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Can it be true? New scientific evidence doesn't support tight glycemic control.

The scientific evidence does not support tight glycemic control as a means to prevent the complications of type 2 diabetes, even though most clinical practice guidelines, quality-of-care measures, quality improvement interventions, and academic and clinical statements unequivocally endorse tight glycemic control for that purpose, according to a report published in Circulation: Cardiovascular Quality and Outcomes.

There is an enormous disconnect between the widespread consensus that tight glycemic control is essential on the one hand, and the overwhelming data demonstrating that it doesn't prevent 10 of the 11 micro- and macrovascular complications that matter most to patients on the other hand. "This consensus and its downstream consequences to practice, policy, and research" must be recalibrated, said Rene Rodriguez-Gutierrez, MD, and Victor M. Montori, MD, both of the Knowledge and Evaluation Research Unit, Division of Endocrinology, Mayo Clinic, Rochester, Minn.

Paul S. Jellinger, MD, raised concerns about the trial's design and some of its findings. There has been evidence over the decades "that tight glycemic control makes a difference, particularly in microvascular complications," he said.

Dr. Rodriquez-Gutierrez and Dr. Montori and their associates systematically reviewed the current evidence regarding tight glycemic control (achieving hemoglobin [A.sub.1c] under 7%) published in the five "most impactful" general medical journals (the New England Journal of Medicine, the Lancet, JAMA, the British Medical Journal, and Annals of Internal Medicine) and the two most impactful specialty journals (Diabetes Care and the Journal of the American College of Cardiology) between 2006 and 2015.

This included 328 research articles, 16 sets of treatment guidelines, 11 meta-analyses, and five large, randomized clinical trials and their extension studies, as well as relevant letters, commentaries, and editorials. They also reviewed national guidelines and standards of care published in all languages during the study period.

The investigators focused on the effect of tight glycemic control, as opposed to looser control, on 11 outcomes most important to patients: end-stage renal disease or the need for dialysis, renal death, blindness, clinical neuropathy microalbuminuria, retinal photocoagulation, all-cause mortality, cardiovascular mortality, nonfatal MI, fatal and nonfatal stroke, and peripheral vascular events or amputations.

Regarding the microvascular complications, good evidence shows that tight glycemic control has no significant impact on the risk of end-stage renal disease, renal death, blindness, or clinical neuropathy, and that there is no threshold Hb[A.sub.1c] effect on risk. Moreover, the incidence of such complications is very low (less than 6%). Nevertheless, "practice guidelines and published statements offer a consistent and confident consensus, with 100% of the guidelines and 77%-100% of academic and clinical statements in favor of tight glycemic control to prevent microvascular complications," according to Dr. Rodriguez-Gutierrez and Dr. Montori (Circ Cardiovasc Qual Outcomes. 2016 Aug 23;9:00-00. doi: 10.1161/CIRCOUT-COMES.116.002901).

Dr. Jellinger took issue with this finding, noting in an interview that investigators excluded the landmark Kumamoto study (Diabetes Care. 2000;23[suppl. 2]:B21-9) as an individual study in their analysis and included it only in the meta-analysis, with the effect of diluting its significant findings that tight glycemic control over the decades makes a difference in the rates of microvascular complications in patients with type 2 diabetes mellitus.

Also shortchanged were two other trials: the UK Prospective Diabetes Study (UKPDS) (Br J Clin Pharmacol. 1999 Nov;48 [5]:643-8) and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) (Diabetes Care. 2009 Nov;32[suppl 2]:S357-61) trials. The UKPDS trial showed that tight glycemic control significantly reduced the risk of microvascular complications, predominantly retinopathy and to a lesser degree kidney disease and neuropathy. However, the investigators seemed to minimize the importance of those benefits by emphasizing it was primarily a retinopathy benefit, according to Dr. Jellinger, an endocrinologist in Hollywood, Fla. With ADVANCE there was a significant reduction in microvascular comoplicatioons, specifically protein leakage in urine. In fact, that is an important benefit because it shows that tight glycemic control offers kidney protection.

Data from the current analysis show that, with regard to macrovascular complications, the evidence consistently shows that tight glycemic control exerts no significant effect on all-cause or cardiovascular mortality or on fatal or nonfatal stroke. The putative protective effect reported on amputations is "imprecise," as it is based on very few such events. The only protective effect of tight glycemic control in this category of complications is that it reduces the risk of nonfatal MI by 15%. Dr. Jellinger commented "that another important issue with the current analysis is the confounding use of sulfonylureas in many of these studies. These agents have been and continue to be implicated as increasing the risk of cardiovascular disease."

Since the publication of the ACCORD trial, which clearly questioned the ability of tight glycemic control to prevent macrovascular complications, the consensus on this point has "withered." At present, 64%-79% of published statements now express "uncertainty and skepticism" that tight glycemic control is essential. Yet two sets of guidelines--the American Diabetes Association standards and the 2009-2016 American Association of Clinical Endocrinologists--continue to recommend individualized tight glucose control.

Dr. Jellinger pointed out the widely held belief that "it is not the [A.sub.1c] achieved but how you get there that counts. ACCORD attempted to lower [A.sub.1c] by a very aggressive atypical approach, and it was those patients who were aggressively treated who experienced unexpected sudden death unrelated to the actual [A.sub.1c] achieved."

Dr. Jellinger noted that long-term data from DCCT (Diabetes. 1997;45:271-86) and its extension arm EDIC (Diabetes Care. 2016; Jul;dcl52399) show "a clear and robust reduction in cardiovascular complications" in patients that were tightly controlled during the first 5 years. The current analysis dismisses that finding on the grounds that the patients in DCCT /EDIC had type 1 rather than type 2 diabetes. Yet according to Dr. Jellinger, "a significant cardiovascular benefit was also shown in the tightly controlled patients with type 2 diabetes in the UKPDS study in the 10-year follow-up analysis."

According to Dr. Rodriquez-Gutierrez and Dr. Montori, the study findings indicate that despite good evidence to the contrary, the unsupported "consensus" on tight glycemic control drives most guidelines and quality-of-care interventions. It also underlies "the Food and Drug Administration policy to approve diabetes mellitus drugs only on the basis of their antihyperglycemic effect, without requiring evidence of reduction in the risk of complications," the investigators said.

"This consensus is also driving studies such as the National Institutes of Health-funded GRADE trial comparing antihyperglycemic drugs on their ability to reduce Hb[A.sub.1c], rather than to reduce the risk of diabetes complications," they added.

The narrow focus on tight glycemic control has undercut research on other possible interventions to prevent these complications. There are zero trials currently under way assessing treatment possibilities other than drugs that reduce hyperglycemia, and there are zero evidence-based therapies either mentioned in guidelines or routinely prescribed to patients for preventing these complications, Dr. Rodriguez-Gutierrez and Dr. Montori wrote.

"A careful and thoughtful recalibration" is needed. "Today, patients with type 2 diabetes, at least in some parts of the world, seem to live longer lives with fewer complications. The evidence summarized here requires us to explore factors other than tight glycemic control to explain this improvement and better address the diabetes epidemic," they noted.

This study was supported by the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Dr. Rodriguez-Gutierrez and Dr. Montori reported having no relevant financial disclosures. Dr. Jellinger reported that he is on the speakers bureau for a number of pharmaceutical companies that make drugs for type 2 diabetes.


Courtesy Dr. jellinger

Caption: Dr. Paul S. Jellinger
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Author:Moon, Mary Ann
Publication:Family Practice News
Date:Sep 15, 2016
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