; 95% CI: 1.25–1.41). Six studies examined the association between baseline diabetes complications and subsequent depression, of which two studies involving over 230 000 participants were suitable for meta‐analysis. The results showed that diabetes complications increased the risk of incident depressive disorder (HR = 1.14; 95% CI: 1.07–1.21). The quality analysis showed increased risk of bias notably in the representativeness of selected cohorts and ascertainment of exposure and outcome. Depression in people with diabetes is associated with an increased risk of incident macrovascular and microvascular complications. The relationship between depression and diabetes complications appears bi‐directional. However, the risk of developing diabetes complications in depressed people is higher than the risk of developing depression in people with diabetes complications. The underlying mechanisms warrant further research.     

Prevalence of diabetes in liver cirrhosis: A systematic review and meta‐analysis

An association between diabetes mellitus (DM) and liver cirrhosis is well‐known, but estimates of the prevalence of DM in patients with liver cirrhosis vary widely. A systematic review was undertaken to determine the prevalence of DM in adult patients with liver cirrhosis. The Medline, EMBASE, and Cochrane Library databases were searched for peer‐reviewed studies published in English (1979‐2017) that investigated the prevalence of diabetes in adult patients with cirrhosis. Pooled estimates of prevalence of DM were determined for all eligible patients and according to aetiology and severity of liver disease. Fifty‐eight studies satisfied criteria for inclusion, with 9705 patients included in the pooled prevalence analysis. The overall prevalence of DM was 31%. The prevalence of DM was highest in patients with nonalcoholic fatty liver disease (56%), cryptogenic (51%), hepatitis C (32%), or alcoholic (27%) cirrhosis. For assessing prevalence of DM as a function of severity of liver disease, evaluable data were available only for hepatitis C and hepatitis B cirrhosis. DM may be more prevalent in cirrhosis than previously thought. This has implications for prognosis and treatment in these patients.     

Preterm birth and risk of type 1 and type 2 diabetes: systematic review and meta‐analysis

Preterm birth is suggested to play an important role in the development of diabetes. However, results have been inconsistent. We conducted a systematic review and meta‐analysis to clarify the relationship between preterm birth and type 1 and type 2 diabetes. PubMed, Embase and ISI Web of Science were searched. A total of 18 studies (including 2,176,480 participants and 22,073 cases) for type 1 diabetes and five studies (including 31,478 participants and 1,898 cases) for type 2 diabetes were included in the current meta‐analyses. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) using fixed‐effects model to evaluate the relations between preterm birth and type 1 and type 2 diabetes. The results suggested that preterm birth was significantly associated with increased risk of type 1 diabetes (OR = 1.18, 95% CI = 1.11–1.25), with no evidence of between‐study heterogeneity (I² = 13.2%, P = 0.296). Preterm birth was also significantly associated with increased risk of type 2 diabetes (OR = 1.51, 95% CI = 1.32–1.72), with no evidence of (I² = 0.0%, P = 0.557). Subgroup analyses suggested that there was significant association in both case‐control studies (OR = 1.16, 95% CI = 1.06–1.26) and cohort studies (relative risk = 1.20, 95% CI = 1.11–1.29) for type 1 diabetes, and similar results were found for type 2 diabetes. The results suggested that preterm birth was a significant and independent risk factor for both type 1 and type 2 diabetes.     

Socio‐economic status and HbA1c in type 2 diabetes: A systematic review and meta‐analysis

Up until now, differences in HbA_1c levels by socio‐economic status (SES) have been identified, but not yet quantified in people with type 2 diabetes. The aim of this study was therefore to assess the difference in HbA_1c levels between people with type 2 diabetes of different SES in a systematic review and meta‐analysis. A systematic literature search was conducted in MEDLINE, Embase, Ebsco, and the Cochrane Library until January 14, 2018. Included studies described adults with type 2 diabetes in whom the association between SES and HbA_1c levels was studied. Studies were rated for methodological quality and data were synthesized quantitatively (meta‐analysis) and qualitatively (levels of evidence), stratified for type of SES variable, i.e., education, income, deprivation, and employment. Fifty‐one studies were included: 15 high, 27 moderate, and 9 of low methodological quality. Strong evidence was provided that people of low SES have higher HbA_1c levels than people of high SES, for deprivation, education, and employment status. The pooled mean difference in HbA_1c levels between people of low and high SES was 0.26% (95% CI, 0.09‐0.43) or 3.12 mmol/mol (95% CI, 1.21‐5.04) for education and 0.20% (95% CI, ?0.05 to 0.46) or 2.36 mmol/mol (95%CI, ?0.61 to 5.33) for income. In conclusion, our systematic review and meta‐analysis showed that there was an inverse association between SES and HbA_1c levels in people with type 2 diabetes. Future research should focus on finding SES‐sensitive strategies to reduce HbA_1c levels in people with type 2 diabetes.