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Progress and controversies in diabetes trends and treatments
Warning about the epidemic in diabetes has been one of the most common public health medicine mantras in recent times. It is true that the numbers of people with type 2 diabetes have soared over the past two decades as a result of societal shifts in lifestyle. However, at the recent Irish Endocrine Society 2016 Annual Meeting, renowned US consultant endocrinologist Prof David Nathan, Director of the MGH Diabetes Centre and Clinical Research Centre Professor of Medicine, Harvard Medical School, suggested that a corner might have been turned in this regard.
Delivering the inaugural IES Hadden Lecture on the subject of ‘Controversies in diabetes 2016: Where do we go from here?’, Prof Nathan quoted statistics showing for the first time in 20 years that the annual rate of diabetes developments in the US has decreased. Between 1990 and 2008, the increase in diabetes incidence each year was about 5 per cent per annually, with two million new cases seen in 2008.
However, over the past number of years, the incidence rate has fallen by about 5 per cent per year. The most recent data shows new cases had reduced to 1.4 million in 2014. Prof Nathan said that while the war against diabetes has not been won, the new figures do show significant progress has been made in the area of prevention.
Yet big challenges still remain. It is estimated there are 86 million people with pre-diabetes in the US, and 493 million in China. Knowing how best to target this population in terms of preventative strategies is vital, according to Prof Nathan. He was involved in the landmark Diabetes Prevention Programme Outcomes Study (DPPOS), which was funded by the US National Institutes of Health (NIH). The DPPOS was conducted as an extension of an earlier major study, the Diabetes Prevention Programme (DPP). The original project was a major multi-centre clinical research study aimed at discovering whether modest weight loss through dietary changes and increased physical activity or treatment with the oral diabetes drug metformin could prevent or delay the onset of type 2 diabetes in study participants. The DPP found participants who lost a modest amount of weight through dietary changes and increased physical activity sharply reduced their chances of developing diabetes. Taking metformin also reduced risk, although less dramatically. The DPP resolved its research questions earlier than projected and, following the recommendation of an external monitoring board, the study was halted a year early.
The new study was designed to determine the longer-term effects of the two interventions, including further reduction in diabetes development and whether delaying diabetes would reduce the development of the complications that can lead to blindness, kidney failure, amputations and heart disease.
The study showed that lifestyle intervention and metformin treatment have beneficial effects, even years later, but did not reduce microvascular complications. Participants in the study who were originally assigned to lifestyle intervention and metformin during DPP continued to have lower rates of type 2 diabetes development than those assigned to placebo, with 27 per cent and 17 per cent reductions, respectively, after 15 years.
“Interestingly, lifestyle worked best in the older people, which was a total surprise to us,” Prof Nathan said.
“We thought older people wouldn’t be able to follow the lifestyle changes. They did. To a great extent, their families were grown, they were retiring, this is what they did. They took it on with a passion. They formed walking clubs. As opposed to the younger population, who did well, but not nearly as well as the older group. Conversely, metformin worked better in the younger population, who were less than 60 and in those who were more overweight, where their BMI was actually quite high.”
In terms of treatment for people who go onto develop diabetes, Prof Nathan said that better glycaemic control has been the greatest advance since he began working in the specialty.
“No longer do people with type 1 diabetes, and to a greater extent people with type 2 diabetes, have to face a future of losing their vision, of having kidney failure and losing their limbs,” Prof Nathan said.
“We haven’t eliminated it entirely by any means, but we have certainly taken a huge bite out of that problem.”
However, in his talk, Prof Nathan said the most appropriate levels of chronic glycaemia and the best means of achieving them remain unknown. Specific research is needed, he said, to determine the most appropriate levels.
“I think there is a fair amount of enthusiasm; we all have electronic medical records now, and you can do this kind of study, just by looking observationally at what happens,” Prof Nathan told the Medical Independent (MI).
“The problem is that, when you do that, it very much can confuse the means by which you can lower the glucose compared to the level of the glucose that you achieve… I think you need to have interventional studies that look specifically at different levels of glucose control, or compare different agents head-to-head. Those are two slightly different studies.
“One is comparing one agent versus another, and one is comparing one level of control against the other. Mixing those two types of studies into one is a recipe for scientific disaster, because in the end, you don’t know whether it is the lower glucose or the different agents that you were using, so those need to be kept independent.”
Prof Nathan is currently leading a major head-to-head study that will have major implications for the future of diabetes care. GRADE is the first comparative effectiveness study of major pharmacologic treatments in metformin-treated type 2 diabetes and is long enough (four-to-seven years) to be clinically relevant.
More specifically, it is a randomised clinical trial of participants diagnosed with type 2 diabetes within the past 10 years who are already on metformin. Participants will be randomly assigned to one of four commonly-used glucose-lowering drugs (glimepiride, sitagliptin, liraglutide and basal insulin glargine), plus metformin, and will be followed for up to seven years.
The goal of the GRADE study is to determine which combination of two diabetes medications is best for achieving good glycaemic control, has the fewest side-effects, and is the most beneficial for overall health in long-term treatment for people with type 2 diabetes.
“It is looking at people who are relatively early on in their diabetes, who have diabetes control that is in a modest range, that is typical for when people first develop diabetes,” explained Prof Nathan.
“They are already on metformin and we just make sure they are on the maximum dose of metformin they will tolerate. Then we randomly assign them to one of the foremost common agents as a second drug. And then we compare them… and determine hopefully, for the first time, which are the better drugs to use for individual patients [and] for groups of patients.”
It is hoped that the GRADE study will provide much-needed evidence for physicians in how diabetes medications should be prescribed for the benefit of patients and the health system as a whole.
Prof Nathan said there is a lack of appetite within the pharmaceutical industry to conduct such head-to-head studies so it is important for public bodies, such as the NIH in the US, to fill the void.
“There has been no incentive for the group that funds most of this kind of research to do it, therefore it is left up to governments to do it,” he said.
For Prof Nathan, one of the big challenges in diabetes care is cost, with the price of medications continuing to rise steeply.
An important question, he said, is whether the benefits of the new medications are worth a 10- to 100-fold higher cost than the ‘generic approach’.
Lower hydrocortisone replacement doses associated with better quality of life
Clinical practice for hydrocortisone (HC) replacement in hypopituitary patients remains variable, according to Prof Amar Agha, Consultant Endocrinologist, Beaumont Hospital, Dublin.
Prof Agha made the observation during the inaugural IES McKenna Lecture, entitled ‘Pituitary replacement therapy: Refinement, interactions and unanswered questions’ during the Irish Endocrine Society 2016 Annual Meeting, which was held in Belfast on 14-15 October.
In his lecture, Prof Agha ruminated on the appropriate dose of HC, remarking that over 20mgs daily is associated with higher mortality.
He said questions remained as to whether HC should be administered twice or three times daily, and the manner in which the therapy is monitored.
Research shows that when compared to higher doses, lower-dose HC (10/5mgs) is associated with greater physiological serum cortisol levels and tissue cortisol exposure.
It is also associated with a better bone remodelling index, better blood pressure dynamics and no deterioration in quality of life.
Prof Agha said remaining questions are: do patients with partial adrenocorticotropic hormone (ACTH) deficiency require any glucocorticoid replacement and can patients with severe ACTH deficiency be managed with lower HC doses (5/5mgs)?
The causal association between HC dose and mortality also has to be established, he said.
Prof Agha also spoke about the interaction between growth hormone (GH) replacement and the thyroid axis.
He highlighted how research into GH replacement in hypopituitary patients has shown reductions in FT4, r-T3, an increase in FT3, and no change in TSH levels.
“Changes in deiodinase activities in SC tissue do not explain the THs alterations,” according to Prof Agha.
“GH-associated improvement in bone turnover may be mediated, at least in part, by changes in peripheral TH levels.”
However, he said the mechanism of alteration in peripheral TH levels following GH replacements remains unanswered.
Irish Endocrine Society 2016 Award Winners
The IES Lifetime Achievement award was presented to Prof AB Atkinson for his dedication and commitment to Irish endocrinology during the Irish Endocrine Society 2016 Annual Meeting in Belfast last month.
The O’Donovan medal was awarded to Dr HJ Wallace from the Royal Victoria Hospital, Belfast, for her work titled ‘The effect of vitamin D supplementation on insulin resistance in a pre-diabetic population: A double-blind, randomised, placebo-controlled trial’.
This study employed a robust assessment of insulin resistance and targeted a high-risk population and found that vitamin D supplementation had no effect on insulin resistance in people with pre-diabetes.
The Montgomery medal was awarded to Dr Emma Harper from the School of Biotechnology, Dublin City University, for a study entitled ‘Investigating the protective effect of TRAIL on RANKL-induced calcification using a vascular co-culture model’.
The study found in both mono- and co-culture models, TRAIL has the ability to block the pro-calcifying actions of RANKL on vascular cells, yielding valuable information on VC pathogenesis and on the potential therapeutic value of TRAIL.
The Best Clinical Case Posters prizes were awarded to Dr Julie Martin Grace from St Vincent’s University Hospital, Dublin, and Dr F Keane from University College Hospital Galway.
Next year’s Irish Endocrine Society Annual Meeting will be held in the Grand Hotel, Malahide, Dublin, on 13-14 October.
Study finds abnormal aldosterone-renin ratio rarely associated with abnormal adrenal imaging characteristics
Abnormal aldosterone-renin ratio (ARR), which is more common in patients of African compared to European origin, is associated with hypokalaemia and left ventricular hypertrophy, but is rarely associated with abnormal adrenal imaging characteristics, according to a study presented at the Irish Endocrine Society 2016 Annual Meeting.
Adrenal mineralocorticoid biochemistry is known to differ between people of African and European ancestry. The ARR is the initial screening test for primary hyperaldosteronism (PHA), but little data exists regarding ethnic variations in this.
Following clinical observation of a high prevalence of abnormal (increased) ARR in patients of African origin, the authors retrospectively reviewed all ARR measurements in Tallaght Hospital, Dublin, over 10 years.
Rates of hypokalaemia and intraventricular septal thickness (IVS, by echocardiography) were studied as end-points of PHA, and adrenal imaging was reviewed.
ARR was available in 1,947 patients and abnormal findings were detected in 315 (16.2 per cent).
Abnormal ARR occurred in 267/1,823 (14.6 per cent) of European-origin and 48/124 (38.7 per cent) of African-origin patients (p<0.05).
Among 101 of those with abnormal ARR, hypokalaemia (<3.5mmol/l) was documented on at least one occasion in 153/267 (57.3 per cent) European-origin and 33/48 (68.8 per cent) African-origin patients (p=ns). Median (range) IVS was 1.57cm (0.78 to 2.80) in African-origin and 1.2cm (0.69 to 2.18) in European-origin patients (P<0.005). Adrenal adenoma was identified in 2/48 (4.3 per cent) African-origin and 41/267 (15.4 per cent) of European-origin patients (P<0.05).
In summary, ARR was abnormal in 108 or 39 per cent of African-origin patients screened at Tallaght Hospital, but only 4.3 per cent had demonstrable adrenal pathology.
Rates of hypokalaemia were similar between European-origin and African-origin patients, while cardiac hypertrophy was more marked in African-origin patients.
These findings have implications for the use of current screening guidelines for ARR in African-origin patients and also for the mechanistic role of aldosterone in hypertensive complications in these patients.
“Guidelines for screening ARR in African-origin patients potentially result in unnecessary investigations, which are expensive and carry inherent risks,” according to the study author.
“Our findings prompt investigation of whether mineralocorticoid-receptor antagonists should be the anti-hypertensive agents of choice in African-origin patients with elevated ARR as they are in European patients with PHA.”
Further research recommended into growth hormone replacement
Changes in the hypothalamic-pituitary-thyroid axis, following growth hormone (GH) replacement, are reflected in hepatic and bone markers of thyroid hormone action, according to a study presented at the Irish Endocrine 2016 Annual Meeting in Belfast.
The study, which was a collaboration between different centres, including Beaumont, Tallaght and St Vincent’s University Hospitals, Dublin, also found that cardiac time intervals and resting energy expenditure (REE) are insensitive to changing levels of thyroid hormone provoked by GH.
Alterations in hypothalamic-pituitary-thyroid (HPT) axis have been reported following GH replacement.
However, the clinical significance of GH-induced alterations is unclear.
The authors aimed to examine the relationship between changes in serum concentration of thyroid hormones and known biological markers of thyroid hormone action. Twenty hypopituitary men were prospectively studied before and after routine GH replacement. Serum TSH and thyroid hormone (free and total T4, free and total T3, reverse T3) were measured.
Changes in thyroid hormone concentrations were compared to alterations in serum biomarkers of thyroid hormone action.
REE and cardiac time intervals were also evaluated as sensitive markers of peripheral thyroid hormone exposure.
GH replacement provoked a decline in freeT4 concentration; freeT3 level increased (+0.34 ± 0.15; p=0.03).
REE did not rise, as expected, with GH substitution.
Sex hormone-binding globulin level was unchanged.
However, decline in serum ferritin correlated with a fall in freeT4.
Significant increases were recorded in serum bone turnover markers and changes in bone formation markers occurred in parallel with fluctuations in thyroid hormone.
Alterations in lipid profile, including a rise in large, high-density lipoprotein subfractions, did not correlate with thyroid hormone levels.
“GH replacement alters the balance of circulating thyroid hormone levels,” the study concludes.
“GH-induced fluctuations of thyroid hormone levels within the normal range are of uncertain clinical significance and warrant further research.”
Data challenges guidelines on SIAD treatment
A study presented at the Irish Endocrine Society 2016 Annual Meeting has challenged the conventional wisdom that fluid restriction (FR) is first-line treatment for the syndrome of inappropriate antidiuresis (SIAD).
SIAD is the commonest cause of hyponatraemia in clinical practice and FR is recommended as first-line therapy for SIAD by both the European and the American guidelines.
The American guidelines have identified clinical predictors of failure to respond to FR. These include: (1) Urine osmolality (UOsm) >500 -211 mOsm/Kg; (2) Furst formula (ratio UNa + UK/pNa) >1; and (3) 24 h- 212 urine volume <1,500ml.
Although the guidelines recommend FR as first-line therapy in SIAD, there are no randomised, controlled trials to support this recommendation.
Also, the authors pointed out that FR is difficult to implement, particularly if patients require intravenous antibiotics or nutritional supplementation.
The study, which took place in Hospital Clinico San Carlos, Madrid, Spain, and Beaumont Hospital, Dublin, aimed to ascertain the frequency with which patients with SIAD display at least one criterion for prediction of no response to FR.
A total of 183 patients with SIAD were prospectively and consecutively recruited, 51 from Madrid and 132 from Dublin.
The investigators did not interfere in the management of hyponatraemia unless specifically requested.
A significant proportion of the well-defined, consecutive, prospectively-studied cohort of SIAD patients had clinical parameters that the US/Irish guidelines would suggest could predict failure of response to FR.
The results showed 59 per cent of patients had one criteria and 37 per cent of patients had two criteria to predict poor response to FR.
“More than half of SIAD patients had at least one criterion, which have been recommended to predict failure to respond to FR, the first-line therapy for SIAD,” according to the study authors.
“If the predictors of non-response to FR are correct, our data challenges the conventional wisdom that FR is first-line treatment for SIAD. Further studies are needed to test the validity of the predictors of non-response in the US guidelines.”
Research investigates link between obesity and immune system
Preliminary results from consultant endocrinologist Prof Donal O’Shea’s research group show that IL-1b is reduced in type 2 diabetes patients, which may be due to a direct cellular effect.
Glucagon-like peptide-1 (GLP-1) receptor agonists are currently licensed for use in type 2 diabetes and obesity.
Previous reports showed that GLP-1 therapy reduces IL-1b levels in type 2 diabetes patients. IL-1b is a pro-inflammatory cytokine that has been implicated in the pathogenesis of type 2 diabetes and obesity.
The aim of the current study is to elucidate the 349 mechanisms through which GLP-1 reduces the production of IL-1b.
A total of 47 patients who started GLP-1 therapy (liraglutide) for management of their type 2 diabetes or obesity were recruited to the study.
Research samples were taken before commencement of therapy and after 12 weeks.
Peripheral blood mononuclear cells (PBMC) were isolated and stimulated ex vivo with lipopolysaccharides (LPS) for 24 hours and the level of IL-1b was measured in the cell culture supernatants using the ELISA technique.
To date, 12 participants (58 per cent male; mean age 51.6 years) have completed the study.
GLP-1 therapy was associated with a reduction in mean BMI from 44.6 to 42.8 kg/m2 (p = 0.002) and mean HbA1c. FBG also decreased but cholesterol profiles were not significantly affected.
IL-1b production was reduced from a mean of 3,065.6pg/ml pre-treatment to 392.6pg/ml.
“Increased presence of pro-inflammatory intermediate monocytes in obese patients suggest attenuation of monocyte subpopulations in obesity,” thus the results suggest a greater degree of inflammation in diabetes. “By reducing Il-1b production, GLP-1 therapy attenuates immune responses in obesity,” according to the results.
Future plans for the research group include further investigation into the systemic inflammatory profile in the separated obese diabetic and non-diabetic cohorts, as well as further characterisation of monocytes in pre- and post-GLP-1 therapy.
Meanwhile, another study was presented at the meeting, a multi-centre collaboration, which showed changes in adipose tissue gene expression profile and fat mass are associated with deteriorating glucose tolerance.
Increasing adiposity is associated with worsening glucose tolerance and insulin resistance.
However, not all obese individuals share the same risk of metabolic deterioration.
The study selected obese individuals to identify factors including subcutaneous adipose tissue (SAT) gene expression profiles that may predict, or track, worsening metabolic phenotype.
According to the results, increasing fat mass was associated with worsening glucose tolerance.
SAT gene expression profiles in the deteriorators demonstrated significant increased expression of genes involved in lipid metabolism (CD36, LPL, PNPLA2 and, DGAT) adipocytokines (LEP and ADIPO1), adipocyte differentiation (PPARG, GPD and CEBPA/B) and ER stress and inflammation (HSPA5 and TNF).
“We have demonstrated that lower lean mass, increasing fat mass and altered SAT gene expression profiles are associated with worsening glucose tolerance,” the study stated.
“These factors may identify individuals at risk of developing metabolic disease and in whom interventions should be prioritised.”