Endocrine Society Shines Light on Diabetic Microvascular Disease

Liam Davenport

November 10, 2017

Beyond simple blood glucose and blood-pressure control, clinicians have few tools to tackle the wide range of damaging and potentially fatal microvascular complications than can occur in patients with diabetes, warn experts from the Endocrine Society.

In a summary of the current knowledge and research gaps in this crucial area of diabetes management, the researchers say that, while there has been a huge growth in the understanding of the pathogenesis and risk factors of such complications, there has not been a corresponding increase in treatments to exploit that knowledge.

The 68-page scientific statement, which was published online November 8 in the Journal of Clinical Endocrinology & Metabolism, sets out the potential targets for novel therapies, which include not only reducing hyperglycemia but also activating protective factors found in normal tissue.

As such, this acts as a clarion call to researchers to improve the current "limited" ability of clinicians to tackle this problem, say Eugene J Barrett, MD, PhD, University of Virginia Health Sciences Center, Charlottesville, Virginia, and coauthors.

Still Much Room for Improvement

Dr Barrett, who chaired the task force that developed the statement, said that, while the risk of microvascular complications can be reduced by tight glycemic and blood-pressure control, this can conversely place patients at risk of "dangerous" hypoglycemic episodes and cardiovascular complications.

"Healthcare providers need to balance the competing goals and consider the individual patient's needs to develop an appropriate treatment plan," he notes in a press release.

Dr Barrett added that, while understanding of diabetic microvascular complications "is gradually improving…it is disappointing that these complications continue to compromise the quantity and quality of life for people with diabetes.

"By understanding and building on current research findings, we hope the future will bring new preventive approaches and treatments that will be effective for future generations."

Talking to Medscape Medical News, Dr Barrett also pointed out that, despite improvements in blood glucose control in recent years, "we still don't make headway on the improvements in lifestyle that are needed, particularly in dietary interventions."

And "we don't have a specific way of intervening on the damage that glucose does to the endothelium and other portions of the vasculature, so I think that's an area that definitely needs more research."

"A number of approaches have been tried…but so far none of them have really turned out."

Dr Barrett continued: "The best thing we can do at the present time is exercise, which has angiogenic effects and can restore some microvasculature. But for things like the eye…we don't have a way to exercise the eye, and similarly we don't have a way to exercise the kidney."

Future Therapies Must Target Basic Processes Underlying the Damage

In terms of future research, he believes that one important focus needs to be the development of a way of preventing the deleterious effects of hyperglycemia without having to keep lowering glucose levels and thus risk triggering hypoglycemia and without "using a lot of insulin to do that."

And "there's still surprisingly a lot to be done at a basic level as well, just in terms of understanding these processes."

The statement notes that the vascular complications of diabetes result from interactions between systemic metabolic abnormalities such as hyperglycemia, dyslipidemia, and genetic and epigenetic modulators and local tissue responses to toxic metabolites.

"A lot of the damage begins with the overproduction of reactive oxygen species and the generation of inflammation, but we don't have specific ways to intervene on that right now in microvascular tissue," Dr Barrett explained.

Alongside this, hypoglycemia causes the suppression of factors that are protective against microvascular complications, including insulinlike growth factor, antioxidant enzymes, platelet-derived and vascular endothelial growth factors, transforming growth factor beta, and activated protein C.

The statement therefore points out that future treatments to prevent or delay diabetic microvascular complications "must" reverse hyperglycemia, inhibit the major mechanisms of vascular dysfunction, neutralize accelerants such as inflammation and oxidative stress, and activate protective factors.

Prevention Is Currently Main Thrust for Retinopathy and Nephropathy

Discussing specific forms of microvascular complications, the authors highlight that diabetic retinopathy and diabetic nephropathy, which are common and may result in severe impairment and poor quality of life, "are considered the quintessential microvascular complications of diabetes."

In the case of diabetic retinopathy, there has been a great deal of research into its pathogenesis and epidemiology, as well as the major risk factors. However, the main thrust of intervention remains its prevention, typically via intensive glycemic and blood-pressure control.

The statement nevertheless stresses that, despite guideline recommendations, patients "be treated individually, balancing microvascular and macrovascular risk against the risk of hypoglycemia and cardiovascular disease [CVD] mortality."

Noting that there is "no single recipe for the glycemic management of CVD risk" in type 2 diabetes, they add: "The old principles still hold: treat each patient as an individual, and first do no harm."

For renal microvascular dysfunction, the current standard of care is similar to that for diabetic retinopathy: the control of blood glucose levels and blood pressure.

While this has resulted in "gratifying" reductions in the progression to end-stage kidney disease, the authors point out that "the increased prevalence of diabetes significantly offsets this progress."

They note: "Developing a more complete understanding of the genetic/molecular factors contributing to initiation and progression of microvascular disease will hopefully lead to even more successful preventive strategies."

Need to Join the Dots in Diabetic Neuropathy

Another major area of consideration is that of diabetic neuropathy, which is "very common" and results in "troublesome complications" that lead to patient morbidity and mortality and is "a huge economic burden for diabetes care."

Diabetic neuropathy comprises several clinical syndromes, and includes "dysfunction of almost every segment of the somatic, peripheral, and autonomic nervous system."

The most common form of diabetic neuropathy is distal symmetric polyneuropathy, which accounts for up to 75% of nontraumatic amputations, while other types include focal neuropathies due to entrapment syndromes and cranial neuropathies.

Again, the authors underline that the development and progression of diabetic neuropathy can be modulated by intensive glucose and metabolic control. However, such interventions cannot reverse neuropathy once it has been established.

To those ends, there have been encouraging results with therapies such as benfotiamine, aldose reductase inhibitors, and alpha-lipoic acid.

Turning to microvascular disease in the brain, the authors observe that there is an increased risk of dementia in adults with type 2 diabetes.

Indeed, recent studies demonstrate that diabetes patients develop structural and functional brain abnormalities similar to those seen in dementia patients, many of which are linked to microvascular disease.

However, it is unclear at this stage whether the presumed causative factors linked to microvascular complications in the periphery underlie the development of such complications in the brain, and therefore more research is required.

The authors also emphasize that microvascular dysfunction and disease is not confined only to these organs but "rather, it is a generalized phenomenon affecting multiple tissues throughout the body," including skeletal and cardiac muscle, skin, and adipose tissue.

Summarizing, they write: "Clearly, there is much we still do not understand, and consequently, our ability to successfully intervene to prevent or reverse microvascular disease is quite limited.

"Insights gained by the use of newer tools, including genetic, proteomic, metabolomics, and other analyses, will certainly add new insights in the basic functioning of microvascular cells, and these insights will light the way to improved therapies."

Dr Barrett has no relevant financial relationships. Disclosures for the coauthors are listed in the paper.

J Clin Endocrinol Metab. Published online November 8, 2017. Abstract

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