medwireNews: Symposia on the penultimate day of the 2017 American Diabetes Association 77th Scientific Sessions looked at, among other things, healthy lifestyle matters for patients with diabetes and kidney disease, preserving the beta-cell function, and systemic correlates of diabetic retinopathy.
Combination therapy in type 2 diabetes
James Gavin (Emory University School of Medicine, Atlanta, Georgia, USA) opened the session on combination therapy in type 2 diabetes with an informative overview of the pathophysiology of the disease. The purpose was to demonstrate that “current treatment is indifferent to pathophysiology,” but combination therapy can go some way to address this.
He said up to now, there has been “excessive dependence” on monotherapy, which has led to the simple and convenient stepwise treatment approach. The problem with stepwise treatment is its heavy reliance on metformin, which has limitations including the fact that it does not improve insulin sensitivity, and there is only modest evidence that it benefits beta-cell function.
Monotherapy also drives clinical inertia, according to Gavin, which can expose patients to periods of sustained hyperglycemia and the associated increased risk for complications. He says the answer is a more proactive, that is, physiologic approach to treatment that can enhance insulin action and sensitivity, suppress glucose production, slow down gastric emptying, and more.
There is no one drug that can do this. Instead there needs to be increased early use of combination therapy “that is respectful of the underlying complex pathophysiology of type 2 diabetes,” Gavin concluded.
Roopa Mehta (Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City) reiterated what Gavin said about the need for combination therapy in type 2 diabetes and went on to discuss the fixed-dose (FD) and fixed-ratio combinations (FRC) that are currently available.
She explained that these fall into three groups:
- Metformin based – metformin plus dipeptidyl peptidase-4 inhibitors or sodium glucose transporter 2 inhibitors
- Non-metformin based – alogliptin plus pioglitazone
- Injectible – insulin degludec plus insulin aspart or basal insulin plus a glucagon-like peptide-1 receptor agonist.
Mehta then showed data from a number of studies demonstrating that these combinations improve glucose control relative to monotherapy. They are also associated with less weight gain/greater weight loss, less hypoglycemia, lower medication doses, fewer injections, and an improved side effect profile.
She added that she believes clinical trials will show that FDC/FRC therapy improves adherence. Mehta concluded: “FDC and FRC are here to stay.”
Also speaking in this session were Luigi Meneghini (University of Texas, Dallas, USA) and John Buse (University of North Carolina School of Medicine, Chapel Hill, USA). Meneghini talked about the limitations of FDC/FRC therapy, the biggest of which is a lack of carefully designed, prospective, “real-life” trials to assess the clinical effectiveness of these combinations versus sequential treatment in controlled type 2 diabetes.
Then Buse discussed the future of FDC/FRC therapy saying that as well as developing novel combinations, researchers can also improve on current ones, some of which are underused and understudied. Novel combinations that he suggested may be helpful in diabetes management were diabetes drugs combined with a weight-loss agent, and multiple and multivalent peptides, which Buse described as the “most exciting” due to the excellent results shown in rodents.
Metformin or glyburide in pregnancy?
To set the scene for a debate on the use of metformin versus glyburide in pregnancy, Mary Loeken (Joslin Diabetes Centre, Boston, Massachusetts, USA) gave a whistle stop tour of the biochemical pathways that may be affected by metformin and may, in turn, affect fetal growth.
She explained that embryos do not appear to have metformin transporters, whereas fetal and placental cells do, meaning that while fetal and placental cells may be affected by metformin, it is unlikely in embryos.
Loeken also noted that embryos have no beta cells, and are therefore also unlikely to be affected by insulin stimulation. Fetal cells, on the other hand, do have beta cells and may be affected by glyburide treatment during pregnancy.
Christina Scifres (University of Oklahoma, Normal, USA) began her defense of glyburide use in pregnancy by citing data showing that patients using this drug have similar glycemic control to those using insulin during pregnancy. In addition, treatment failure rates are significantly lower with glyburide than with metformin, which Scifres said makes it an attractive option.
However, she accepted that controversies surrounding the use of glyburide in pregnancy exist, mainly due to the publication of a meta-analysis comparing glyburide with metformin, which concluded that glyburide should not be recommended for use during pregnancy, even though the same publication found an increased risk for preterm birth with metformin.
By contrast, a subsequent Cochrane review concluded that there was no difference in neonatal or maternal outcomes between the two drugs.
Arguing in favor of metformin, Janet Rowan (National Women’s Health, Auckland, New Zealand) only gave a very brief overview of published efficacy and safety data because she said “it’s obvious that metformin is better than glyburide in pregnancy.”
So instead, she discussed the long-term impact of fetal exposure to metformin during pregnancy, noting that there are no such data available for glyburide. Scifres did, however, point out that this is something her team is working on.
Rowan presented 7- and 9-year follow-up data for children of mothers enrolled in the TOFU trial, which compared metformin with insulin in women with gestational diabetes. She said that the data show no significant differences between the children in each of these groups in parameters such as body fat percent and metabolic measures, at both 7 and 9 years.
Successes with type 1 diabetes complications
The final session on day 4 of the conference looked at how diabetes complications have changed over time and how older patients with long-duration diabetes should be cared for.
Both Janet Snell-Bergeon (University of Colorado, Denver, USA) and Trevor Orchard (University of Pittsburgh, Pennsylvania, USA) showed data from multiple trials highlighting temporal declines in morbidity and mortality among patients with diabetes.
Orchard, however, emphasized that although the development of complications in type 1 diabetes is slowing, it is not universal across the different complications and is not happening quickly enough.
Snell-Bergeon reported that the increased life expectancy observed among people with type 1 diabetes is largely due to improved glycemic control and reduced complications including cardiovascular disease, although this remains the leading cause of death.
In spite of these improvements, Snell-Bergeon showed that a substantial gap remains between men and women, with women seeing less improvement in life expectancy than men. For example, in one Swedish cohort, life expectancy among men was 47.4 years between 2002 and 2006, increasing to 49.7 years between 2007 and 2011. The comparative rates for women were 51.7 and 51.9 years.
Snell-Bergeon also said that the gap between Black and White patients remains, with Black patients worse off.
She concluded: “Future improvements in care hold promise for eliminating the gap in mortality [between patients with and without diabetes] but access to care, medication, and technology is necessary” to reduce excess mortality in type 1 diabetes.
Hillary Keenan (Joslin Diabetes Centre, Boston, Massachusetts, USA) then talked about the lessons learnt from patients who have lived with diabetes for more than 50 years. Her research group is studying three cohorts of patients from the UK, the USA, and Canada to understand factors enabling longevity in type 1 diabetes.
She said that physical activity and parental longevity – the parents of these patients lived for around 30 years longer than expected – were important contributors to their prolonged survival. They also had a positive lipid profile and preserved renal function, indicating a lack of insulin resistance.
Furthermore, all 48 postmortem samples tested had insulin-positive cells in the pancreas, and when Keenan and team tested the living patients’ beta-cell function, they observed a fluctuation in C-peptide autoantibody levels over a median of 4.2 years, potentially indicating neogenesis.
She concluded there is definitely a “survivor effect” among these patients but this may dissipate as more people live with diabetes for longer.
Trisha Lynette Dunning (Deakin University, Burwood, Victoria, Australia) closed the session by talking about how best to care for older patients with diabetes.
To develop a suitable care plan, Dunning said there are a number of factors to consider. These include:
- Disease trajectory: Patients could have stable chronic disease or be terminally ill
- Glycemic target: Manage cardiovascular risk, but may not need tight control
- Medicine management: Be aware of polypharmacy
- Communication: Respect the patient’s accumulated diabetes knowledge
- Education: Family members/care workers may be uncomfortable giving insulin
- Cognitive function: Dementia can mask depression
- Falls: Sensory problems can increase the risk
- Pain: Often under recognized and under treated
Dunning concluded that this is a heterogeneous group that should be listened to in order to personalize their care.
By Laura Cowen
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