Day 3: Hot topics
Friday 10th March
medwireNews: The hot topics sessions, on the last day of the Diabetes UK professional conference, covered areas including medical prevention and reversal of type 2 diabetes, the role of the gut microbiome, blood pressure targets, and adjunct therapies.
Harnessing the power of diet
In the first of seven hot topic presentations, Rod Taylor (Newcastle University) discussed the ongoing cluster randomized, Diabetes-UK–funded Diabetes Remission Clinical Trial (DiRECT), which is testing the ability of a very-low-calorie liquid diet (820 kcal/day) to achieve significant weight loss and reversal of type 2 diabetes among patients diagnosed less than 6 years previously.
The idea, said Taylor, is that the calorie reduction will lead to a reduction in liver fat, improving insulin sensitivity and reversing the accumulation of triglycerides in pancreatic islet cells, leading to redifferentiation of beta cells. Indeed, the patients recruited to DiRECT had average liver fat of around 15%, suggesting an “extent of liver disease that has not hitherto been fully appreciated.”
Taylor said that the separate parts of this hypothesis have been tested in previous smaller trials, and based on these smaller studies, the investigators expect that around 90% of patients will achieve the co-primary endpoint of 15 kg of weight loss and a glycated hemoglobin (HbA1c) level below 48 mmol/mol at 12 months. The 12 months includes a period on the liquid diet, a managed transition back to normal eating, and then weight maintenance.
All the patients’ antidiabetic and antihypertensive drugs are stopped at baseline, which Taylor described as a “revolutionary approach,” and the patients are forbidden from exercising during the weight-loss period, to avoid compensatory overeating, although Taylor stressed the importance of exercise for weight maintenance.
The team hopes to present the 1-year findings in December this year, and has also applied for funding to follow up the patients over 5 years of regular appointments with the practice nurse, to assess the degree of weight regain.
Big data, national trends
The second presentation, by Helen Colhoun (University of Edinburgh), provided an overview of diabetes trends in the UK – mostly in Scotland because of the good availability of data.
She revealed that diabetes prevalence is still rising, but now because of improved survival rather than increasing incidence. There is good news for type 1 diabetes, with mortality and cardiovascular disease rates falling faster than in the general population, but for type 2 diabetes rates are falling no faster, so rate ratios remain the same.
Retinopathy is now being diagnosed earlier, however, thanks to screening, and its incidence appears to be stable, reported Colhoun. Data from both Scotland and England suggest that the severity of diabetic nephropathy may be improving, but it is hard to be sure because of recent changes in measurement methods.
The prevalence of acute complications is coming down, but Colhoun described it as “a national disgrace that we have any deaths from diabetic ketoacidosis.” She also noted that HbA1c levels remain stubbornly high and unchanged, although there is some evidence of improvement among children.
Finally, she stressed that by 2031 there will 2.9 million people aged 85 years or older in the UK population, highlighting this as a future challenge for diabetes care.
Can manipulating the microbiome combat insulin resistance?
In a very different vein, the third talk focused on the latest research on the gut microbiome in obesity and diabetes. Although there has been an explosion of research in the field recently, Hilde Herrema (Academic Medical Center, Amsterdam) cautioned that most of it is associative and subject to confounding, with the only studies potentially demonstrating causality conducted in mice.
However, recent research by Herrema’s team has shown that fecal transfer from lean people is associated with insulin sensitivity in recipients with the metabolic syndrome. The effect was only apparent in some participants, but the success of the procedure was associated with how much of the donor microbiota ultimately take up residence in the recipient – engraftment, as Herrema referred to it.
Another potential application of the gut microbiome in diabetes patients is for refining diet; Herrema related the results of a study showing that a computer algorithm based on the gut microbiome could assign a diet that reduced postprandial dysglycemia with greater success than a dietician.
Herrema again stressed the limitations of the research so far, including the acute effects of diet changes, medication history, and previous antibiotic use. But she said that, nevertheless, “we do think we can work to personalized strategies, based on the bacterial composition, in treating insulin resistance in the obese.”
Insights into managing chronic kidney disease
Back on more conventional ground, Luigi Gnudi (King’s College London) discussed the challenges of achieving glycemic control in diabetes patients with chronic kidney disease, which carries an increased risk for hypoglycemia.
“Clearly, safety is paramount,” he said.
Gnudi said doctors should consider whether patients are frail and finding diabetes management difficult or whether they are robust and engaged, and choose a less or more stringent HbA1c target with this in mind. “Just chat with your patient,” he said. “Look at who is sitting in front of you.”
Personalized treatment targets are also necessary for blood pressure (BP) control, he stressed, reminding delegates of the J-shaped association between BP and mortality in older patients.
Moving on to medications, Gnudi noted that double renin–angiotensin–aldosterone system blockade to prevent diabetic nephropathy “died” with the publication of the NEPHRON-D study, due to an increased risk for adverse events, although ongoing studies are investigating whether suboptimal doses might be beneficial. “Time will tell whether this story is still open,” he said.
And there are many drugs in the pipeline, said Gnudi, including some that are potentially relatively close to clinical use, such as endothelin antagonists and mineralocorticoid receptor antagonists.
Moreover, the recent cardiovascular outcomes trials of antidiabetic drugs in the glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT-2) antagonist classes have also demonstrated renoprotective benefits, although Gnudi stressed that definitive results will only emerge from trials powered for renal outcomes, which are in progress.
Does SPRINT inform diabetes care?
In the next talk, Martin Rutter (University of Manchester) assessed whether the results of the SPRINT trial have any relevance for treating diabetes. His view was that, on the whole, they are not, given that diabetes patients were excluded from the trial and there is evidence of different responses to BP-lowering between patients with and without diabetes.
Instead, Rutter argued that the ACCORD trial findings need further consideration, saying that the general rise in BP guideline targets for diabetes patients that followed the publication of this seemingly negative trial was an overreaction.
Comparing the two trials, he argued that ACCORD may have been underpowered, noting that although the hazard ratio of 0.90 for the primary cardiovascular endpoint was nonsignificant, the 95% confidence interval of 0.78 to 1.04 is suggestive of a beneficial effect.
Breaking down the ACCORD findings further, Rutter flagged up signs of increased cardiovascular mortality and all-cause mortality among patients who were also receiving intensive glycemic control, suggesting that side effects of this intensive combination may have obscured treatment benefits of BP control.
“This is somewhat exploratory, but it may be that just the aggressive nature of the glucose-lowering in ACCORD, when you combine it with lowering blood pressure, could be a toxic combination,” he said, noting also that the ACCORD HbA1c target of 6.0% is rarely adopted in clinical practice today, “and it could be that this is just history and we may not need to be too worried about it.”
In clinical practice, Rutter said he would like to see a move away from BP targets and toward a BP range, in a bid to avoid hypotension in vulnerable patients, with the target range being determined by factors including patient engagement, postural hypotension, cognition, and life expectancy.
He described this as a practical approach, which “brings in trial evidence and some sensible clinical thoughts too.”
The double whammy of heart failure and diabetes
Moving on to the subject of heart failure (HF), Mark Kearney (University of Leeds) outlined the major impact of diabetes on patients with HF; these patients have more ischemia, lower hemoglobin, worse renal function, a higher risk for HF hospitalization, and a strikingly increased mortality rate.
“Heart failure and diabetes is a lethal combination,” said Kearney, noting that diabetes has an impact equivalent to that of ventricular fibrillation on the risk for sudden cardiac death.
However, since the advent of implantable cardioverter defibrillators, patients more often die of HF progression, driven by the body’s own protective systems that are designed to activate acutely and protect the body in response to acute trauma, but which are activated chronically in response to a chronic reduction in cardiac output. And again, this process is exacerbated in the presence of diabetes.
This calls for a multipronged treatment approach, including loop diuretics, neurohumoral blockade with ACE inhibitors and beta blockers, and cardiac device use where applicable.
In addition, Kearney noted that the recent EMPA-REG cardiovascular outcomes trial showed that diabetes patients taking the SGLT-2 inhibitor empagliflozin had a significantly reduced risk for HF hospitalization, compared with those taking placebo. This effect was seen from very early in the trial, suggesting that the drug may have both acute and chronic beneficial effects on HF risk.
Closing in on adjunct treatment for type 1 diabetes
In the final presentation, Parth Narendran (University Hospital Birmingham) looked at the possibilities for adding adjunct therapies to insulin to improve glucose control in patients with type 1 diabetes. No pharmaceutical therapies except insulin are currently approved in the UK for type 1 diabetes patients, but Narendran provided an update on the two that seem the most promising: SGLT-2 inhibitors and GLP-1 receptor agonists.
Small studies have suggested that type 1 diabetes patients can achieve tighter glycemic control, at a lower insulin dose, when given an SGLT-2 inhibitor. This is now being tested in a large trial – DEPICT 2, a phase III study of more than 700 patients, which is due to complete in the autumn of this year. Other, smaller studies are looking at combined SGLT-1 and -2 blockade, also with promising results.
However, Narendran highlighted the risk of ketoacidosis associated with SGLT inhibition in insulin-dependent patients, underlining the importance of testing ketone levels.
A GLP-1 receptor agonist has also been the subject of a large trial in type 1 diabetes – ADJUNCT ONE. In this trial, adjunct liraglutide treatment resulted in improved glycemic control, but was also associated with an increased risk for hypoglycemia and for hyperglycemia with ketosis, and the manufacturer decided against attempting to license the drug for type 1 diabetes.
“As a center in Birmingham we had some patients in this trial and many of them really had benefit with [liraglutide],” said Narendran. “So after this came out, we had to talk to the general practitioners and arrange to have it prescribed off-license.”
He noted that the risk increase for hypoglycemia and hyperglycemia with ketosis was largely absent in patients with residual C-peptide, and these patients also had the greatest benefits from the drug, leading him to suggest that “we may have an indication for stratifying our patients a bit more.”
Finally, he noted that the REMOVAL study of metformin in type 1 diabetes patients is due to report at the American Diabetes Association conference in June this year.
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