Horizon placement: Editorial feed

Posted on | by Lee Webber

In a new series of films on Horizons, leading researchers and clinicians from around the world talk about the journal articles that have left a deep impression on their understanding and practice in the field of diabetes.

Scientific discovery is a slow, painstaking business. Eureka moments are few and far between. Even so, it’s the breakthroughs that stick in the mind. Those turning points – usually accompanied by a much pored-over journal article and hinging on the sharing and accumulation of knowledge over many years – when, for the scientific community, the penny finally drops and our collective understanding advances.

The history of diabetes research is unusually blessed with such moments. The Diabetes Control and Complications Trial, which conclusively demonstrated the importance of tight glycaemic (and blood pressure) control in preventing the complications of type 1 diabetes. The United Kingdom Prospective Diabetes Study, which did much the same for type 2 diabetes. And of course, just over a century ago, the discovery of insulin itself.

We wanted to know which trial results and articles had been breakthrough moments for our authors and collaborators. Starting earlier this year, whenever we were filming a module or panel discussion, we began asking presenters or participants to choose the diabetes-related journal article that had had the biggest impact on them, and to explain how it had affected their understanding of diabetes and their practice as a researcher or clinician. The result is a new film series -‘Gamechangers’ – which starts on Horizons this week.

To kick the series off, EASD President Professor Stefano Del Prato chooses two articles, separated by 20 years but closely connected by subject (the effects of phlorizin on glycaemia and insulin secretion) and ultimately by their potential to transform the treatment of diabetes:

Rossetti L, Shulman GI, Zawalich W, De Fronzo RA. Effect of Chronic Hyperglycemia on In Vivo Insulin Secretion in Partially Panceatectomized Rats. J Clin Invest. 1989 (Oct):80; 1037-1044. https://pubmed.ncbi.nlm.nih.gov/3308956/

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. NEJM. 2015 (Nov): 2117-2128. https://pubmed.ncbi.nlm.nih.gov/26378978/

Watch the first film in the ‘Gamechangers’ series, ‘New vision, new treatment’ presented by Professor Stefano Del Prato, launching this week on Horizons.

For more on this topic, enrol on the following EASD e-Learning course:

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on | by Lee Webber

In his new module for EASD e-Learning, Professor Eelco de Koning considers the various options available for restoring normal glucose regulation by replacing insulin-producing cells – whether through islets or whole pancreas transplantation.

Eelco de Koning, Professor of Diabetology at Leiden University Medical Center, The Netherlands, is in no doubt about the challenges posed by diabetes self-management. “We should all realise that the insulin-producing cell is the perfect closed-loop system,” he says. “It measures glucose continuously. It provides the right signals to the secretory part of the insulin-producing cell, providing exactly the amount of insulin that is needed. The insulin will have its effect on glucose uptake, especially in muscle and fat tissue. And the lowering of glucose by increased glucose uptake will be detected by the glucose sensor. In our treatment of patients with severe beta cell failure, we try to mimic this sensory function and the secretory function of the cell as well as possible. But it is impossible to achieve a perfect mimicry of this. And therefore, chronic hyperglycaemia will always exist, even with the advanced hybrid closed-loop systems that are currently available. So the only real solution for completely normal glucose regulation without risk of hypoglycaemia is replacement of the insulin-producing cells. But how do we do that?”

This last point is the central question addressed by Eelco’s module. Several transplantation options are now available, including islet transplants, simultaneous pancreas-kidney transplants and pancreas transplantation alone. All carry risks – not least the necessity for immunosuppressive treatment for as long as the transplant endures. Whole pancreas options carry additional surgical risk, including bleeds, leaks and fistulas. Islet grafts will likely require more than one infusion of islets due to the high rate of beta cell mass-loss involved. All are constrained by availability of donor tissues.

Weighed against these are the benefits in terms of glycaemic control, risk of diabetes complications, long-term survival and quality of life. Of huge significance for many transplant recipients is the associated relief from hypoglycaemia – a benefit Eelco is keen to highlight, and spoke passionately to in his podcast on ‘The patient who changed the way I think about diabetes’. He describes the case of a middle-aged woman whose life had been seriously disrupted by repeated episodes of severe hypoglycaemia and loss of hypo awareness. “When we performed an islet transplantation it really transformed her life. She still needed a little bit of long-acting insulin, but still her life changed in a way that she was able to go out again, to go shopping, to interact with her friends, to have a social life. This example showed me what the impact of type 1 diabetes can be on patients that have to live with type 1 diabetes every minute of their life. And it also showed me the power of islet replacement therapy, the enormous impact that can have in a positive way on the lives of patients with type 1 diabetes.”

Eelco’s module ‘Pancreas and islet transplantation’ launches this week on the EASD e-Learning platform.

Don’t miss ‘Hypo impact’, Eelco’s contribution to our series The patient who changed the way I think about diabetes’, available on Horizons.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on | by Lee Webber

The impact of sedentary behaviour in pregnancy and how to address it was a hot topic at the ADA’s latest conference. Lisa Buckingham reports.

Light-intensity physical activity (PA) and its health benefits is a growing area of research.  Compared with formal exercise and moderate/vigorous-intensity exercise, it’s a topic we have much to learn about, according to Dr Sylvia Badon, perinatal epidemiologist at the Kaiser Permanente Northern California Division of Research. Her presentation at the American Diabetes Association’s (ADA) Scientific Sessions in June centred on sedentary behaviour, 24-hour movement and diabetes in pregnancy.

Sedentary behaviour is how a large proportion of people spend their days and Dr Badon began by defining it as any waking behaviour characterised by an energy expenditure of 1.5 metabolic equivalents of task (METs) or less while in a sitting, reclining or lying posture. It’s distinct from inactivity, which is activity that doesn’t accumulate enough to be classed as light-intensity PA.

With regard to sedentary behaviour during pregnancy, research suggests that it has adverse effects on glucose metabolism. It also shows that pregnant individuals tend to be more sedentary than the general adult population, which is important to bear in mind when considering interventions, said Dr Badon. On average, they spend between seven and 18 hours a day being sedentary and the few studies that look at how this pans out across pregnancy suggest there may be an increase in sedentary behaviour as the pregnancy progresses.

Several studies have looked at how total time spent being sedentary impacts risk for gestational diabetes (GDM). Dr Badon highlighted a piece of research from 2022, which showed that the more time spent sitting in the early to mid-pregnancy stage, the higher the risk of GDM.

There have also been studies that looked at the impact of sedentary behaviour in pregnancy on glucose metabolism outside the context of GDM. This research finds that higher levels of sedentary behaviour is associated with higher fasting glucose, higher fasting insulin and higher insulin resistance as measured by HOMA-IR.

Sedentary recommendations

As a result of this and other work showing negative impacts on cardiometabolic outcomes, the World Health Organisation (WHO) and other bodies added targeting sedentary behaviour in pregnancy to their recommendations. For example, the WHO recommends limiting the amount of time spent being sedentary, and says that the time that would have been spent being sedentary should be replaced with physical activity of any intensity (including light intensity) because it provides health benefits.

Here, Dr Badon showed a pie chart of a day to illustrate that the 24-hour day is a limited period of time and we can’t pull extra hours out of it when we discuss increasing beneficial movement – therefore, behaviour change is about replacement of one behaviour for another. Recommendations include not only replacing sedentary behaviour with light-intensity PA but also including some moderate to vigorous-intensity PA.

Activity and glycaemia

But if these specific behaviour-replacement recommendations are carried out, are they associated with better glucose metabolism during pregnancy? To try to answer this, her team used data from an RCT conducted in pregnant individuals with pre-pregnancy overweight and obesity who were randomised to either a lifestyle intervention or a usual-care control group. They attended the study clinic at 8-15 weeks, where they self-reported on measures such as sleep and also wore an accelerometer to create an average 24-hour movement profile. At 29-38 weeks, the researchers used blood tests and other measures of glucose metabolism.

In the control group, participants spent an average of 8.1 hours sleeping, almost nine hours in sedentary behaviour, 6.4 hours of light PA and just over half an hour of moderate to vigorous- intensity PA. This meant that they were meeting recommendations (Dr Badon reminded the audience that people who volunteer for these types of trial are quite different to the general population).

They then used a compositional data analysis approach to look at all of the movements in the 24-hour day, account for the correlation between them and model (through isotemporal substitution modeling) how specific behaviour replacements might impact later cardiometabolic biomarkers, specifically glucose and insulin.

They found that replacing up to 30 minutes of sedentary behaviour with light or moderate to vigorous-intensity PA was not associated with predicted changes in glucose in late pregnancy. The results were similar for insulin and insulin resistance. However, she points out that this was an observational study in a very specific population.

Behaviour replacement

When we think about controlled lab experiments when studying PA, Dr Badon said, we have a sedentary control group. However, when we use cross-over studies where the same individual comes in and does different types of PA, we begin to understand what happens when one behaviour truly is replacing another.

She used an example of research from 2001, in which 20 women with GDM came in and, on the first day, consumed a standard breakfast. They then sat down for two hours and their fasting glucose was measured at one and two hours. The following day, they consumed breakfast and then took a leisurely walk at their own pace followed by sitting for the next hour. This was therefore a direct behaviour replacement. In the walking group, there was a decrease in the one-hour post-prandial glucose (5.35 mmol/l compared with 6.02 mmol/l in the sitting group). It remains to be seen whether this can be replicated in less controlled environments at the population level.

Additional research needs to be done, she concluded, to understand 24-hour movement replacements and glucose metabolism in pregnancy in both individuals with GDM and those with normal glucose tolerance, how these behaviour replacements may change across pregnancy, and whether other specific replacements may be more or less beneficial in pre-pregnancy diabetes management.

In the post-presentation questions, the issue of sleep and timing of sleep was raised, and Dr Badon said that it’s an extremely important missing piece in the 24-hour movement space. There is a lot to be explored on the relationship between waking behaviour and sleep, and how chronotype, timing of sleep and timing of physical activity play their part.

For more on the topics raised in this article, enrol on the following EASD e-Learning courses:

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on | by Lee Webber

Revealing the transcriptome of each pancreatic islet cell type could take us a long way towards clarifying the underlying mechanisms of type 2 diabetes. Single-cell RNA sequencing offers this level of genetic information and the opportunities and challenges posed by this emerging technology are discussed in a recent paper in Diabetologia. Dr Susan Aldridge reports.

The study of islet cells is central to advancing our understanding of the pathophysiology of type 2 diabetes. The best known of the islet cells is the beta cell, which produces insulin. But there are also alpha, delta, PP and ghrelin cells, producing glucagon, somatostatin, pancreatic polypeptide and ghrelin respectively. What role do they play in type 2 diabetes?

Work on animal models has certainly improved our understanding of islet biology, as have experiments on human islets from organ donors. And now we have a new technology for exploring islet pathophysiology – single-cell RNA sequencing (scRNAseq). As the name suggests, scRNAseq allows the profiling of individual cell transcriptomes. It allows for transcriptome profiling of rare cell populations and detailed study of gene expression. Most tissues and cell populations, including islet material, are heterogeneous and scRNAseq allows the characterisation of this heterogeneity. 

Other advantages of scRNAseq include defining how distinct cell populations respond to stimuli and predicting cellular progression in, for instance, the path from progenitors to mature lineages. 

However, scRNAseq is still in its infancy. Most protocols currently capture only 5 to 20% of the transcripts in a cell. And in the current state of computational analysis, its output needs to be complemented by biological knowledge for validation. Nevertheless, scRNAseq has the potential to have a significant impact on our understanding of disease processes in complex tissues like pancreatic islets. Nils Wierup and Mtakai Ngara, of Lund University Diabetes Centre, have reviewed key scRNAseq studies on human and mouse islets that have been carried out in the last five years and discuss how these have increased our understanding of islet biology.  

Islet donors without diabetes

So far, there have been 19 scRNAseq studies on human islets, seven of which compared samples from donors with, and without, type 2 diabetes. These have shown that the technology is technically feasible in human islets and that the different protocols have various pros and cons – a good foundation for future research. The studies have generated road maps of cell type-specific gene expression with potentially valuable information on receptors, transcription factors and cell surface markers. The authors note that perhaps the most significant contribution is the characterisation of the rarer islet cell types – namely delta, PP and ghrelin cells – which has not previously been possible. 

When it comes to beta cells, it’s long been known that they are not all the same, and some of these scRNAseq studies have revealed subpopulations of these cells. However, we don’t yet know if these arise from donor differences – so this apparent heterogeneity should be carefully validated.  

Other highlights include a study that found 1188 beta cell genes associated with obesity and another showing differences in alpha and beta cell gene expression according to age, implying incomplete differentiation in juvenile donors. There was also evidence that alpha cells proliferate at five times the rate of beta cells from the same donor. 

We don’t know how pancreatic cells are renewed, but one of the scRNAseq studies revealed subpopulations of pancreatic duct cells as potential multipotent cells. This is supported by work that showed that when these cells were transplanted into mice, differentiation into all pancreatic lineages was observed – an important insight into islet cell biology. 

Islet donors with type 2 diabetes

One study noted differential expression (DE) – upregulation and downregulation – of 76 genes in beta cells, 100 genes in alpha cells and five genes in PP cells from type 2 donors. Further analysis showed genes responsible for mitochondrial energy metabolism and protein synthesis were downregulated, whereas apoptosis and cytokine-signalling genes were upregulated. Another study found as many as 1368 type 2 diabetes-associated genes in beta cells, many of which were affected similarly by type 2 diabetes and obesity. 

The ultimate goal of these studies, comparing cells from donors with and without type 2 diabetes, was to identify disease mechanisms in beta cells. In three studies, systematic global DE analysis was carried out. But when the authors compared these findings with their own dataset, they found no differentially expressed gene in common across the four studies that could be focused on for further research. And they further note that only one gene, FXYD2, has been convincingly replicated between studies. One interpretation might be that altered FXYD2 expression is a major cause of beta cell dysfunction in type 2 diabetes. We know that FXYD2 knockout mice show improved glucose tolerance, beta cell hyperplasia and elevated fasting and postprandial plasma insulin. But the authors point out that FXYD2 expression doesn’t actually seem to be genetically associated with either type 2 diabetes risk or beta cell function, as would be expected if altered expression of this gene was of major importance. 

So, an alternative interpretation is that current scRNAseq approaches do not really capture type 2 diabetes disease biology. If they did, you would expect genes with proven roles in beta cell pathophysiology to appear in DE work and to be replicated between studies. 

The authors suggest several reasons for this apparently disappointing observation. The inherently low detection rate of scRNAseq, mentioned above, could mean that disease biology is being missed. Also, studies are still small in terms of cell counts and individuals, leading to low statistical power. It is also becoming increasingly apparent that type 2 diabetes is a heterogeneous disease. Beta cells from an insulin-resistant individual will likely have different gene expression from one with a primary beta cell defect. Finally, suboptimal methods are being used in DE analysis and the data lacks adjustment for donor variance. 

In summary, studies currently find no association between type 2 diabetes and either cell-type composition or subpopulations of islet cells. Individual reports have put forward novel type 2 diabetes-associated genes, some of which have been functionally validated. But few have been replicated between studies.

The way forward

The scRNAseq studies described above, and others, have certainly increased our knowledge of islet cell biology. But, the authors say, the contribution they have made to our understanding of type 2 diabetes has so far been limited. This is because DE analysis has proved to be rather a blunt tool for identifying actual differences between two groups in these small-scale studies with heterogeneous starting material. A recent study has highlighted these shortcomings – for instance, identifying a bias towards highly expressed genes, but maybe missing others of significance? The authors are calling for better computational tools to use the full potential of scRNAseq technology. The ultimate test of such tools would be their ability to reproduce known patterns of gene expression. Fortunately, there are a number of approaches that fulfil this requirement and actually exploit cellular heterogeneity rather than averaging it, as is done in DE analysis. 

Another limitation is that most approaches used to analyse scRNAseq data overlook the possibility that gene expression might actually be organised and synchronised in genetic programmes – maybe for orchestrating specific cellular functions. An approach known as network analysis can deal with this – for example, by assessing co-expression of mRNAs within a population of cells. Network analysis has been shown to be applicable to identifying disease-relevant pathways and regulatory networks. In particular, differential network analysis (diNA), which enables detection of changes in the interplay between mRNAs rather than assessing changes in single mRNAs, has been shown to outperform DE analysis. Although diNA has not yet been applied to scRNAseq data, the authors suggest that combining this approach with a reliable method for addressing donor variation could be one way forward for exploiting the potential of scRNAseq technology. 

In addition, increased numbers of both samples and sequenced cells are needed to increase the analytical power of scRNAseq,  to increase the diversity of donors to allow for studies of the different subtypes of diabetes. One way would be to integrate existing datasets into the analysis. But, going forward, large-scale studies with uniform sampling and analysis protocols with freshly isolated islets from donors well characterised with clinical data, medical records and genome sequencing, will clearly be needed. 

In conclusion, scRNAseq has provided new insights into islet cell biology through revealing cell-type-specific gene expression in all islet cell populations. But when it comes to increasing our understanding of type 2 diabetes pathophysiology, the technology has not reached its full potential. However, the ongoing rapid development of scRNAseq technology with respect to analysis tools and protocols, along with decreased costs, promises much in terms of our understanding of the altered biology of each islet cell type in type 2 diabetes.

To read this paper, go to: Ngara M, Wierup N. Lessons from single-cell RNA sequencing of human islets. Diabetologia online 28 April 2022. https://doi.org/10.1007/s00125-022-05699-1 

For more on this topic, enrol on the following EASD e-Learning modules:

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on | by Lee Webber

Thanks to the GLP-1 receptor agonists and newer, related drugs, it’s now possible to go beyond the traditional glucocentric model of diabetes treatment and address obesity too. The implications of this new approach, and the latest findings on anti-obesity medication, were under discussion at the recent ADA conference, as Dr Susan Aldridge reports.

Given that 86% of people with type 2 diabetes are also overweight or obese*, Dr Ivania Rizo of the Boston Medical Center suggests a new treatment paradigm driven by the overlap between type 2 diabetes, obesity and cardiovascular disease. “We can now go beyond a glucocentric model of care, where the management of obesity is not a competitor, but an addition,” she told delegates at the recent American Diabetes Association Scientific Sessions.

The Diabetes Control and Complications Trial (DCCT) led to a very glucocentric model of care, but older diabetes drugs cause weight gain.  “GLP-1 receptor agonists really did change the landscape,” says Ivania. “Importantly, they act on the brain to reduce appetite and food cravings and lower the preference for energy and fat dense foods.” There are now five GLP-1 receptor agonists available and the amount of weight loss achievable with them has steadily improved over time – from 1-3% with exenatide, to approximately 3-4% with liraglutide, more with semaglutide and higher doses of dulaglutide – and, now, even more with tirzepatide.

Semaglutide was evaluated in the SUSTAIN clinical trial programme and showed more reduction of HbA1c and weight than comparators. Earlier this year, the SUSTAIN FORTE trial showed that semaglutide 2 mg is more effective than the 1 mg dose in helping people lose 10% of their body weight. There have also been seven randomised controlled trials of GLP-1 receptor agonists that show reduction in three-point MACE (major adverse cardiovascular events – cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke).

Beyond GLP-1 receptor agonists

“There is now Intense interest in developing molecules with dual or triple agonist action – against GLP-1 and GIP (glucose-dependent insulinotropic peptide) and/or glucagon – using the complementary actions of gut hormones,” Ivania says. GLP-1 and GIP are the two main gut hormones responsible for the amplification of insulin after oral nutrition, but people with type 2 diabetes have an impaired response to both. The dual agonist tirzepatide, approved by the FDA for type 2 diabetes earlier this year, restores this response by activating the gut hormone receptors in sequential fashion – GIP after GLP-1. And, according to the SURPASS-2 trial, it reduces HbA1c and body weight even more than semaglutide.

There are other dual agonists on the horizon now, such as cotadutide, a dual GLP-1 and glucagon receptor agonist which, at a higher dose, is superior to liraglutide in reducing HbA1c and weight. Cotadutide also has the extra advantage of reducing markers of non-alcoholic fatty liver disease (NAFLD). 

Anti-obesity medications

“Anti-obesity medications are truly underutilised,” says Ivania. “There is a large unmet need in obesity, compared with type 2 diabetes. For 8% of the population has type 2 diabetes and 86% of them receive anti-diabetes medication. But half the population has obesity and only 2% of them are being treated with anti-obesity medication.”

Returning to type 2 diabetes, a stepwise approach to obesity management with medication can be considered. So, GLP-1 agonists/dual agonists or SGLT-2 inhibitors could be used alongside metformin and lifestyle in a patient-specific way. And there are also anti-obesity medications that could be added to the treatment toolbox. Tirzepatide is not yet approved for the treatment of obesity, although it is the first investigational drug to deliver more than 20% weight loss in a clinical trial, so the best choice is semaglutide. Other options include phentermine/topiramate, naltrexone/bupropion and liraglutide. The STEP-8 trials of liraglutide 3 mg versus semaglutide 2.4 mg in people without diabetes, but with overweight or obesity, showed that the latter produces substantially more weight loss. Ivania starts her own patients on liraglutide and then switches to semaglutide, if necessary. And now there is cagrilintide, the first long-acting amylin analogue for weight management, given once a week, which can be used with semaglutide for significant weight loss.   

So, in conclusion, diabetes and obesity are complex diseases that progress over decades. Double-digit weight loss addresses both insulin resistance and obesity. “We need to go beyond the glucocentric model to address weight-centric goals too,” Ivania says. “A combination of agents with complementary modes of action is essential in diabetes and weight management, and we also need equitable access to these medications.” 

For more on obesity and diabetes, enrol on the following EASD e-Learning modules:

*Daousi C, Casson IF, Gill GV, MacFarlane IA, Wilding JPH, Pinkney JH. Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors. Postgrad Med J. 2006 Apr;82(966):280-4.  https://pubmed.ncbi.nlm.nih.gov/16597817/

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on | by Lee Webber

Obstructive sleep apnoea, with its various health consequences, is more common among people with type 2 diabetes than those without the condition. A new study, reported in a recent issue of Diabetologia, finds that those with type 1 are also more at risk of this common sleep disorder, with autonomic neuropathy possibly playing a role, independent of obesity. Clinicians should therefore be on the alert for obstructive sleep apnoea as yet another potential complication of type 1 diabetes. Dr Susan Aldridge reports.

Obstructive sleep apnoea (OSA) is a common disorder characterised by repeated complete or partial upper airway obstruction during sleep. This leads to repeated episodes of oxygen saturation and desaturation, changes in heart rate, blood pressure and sympathetic activity, along with disruption of sleep architecture. Consequences include an increased risk of road traffic accidents, reduced workplace productivity, hypertension, coronary heart disease, impaired quality of life and increased mortality.

And OSA is also a well-established risk factor for type 2 diabetes. Recently, it’s been shown that those who already have type 2 diabetes are also at increased risk of developing OSA, suggesting a bi-directional relationship. Furthermore, cohort studies have shown that OSA in people with type 2 diabetes is associated with micro- and macrovascular complications.

However, little is known about OSA in type 1 diabetes. It’s certainly plausible that people living with type 1 are at risk of OSA because of the increasing prevalence in this population of obesity and the high prevalence of autonomic neuropathy, both of which contribute to OSA. Therefore, Ziyad Alshehri at the University of Birmingham, UK, and colleagues, have carried out a cohort study to assess whether people with type 1 diabetes are at an increased risk of incident OSA when compared with matched controls without diabetes. They also looked at factors influencing the risk of developing OSA in the type 1 diabetes cohort.

The researchers drew upon The Health Improvement Network (THIN), a primary care database, using records from January 1995 to January 2018. From this, they identified 34,147 people with type 1 diabetes who were matched to 129,500 people of the same sex, age and body mass index (BMI). The study population was a ‘typical’ type 1 diabetes population – young, poor glycaemic control, low prevalence of obesity and with relatively few prescriptions of cardiovascular medications.

OSA – another diabetes complication

By the end of the study, OSA had been diagnosed in 219 (0.64%) of the type 1 diabetes cohort and in 531 (0.41%) of the controls, over a median follow-up of 5.43 years. The median diabetes duration in those with type 1 diabetes who were diagnosed with 0SA was 19.36 years, which is approximately double the duration for those with type 1 who did not develop OSA.

Analysis adjusting for factors that could influence the risk of OSA like age, BMI and smoking and drinking status, revealed that people with type 1 diabetes had a 51% higher risk of developing OSA than those without the condition. Further analysis showed that male sex, age, being overweight or obese, use of lipid-lowering or blood pressure-lowering medication and a history of atrial fibrillation or depression all increased the risk of incident OSA.

This is the first study to look at the longitudinal relationship between type 1 diabetes and OSA. It finds that the risk of developing OSA is similar to that found in type 2 diabetes. At first, this might seem a bit surprising, given the younger age and lower prevalence of obesity in type 1. But there could be another mechanism at play here, other than age or obesity – both of which are known risk factors for OSA. The authors suggest that diabetic autonomic neuropathy might be a contributing factor. This is supported by the fact that OSA was more common among those with a longer duration of type 1 and that atrial fibrillation is a risk factor – for diabetic autonomic neuropathy is associated with both.

Implications

As mentioned above, OSA in type 2 diabetes is associated with a higher risk of micro- and macrovascular complications. Further research should look at whether this is also the case with OSA and type 1 diabetes. In addition, people with type 1 diabetes run an increased risk of hypoglycaemia and, if they also develop OSA, it means they may be at added risk of road traffic accidents. There are also, of course, implications for driving licences.

This new study also found that depression was a risk factor for OSA with type 1 diabetes. This echoes findings from studies in people without diabetes, which finds that depression is common in people with OSA. The good news is that treatment of the OSA with continuous positive airway pressure improves depressive symptoms.

Atrial fibrillation (AF) was another risk factor found in the current study and other research has found that up to 85% of those with AF do also have OSA, confirming the association found here. So, for all these reasons, clinicians looking after people with type 1 diabetes should suspect OSA among those with any of the above risk factors. It is a potential complication that should not be ignored and treatment should be put in place as soon as possible. 

To read this paper, go to: Alshehri Z, Subramanian A, Adderley N, Gokhale KM, Karamat MA, Ray CJ, Kumar P, Nirantharakumar K, Tahrani AA. Risk of incident obstructive sleep apnoea in patients with type 1 diabetes: a population-based retrospective cohort study. Diabetologia 24 May 2022.

https://pubmed.ncbi.nlm.nih.gov/35608616/#article-details

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on | by Lee Webber

Bariatric surgery can lead to health benefits in type 2 diabetes that go way beyond weight loss and remission. The latest findings in this area were presented at the recent ADA conference, making a strong case for using surgery to tackle diabetes and obesity. Dr Susan Aldridge reports.

Addressing the American Diabetes Association (ADA) Scientific Sessions in June, Dr Ricardo Cohen, bariatric surgeon and Director of the Center for Diabetes and Obesity at the Oswaldo Cruz German Hospital, São Paulo, Brazil, said: “Obesity management is not the future for treating diabetes, it’s the present.” He went on to discuss the role that bariatric/metabolic surgery can play in weight loss and management in type 2 diabetes.

The DiRECT trial showed that those who lost the most weight (through diet) were the ones who were more likely to achieve at least glucocentric remission, with HbA1c less than 6.5%. For lower amounts of weight loss, the numbers achieving this decrease. There’s also now a lot of data that show double digit weight loss will prevent cardiovascular events and mortality. “It’s clear that this double digit weight loss is what we need to pursue for diabetes treatment,” Ricardo says.

But clinical trial findings reveal that many participants need additional interventions to maintain this all-important weight loss. Once the diet stops, there is a strong tendency to put the weight back on. Surgery, however, shifts the satiety/meal size curve so the individual doesn’t want to eat so much.   “We need a long-term intervention and this is what I’m here for – to show the benefits of surgery,” he says. “I have no doubts that surgery is great for weight loss and glycaemic control.”

These long-term benefits are confirmed by the follow-up studies. The Swedish Obese Subjects (SOS) study is the most ‘squeezed’ in the bariatric literature, with 90 sub-studies. In one of these, with over 20 years of follow-up, surgery was associated with sustained loss of around 27% of body weight. Gastric bypass was associated with the greatest weight loss. The participants having surgery also enjoyed longer life expectancy that was linked to the amount of weight loss. In another study, 51% of those having gastric bypass surgery were still in diabetes remission after 12 years, compared with just 4% of those on medication.

Furthermore, it looks as if the numbers that could benefit from surgery might be greater than previously thought. A meta-analysis of 94,000 patients in 94 studies shows that those below and above a body mass index (BMI) of 35 reached same rate of glucocentric remission, with 71% achieving an HbA1c below 7% without medication. “So, even in patients with BMIs from 30 to 35, the benefits of surgery are greater than those achieved by medical treatment,” says Ricardo. 

Beyond weight loss and remission  

Bariatric surgery involves more than just weight loss. There are changes in gut microbiota, glucose transport, intestinal glucose metabolism, gastrointestinal nutrient sensing and gut hormones. So, it is not surprising to see other health benefits following surgery. The Diabetes Surgery Study showed improvement in blood pressure at five years, while the STAMPEDE (Surgical Therapy and Medications Potentially Eradicate Diabetes Efficiently) study led to both five- and 10-year improvements in blood pressure, LDL and HbA1c, and a recent trial by Geltrude Mingrone and his team showed a reduction in macro- and microvascular diabetes complications after surgery.  

While there is much observational evidence to show that surgery reduces hypertension, the GATEWAY (Gastric Bypass to Treat Obese Patients With Steady Hypertension) study’s primary endpoint was a reduction of at least 30% in the medication needed to maintain a blood pressure of 140/90 mmHg. At 36 months, this was reached in 73% of patients on surgery versus 11 % on medication. And 35% in the surgical arm actually achieved remission of their hypertension (blood pressure of 130/80 mmHg, without hypertension medication), versus none of those in the medication arm of the trial.   

Bariatric surgery also helps with kidney disease. Ricardo was involved in the MOMS (Microvascular Outcomes after Metabolic Surgery) trial, which looked at the effect of surgery versus usual care on early stage chronic kidney disease (CKD) in patients with type 2 diabetes and obesity. Those in the usual care arm were allowed GLP-1 receptor agonists and SGLT-2 inhibitors, which no doubt contributed to their relatively good outcomes. The primary endpoint was remission of CKD, with a urinary albumin creatinine ratio of 30 mg/g or less, which was achieved in 84% in the surgery arm and 56% in the usual care arm.   Those in the surgery arm also needed less insulin and less oral diabetes medication. Finally, quality of life was better in almost all domains following surgery. 

There have also been many studies showing reduction in mortality after surgery, mainly involving gastric bypass. One of these also showed decreases in atrial fibrillation, nephropathy, coronary artery disease, cerebrovascular disease and heart failure. “By operating on 13 patients, one life can be saved,” Ricardo says. Surgery has also led to greater survival in patients with a prior myocardial infarction. “There have only been two papers on this, but I think we can say that metabolic surgery can reduce the likelihood of a secondary coronary event – and it’s safer than a heart bypass,” he adds.  

Finally, in earlier studies, the endpoint was always glucocentric remission of type 2 diabetes, without medication. Ricardo now suggests that this is ‘old fashioned’ and that adjuvant pharmacotherapy should be provided, as in oncology where surgery, radiotherapy and chemotherapy may all be employed. “Some surgeons think that surgery is a miracle on its own – and I was one of them. But now I think it is best to combine our efforts. “

In summary, according to Ricardo, the overall treatment strategy in type 2 diabetes should be self-directed lifestyle change first – showing the patient how they can start their journey to diabetes control. Then comes professionally directed lifestyle change. Then add medications. “We currently have very powerful medications, like tirzepatide and semaglutide. If patients don’t respond to medications, then do surgery. This is our weight-centred approach to diabetes. The best thing is combining both surgery and medication, which will lead our patients to the best outcomes available.”

For more on the topics covered in this article, enrol on the following EASD e-Learning courses:

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on | by Lee Webber

A new study in a recent issue of Diabetologia compares intermittent (flash) glucose monitoring with finger-prick testing in a group of pregnant women with type 1 diabetes. While flash did improve glycaemic control for a while, this was not sustained, and it was also linked to an increased risk of neonatal hypoglycaemia. Dr Susan Aldridge reports.

Continuous glucose monitoring (CGM) can improve outcomes for women with type 1 diabetes and their babies by improving glycaemic control during pregnancy. For instance, the CONCEPTT trial showed that the use of real-time CGM (rt-CGM) by women with type 1 diabetes during pregnancy led to a significant reduction in large-for-gestational age (LGA) infants, neonatal hypoglycaemia and neonatal intensive care admissions. Accordingly, CGM is now widely recommended for all pregnant women with type 1.

In recent years, flash or intermittently scanned (isCGM), with the FreeStyle Libre system has become increasingly popular among people with type 1 diabetes. The cost of rtCGM has prevented its widespread implementation during pregnancy. isCGM could be a cheaper alternative and it has been approved for use during pregnancy. However, it has not yet been shown to have the same benefits during pregnancy as rtCGM, as data from trials has yielded mixed results. Therefore, Verónica Perea, Hospital Universitari Mútua de Terrassa, Barcelona, and colleagues, have looked at whether the addition of isCGM to standard care improves maternal glycaemic control and pregnancy outcomes in women with type 1 diabetes on multiple daily injections (MDI). In Spain, isCGM is government-funded for these women ­– so the findings of this study would be relevant to the economics of the healthcare system here, and elsewhere. 

This was an observational study, involving 300 pregnant women with type 1 diabetes, of whom 132 were using isCGM (FreeStyle Libre or FreeStyle Libre 2). The others used conventional finger prick self-monitoring of blood glucose (SMBG). It was the largest cohort study to date evaluating the effect on isCGM in pregnancy compared with current clinical practice.

HbA1c was measured every 4 to 8 weeks during the pregnancy and one measurement per trimester was selected for the study. Information on the participants was gathered from a web-based Spanish national registry designed by the Spanish Diabetes and Pregnancy Study Group.

The primary neonatal outcome was delivery of an LGA infant and several secondary maternal and neonatal outcomes, often associated with diabetes in pregnancy, were also measured, such as severe maternal hypoglycaemia, Caesarian section and neonatal hypoglycaemia.

Glycaemic control findings

Glycaemic control during pregnancy is crucial when diabetes is involved. All participants showed a significant decrease in HbA1c from the pregestational period to the second trimester. Then there was a slight increase from the second to the third trimester. This increase was greater in the isCGM group. However, the isCGM group actually had a lower median HbA1c in the second trimester than the SMBG group.

The researchers analysed the HbA1c data according to whether women were meeting NICE or ADA recommended targets. These differ in that NICE recommends HbA1c <48 mmol/mol throughout the pregnancy, whereas ADA recommendations are tighter, with targets of HbA1c <48 mmol/mol in pre-pregnancy and the first trimester and HbA1c <42 mmol/mol for the second and third trimesters. When NICE goals were applied, there were no differences between the two groups. But with the ADA goals, significant differences did emerge in the second trimester, where 56% of the isCGM group achieved their goal, versus 42.6% of the SMBG group. And then there was a notable reduction from the second to third trimester in women in the isCGM group meeting their target – from 56% to 36.4%, compared with 42.6% to 35.7% in the SMBG group.

Pregnancy outcome findings

Initial statistical analysis showed no difference in pregnancy outcomes between the isCGM and SMBG groups. But when the analysis was adjusted for well-known confounders like age, pregestational BMI and so on, it turned out that isCGM users had a higher risk of neonatal hypoglycaemia. There were no other differences in pregnancy outcomes between the two groups. Higher glucose levels in the peripartum period can play a role in neonatal hypoglycaemia. In this study, the isCGM users had significantly lower HbA1c in the second trimester, but there were no differences between the groups in the third trimester. So it might be that there were further increases in glucose levels in the weeks or days before delivery in the isCGM group. This might account for the increased risk of neonatal hypoglycaemia, say the researchers. 

In conclusion, this study shows that the addition of isCGM to standard care for pregnant women with type 1 diabetes shows an initial improvement in glycaemic control. However, this was not sustained. And this deterioration late in pregnancy might be linked to the increased risk of neonatal hypoglycaemia with isCGM that this study also reveals. Further studies of isCGM – including the use of the new FreeStyle Libre 2 – are now urgently needed. Until more encouraging data are available, women with type 1 diabetes should be offered the use of rtCGM over isCGM during pregnancy. 

To read this paper, go to: Perea V, Picón M, Megia A, Goya M, Wägner AM, Vega B, Seguí N, Montañez MD, Vinagre I. Addition of intermittently scanned continuous glucose monitoring to standard care in a cohort of pregnant women with type 1 diabetes: effect on glycaemic control and pregnancy outcomes. Diabetologia 12 May 2022.

https://doi.org/10.1007/s00125-022-05717-2

https://pubmed.ncbi.nlm.nih.gov/35546211/

For more on this topic, enrol on the following EASD e-Learning courses:

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on | by Lee Webber

Counselling and pharmacotherapy can each of them aid weight loss in people with obesity. So what happens when you combine the two? Lisa Buckingham reports on the case for pairing these interventions, as presented at the ADA’s 82nd Scientific Sessions.

“Why would you consider this pairing?” asked Dr Scott Kahan, director of the National Centre for Weight and Wellness, and faculty director at Johns Hopkins Bloomberg School of Public Health, addressing the American Diabetes Association’s (ADA) recent conference. The answer is that losing weight is hard – even if you lose weight, physiology pushes back, and even if you fight through the physiological counter-regulatory changes, you need to continue indefinitely. Combination therapy, he said, almost always leads to more weight loss and other improved outcomes.

Dr Kahan highlighted a paper that showed patients losing about 10% of their bodyweight in three months on a medically monitored diet. The participants were then followed for a year. There was some weight regain, as expected, but the study also tested a range of counter-regulatory hormones at three months and then again at a year. At both intervals – even after a year, when some weight had been regained – the participants’ satiety hormones were still significantly lower and their primary hunger hormone (ghrelin) was still elevated.

Some people can keep weight off just with behavioural counselling, but even if you can fight through this and keep it up indefinitely, he said, the fact remains that more weight loss is (usually) better (within reason) in terms of comorbidities. Once we’re into the 10% and above range, we see more benefit over the smaller percentages of weight loss, such as improvement in sleep apnoea, long-term cardiovascular outcomes and quality of life.

To begin the case for combination therapy, he drew a comparison with the evidence for depression treatment. Counselling can be very effective – as can medication – but dozens of studies have shown that when you combine the two, you get much more benefit.

In obesity, there are numerous examples of combination therapy’s effectiveness. However, before outlining the counselling/medication combination, he showed papers looking at combining two medications. For example, one paper showed that with a modest dose of phentermine, you get weight loss of about 7%and topiramate of about 9%. When you combine a half-dose of both of them, you get considerably more weight loss more than either of them alone at double doses.

Data in support of pairing behavioural therapy and pharmacotherapy goes back many decades. He cited one example of sibutramine (no longer on the market). The drug alone didn’t give much benefit; the drug plus basic lifestyle counselling gave more benefit (double the weight loss); those two plus meal replacement gave even more.

Another paper showed that more intensive behavioural counselling plus sibutramine resulted in greater weight loss than basic counselling and sibutramine, showing a gradation of effect.

With regard to the new medications that have been approved in the past decade, he first highlighted a trial using naltrexone/bupropion. Patients got intensive behavioural counselling and achieved 7.5% weight loss. When combined with the medication, they achieved almost 50% more weight loss.

In a comparable study of the same medication, but with less intensive, usual-care counselling, both groups achieved less weight loss compared with the other trial.

Another example was liraglutide combined with intensive behavioural counselling, which resulted in about double the weight loss compared with the counselling alone.

The same group also did another study that Dr Kahan felt better reflects what happens in clinical practice. Both groups had a medically monitored diet for 14 weeks, resulting in about 6% weight loss. At that point, they were randomised to either placebo and ongoing counselling, or the medication plus counselling. With just the counselling, they kept off the weight or lost a little bit more, but with the medication as well, they kept the weight off better and lost even more weight.

A third study involving liraglutide used a medically monitored diet for two months, after which participants were randomised to either basic counselling with a placebo, exercise counselling, the medication, or exercise counselling with the medication. Again, a gradation of outcomes was seen – the more intensive the intervention, the better the outcomes. At a year, one in three of the combination group were keeping off 20% of their bodyweight. This is bariatric-surgery-level weight loss, said Dr Kahan, but without surgery.

It doesn’t need to be one thing or the other, or even a combination to start with but they can be sequentially added as indicated.

He moved on to discuss a key point – obesity is significantly undertreated and that applies to every modality of treatment. His data was specific to the USA, but he explained that less than 1% of eligible people with obesity who have Medicare are given intensive behavioural therapy (IBT); roughly 1% receive pharmacotherapy; 1.5% get bariatric surgery. He compared this to diabetes treatment where 85% of people with diabetes are getting the indicated treatments. This should be 100%, he said, but the comparison is still worlds apart from obesity treatment.

There are several reasons for this. The first is lack of training on obesity among primary care physicians and even specialists. The second is minimal insurance coverage for obesity treatment. And the last is perceived lack of time – doctors perceive that they have to solve the whole problem when they see the patient. It doesn’t need to be done all once, said Dr Kahan, because it’s a chronic condition and it’s something we can chip away at.

He also came back to the point about gradation of treatment – from basic counselling, which provides some benefit, up to intensive counselling plus medication for the most benefit. Whatever we can offer is going to be beneficial, he said. And more is generally better.

For more on obesity and diabetes, enrol on the following EASD e-Learning modules:

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on | by Lee Webber

Tirzepatide is a new class of drug for management of type 2 diabetes. A meta-analysis of its glucose-lowering and weight-loss effects, presented in a recent issue of Diabetologia, will help guide treatment decisions ahead of its imminent approval for clinical use.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), the two main incretin hormones, are released from the gut after eating and stimulate insulin secretion. The incretin effect is decreased in people with type 2 diabetes and this has led in recent years to the development of the GLP-1 receptor agonists (RAs), which mimic the incretin effect. These drugs not only lower glucose levels, they also reduce weight and improve cardiovascular outcomes.

So, what about combining GLP-1 and GIP receptor activation to boost the incretin effect even further? For the two hormones both act in synergy, and complement one another, in pancreatic beta cells.

Enter tirzepatide, a dual GLP-1 and GIP receptor agonist that has been developed for type 1 diabetes. It has a greater affinity for GIP receptors than for GLP-1 receptors and a half-life of five days, allowing for weekly injection. Early trials have suggested that tirzepatide improves markers of both beta cell function and insulin sensitivity compared with GLP-1 RAs. And the SURPASS trial has investigated the efficacy and safety of tirzepatide in comparison with placebo and other glucose-lowering medications, including GLP-1 RAs and basal insulin.

On the basis of these findings, tirzepatide has been submitted for approval to both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of type 2 diabetes. Thomas Karagiannis, of the Aristotle University of Thessalonki, and colleagues have set the scene for its launch later this year with a review of all the randomised controlled trials (RCTs) involving tirzepatide against placebo or other glucose-lowering drugs, including insulin. They found seven RCTs, covering 6609 participants, whose average HbA1c was 66.47 mmol/mol and mean body weight 91.5 kg.

Tirzepatide and glycaemic control

Compared with placebo, reductions in HbA1c ranged between 17.71 mmol/mol with tirzepatide 5 mg and 22.35 mmol/mol with tirzepatide 15 mg. In terms of achieving target HbA1c, all three doses (5 mg, 10 mg, 15 mg) were superior to placebo in reaching HbA1c <53 mmol/mol, £48 mol/mol or <39 mmol/mol targets.

Tirzepatide at all three doses also reduced HbA1c more than GLP-1 RAs. And more participants receiving any tirzepatide dose achieved the two lower HbA1c targets than those on GLP-1 RAs. 

When compared with basal insulin, the three tirzepatide doses were more effective in reducing HbA1c. Mean differences ranged from 7.66 mmol/mol with tirzepatide 5 mg and 12.02 mmol/mol with tirzepatide 15 mg. Tirzepatide was also more successful than basal insulin in helping participants reach all three of the HbA1c targets.

Tirzepatide and body weight

Tirzepatide, as expected, causes significant reductions in body weight. Compared with placebo, average dose-dependent weight loss was 6.31 kg (5 mg), 8.43 kg (10 mg) and 9.36 kg (15 mg). In diabetes management, especially when the goal is type 2 remission, people with diabetes are often advised to lose a percentage of their body weight. This review showed that more participants on tirzepatide had reductions of 5%, 10% or even 15% of their body weight than those on placebo.

The GLP-1 RAs are also notable for their weight loss, as well as their glucose-lowering, effect. So how does tirzepatide compare? It actually produces larger reductions in weight than the GLP-1 RAs, ranging from 1.68 kg with 5 mg to 7.16 kg with the 15 mg dose. And all tirzepatide doses were more effective than the GLP-1 RAs in achieving a body weight reduction of at least 10% and 15%.

Tirzepatide and adverse events

All glucose-lowering drugs can potentially cause hypoglycaemia. The good news is that, with tirzepatide, incidence of any kind of hypoglycaemia was the same as on placebo and was lower than with basal insulin. Severe hypoglycaemia was rare, with only 22 such events being recorded across all the trials.

Gastrointestinal events – nausea, vomiting and diarrhoea – were more common with tirzepatide than on placebo or insulin. Rates were similar to those found with GLP-1 RAs.

When it came to discontinuation of treatment due to adverse events, more patients discontinued on tirzepatide 10 mg and 15 mg compared with placebo. In comparison with the GLP-1 RAs, only those on 15 mg tirzepatide were more likely to discontinue treatment and, in comparison with basal insulin, both the 5 mg and 15 mg were associated with greater odds of discontinuing.

Finally, the incidence of serious adverse events and mortality did not differ between any of the tirzepatide doses and any comparator. There were 41 deaths among 4573 individuals receiving tirzepatide and 39 among 2151 receiving a comparator. The authors note that 19 of these deaths were related to COVID-19.

Looking forward

This meta-analysis has shown that once-weekly tirzepatide is associated with dose-dependent reductions in HbA1c that are clinically significant. These reductions also compare favourably with those achieved by once-weekly GLP-1 RAs and basal insulin. There is also a notable dose-dependent decrease in body weight, even in comparison with the GLP-1 RAs semaglutide and dulaglutide. On the down side, however, there were gastrointestinal side effects to contend with. And the 15 mg dose was associated with at least two-fold risk of discontinuation of the drug, regardless of comparator.

Tirzepatide could receive marketing approval later this year. This meta-analysis could help healthcare professionals and other stakeholders determine where this new medication fits in diabetes care, alongside the many other medications. Its potential for weight loss is likely to be of particular interest, given that even the 5 mg dose can reduce body weight and seems to be superior in this respect to even subcutaneous semaglutide. However, more head-to-head data for tirzepatide versus GLP-1 RAs on weight loss is needed. And it should be noted that an application for a label extension of semaglutide 2 mg has been submitted to the FDA and this has recently received a positive recommendation by the EMA. So, expect further developments in the options available for weight loss in type 2 diabetes. On present evidence, however, it does look as if tirzepatide could be a reasonable choice in this context. Finally, it should be noted that the ongoing SURPASS-CVOT trial should soon provide some answers on the impact of tirzepatide, compared with dulaglutide, on cardiovascular risk – another important consideration when prescribing for type 2 diabetes.

To read this paper, go to: Karagiannis T, Avgerinos I, Liakos A, Del Prato S, Matthews DR, Tsapas A, Bekiari E. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia 17 May 2022. https://doi.org/10.1007/s00125-022-05715-4

For more on this topic, enrol on the following EASD e-Learning course:

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.