Diabetes, obesity and metabolism news and views, April 2020

Abstract

Calorie restriction and exercise are mainstay strategies to lose weight. A study published in the Journal of Endocrinology have shown that limiting access to food increases levels of the “hunger hormone”, ghrelin, which may also increase motivation to exercise. The study conducted in mice showed that a surge in levels of appetite-promoting hormone, ghrelin, triggered by a period of fasting prompted mice to initiate voluntary exercise through actions on the brain reward circuitry that increase motivation to eat. It has also been reported to be essential for endurance exercise by increasing metabolism to meet the energy demands of prolonged exercise. These novel findings indicate that strategies to reduce calorie consumption by not snacking or by intermittent fasting, could facilitate overweight people increase and maintain their exercise routine to help lose weight. While previous studies have reported a relationship between ghrelin and exercise, it is not known whether ghrelin levels have a direct effect on motivation to exercise. In this study conducted by investigators from Kurume University School of Medicine in Japan, the relationship between exercise and ghrelin levels in mice, food intake and wheel-running activity were compared in mice given free access to food and those fed only twice a day for a limited time. Although both groups ate a similar amount of food, the restricted mice ran significantly more. Furthermore, genetically modified mice devoid of ghrelin and on the restricted feeding diet ran less than the mice given free access, which was reversed by administering ghrelin. Additionally, mice given free access to food and given ghrelin also ran significantly more. These findings suggest that ghrelin may play an important role in the motivation for both feeding and exercise. If this is replicated in humans, it may provide not only a physiological rationale to encourage and maintain calorie restriction in tandem with exercise, but may also indicate a new therapeutic application for “ghrelin-mimetic” to enhance exercise.

Although increase evidence have reported a link between poor sleep pattern with increased risk of obesity, type 2 diabetes and heart disease, previous studies have mainly focused on specific foods or macronutrients and only assessed duration rather sleep quality. This new study conducted by researchers at Columbia University Irving Medical Center was therefore designed to get a better understanding between overall diet quality and multiple aspects of sleep quality as risk factors for adverse cardiometabolic risks. In this study, researchers analysed the sleep and eating habits of 495 women, ages 20 to 76 from different ethnic groups. The study looked at sleep quality, the time it took to fall asleep, and insomnia. The women also reported on the types and amounts of foods they typically eat throughout the years. The study found that those with worse overall sleep quality consumed more of the added sugars. In addition, those who took longer to fall asleep had higher caloric intake and ate more food by weight, while women with more severe insomnia symptoms consumed more food by weight and fewer unsaturated fats than women with milder insomnia. The researchers speculate that poor sleep quality may lead to excessive food and calorie intake by stimulating hunger signals or suppressing satiety signals. Thus, improved sleep quality and duration should be incorporated in strategies to dietetic and lifestyle strategies to help lose weight. The study was published in the Journal of American Heart Association.

Liraglutide has been shown to reduced HbA1c levels, induced weight loss and reduce cardiovascular events in people with type 2 diabetes. Its efficacy and safety in overweight or obese people with type 1 diabetes, especially those who are on continuous subcutaneous insulin infusion (CSII) therapy however has not been investigated. A study published in the journal Diabetes, Obesity and Metabolism known as the Lira Pump trial has investigated this. This was a 26-weeks, randomized, double-blind, placebo-controlled trial in 44 overweight or obese adults with type 1 diabetes. Patients were randomized 1:1 to liraglutide 1.8 mg once daily (QD) or placebo added to CSII treatment. The primary endpoint was change in haemoglobin A1c (HbA1c), while secondary endpoints included change in insulin dose, CSII settings, glycaemic variability, body weight and patient-reported outcome measures. Finally, adverse effects including hypoglycaemic events were registered. The study showed significant reduction in HbA1c by 5 mmol/mol (0.5%) compared with a non-significant increase of +2.3 mmol/mol (0.2%) in patients treated with placebo (i.e between-group difference 7 mmol/mol [0.7%], P < 0.001). In addition, Liraglutide reduced total insulin dose by 8 units/day or 16% of total insulin dose (P = 0.008), reduced mean body weight by 6.3 kg (P < 0.001) compared with placebo and increased time spent in glycaemic target range 4–10 mmol/L (71–180 mg/dL), with similar risks of hypoglycaemia between groups at the end of treatment. This was the first study to show the clinical benefits and safety of Liraglutide in overweight or obese patients with type 1 diabetes receiving CSII treatment. Liraglutide therefore should be considered a potential add-on therapy to insulin in this subgroup of patients.

While previous large scale randomised controlled trials have reported risk factors for the development of sight threatening retinopathy and blindness, there remains limited data on the incidence and predictors of visual acuity (VA) loss in type 2 diabetes. A study published in the journal of Diabetes Complications therefore set out to determine the 4-year cumulative incidence of visual impairment and blindness, and the predictors of vision loss, in a representative community-based cohort. The study known as the longitudinal Fremantle Diabetes Study Phase II, recruited 1551 participants with type 2 diabetes between 2008 and 2011. Participants were asked to attend biennial face-to-face assessments including VA measurement. Multivariable logistic regression was used to determine the predictors of vision loss (defined as a decrease in VA by >10 letters at the Year 4 assessment), excluding those with visual impairment (VA >6/19 and ≤ 6/48) and blindness (VA >6/48) at baseline. In this study, 882 participants with normal/near normal vision at baseline had VA data at Year 4 available. During a median [interquartile range] 4.1 [4.0–4.4] years of follow-up, the cumulative incidences of visual impairment and vision loss were 0.9% (n = 8) and 2.9% (n = 26), respectively. No participants developed blindness and 1.9% (n = 17) improved their VA. Multivariable logistic regression showed baseline smoking (OR: 3.17 [95% CI: 1.15–8.76]), prior severe hypoglycemia (5.59 [1.32–23.61]) and urinary albumin: creatinine ratio (uACR) (1.42 (1.09–1.84) for an increase of 1 in ln(uACR)) had higher odds of vision loss during follow-up. While this findings did not suggest causal link between smoking, hypoglycaemia and renal disease with reductions in visual acuity, we could speculate that the implementation of smoking cessation and management strategies that avoid severe hypoglycemia and preserve kidney function are important to prevent vision loss in people with type 2 diabetes. A further prospective intervention study is required to confirm this hypothesis.

Metformin is widely used as the first line treatment option for treating type 2 diabetes but for many years, metformin is contra-indicated in patients with more advanced kidney disease - typically those with estimated glomerular filtration rate (eGFR) of less than 30 – due to potential risks of lactic acidosis. However, the potential benefits of metformin to prevent cardiovascular disease is widely recognised while the risk of lactic acidosis was driven largely by the previous biguanide, phenformin. The present study was therefore set up to investigate the efficacy and safety of metformin in patients with type 2 diabetic kidney disease (DKD). The researchers undertook a retrospective observational cohort study of 10 426 patients with type 2 DKD from two tertiary hospitals. The primary outcomes were all-cause mortality and end-stage renal disease (ESRD) progression. The secondary outcome was metformin-associated lactic acidosis. In order to avoid allocation (selection bias), a propensity score matching (PSM) was conducted to statistically “match” patients who received metformin compared with those who did not receive metformin. Using statistical analysis which adjusted for confounders and by PSM analysis, all-cause mortality and incident ESRD were observed to be significantly lower in the metformin group – i.e. metformin usage was associated with lower all-cause mortality (adjusted hazard ratio [aHR] 0.65; 95% CI 0.57–0.73; P < 0.001) and ESRD progression (aHR 0.67; 95% CI 0.58–0.77; P < 0.001). Crucially and interestingly also, metformin usage did not increase the risk of lactic acidosis events from all causes (aHR 0.92; 95% CI 0.668–1.276; P = 0.629). This retrospective study therefore showed that metformin usage in advanced chronic kidney disease (CKD) patients appears to confer benefits with regards to reduction in the risk of all-cause mortality and incident ESRD. Additionally, metformin did not increase the risk of lactic acidosis. As is the case in retrospective study analysis, the issue of residual bias persists. However, despite the caveats, this study supports the safe and effective use of metformin in patients with DKD. These findings need to be tested in a randomised clinical trial setting.

A previous controversial meta-analysis published in 2007 have highlighted potential increased risk of cardiovascular disease with the thiazolidinediones, rosiglitazone. This finding has revolutionised how new glucose lowering therapy is developed and approved, whilst also heralding important cardiovascular outcome studies with newer glucose lowering agents which included heart failure as an important outcome measure. The cardiovascular safety of rosiglitazone meanwhile continues to be debated, with different studies reporting conflicting data on the cardiovascular safety of rosiglitazone. However, recent efforts by GlaxoSmithKline (GSK) -- the maker of rosiglitazone -- to make Individual Patient level data (IPD) available to external investigators, prompted a team of US researchers to re-analyse the data and clarify some of the uncertainties about rosiglitazone's cardiovascular risk. This new study, which is the most comprehensive evaluation of the cardiovascular risk of rosiglitazone ever done, published in the BMJ have now provided additional evidence that rosiglitazone, is associated with an increased risk of heart problems, especially heart failure. In the present study, the researchers analysed the results of more than 130 trials involving over 48 000 adult patients that compared rosiglitazone with any control for at least 24 weeks. IPD were available for 33 trials, which included 21 156 patients; the remaining trials only had summary level data available. When the researchers analysed the IPD from trials made available by GSK, they found rosiglitazone was associated with a 33% increased risk of a composite cardiovascular event (heart attack, heart failure, cardiovascular and non-cardiovascular related death) compared with controls. This was estimated from the 274 events among 11 837 rosiglitazone patients and 219 events among 9319 control patients. Interestingly, when examining cardiovascular events independently, the analyses of the 33 GSK trials with IPD resulted in higher estimates of the risk of heart attacks than the analyses of trials with IPD and summary level data. These findings highlight the potential for different results derived from different data sources, and demonstrate the need for greater clinical trial transparency and data sharing to accurately assess the safety of drugs, say the researchers.