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‘Keep Glucose in Check’ to Thwart Cardiac Autonomic Neuropathy

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Among patients with type 2 diabetes at high risk of cardiovascular events, treating to tighter A1c and blood pressure targets was associated with a decreased risk of cardiovascular autonomic neuropathy (CAN), in a new posthoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.

Specifically, patients treated to achieve an A1c below 6% (intensive intervention) rather than below 7%-7.9% (standard intervention) had a 17% lower risk of developing CAN during a median 5-year follow-up, after adjusting for multiple variables.

And patients treated to reach a target systolic blood pressure below 120 mmHg, as opposed to below 140 mmHg, had a 22% lower risk of CAN, defined as decreased heart rate variability on ECG.

However, adding fenofibrate to simvastatin was not more effective in lowering CAN risk than adding placebo to the statin, in the analysis by Yaling Tang, MD, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, and colleagues, which was published in the January 2021 print edition of Diabetes Care.

ACCORD “was done a few years ago, and the primary results look at the effect of three interventions — intensive glycemic control, intensive blood pressure control, and lipid lowering — on cardiovascular outcomes,” mainly heart attack and cardiovascular death, senior coauthor Alessandro Doria, MD, PhD, explained to Medscape Medical News.

“When clinicians think about diabetes and cardiovascular disease,” he continued, “they mainly think about heart attack, some very good physicians think about heart failure, but this other complication — CAN — is not thought of as often.”

“Get people screened with ECG, look for the sign of this complication, and if it is present, this is one more reason to implement the guidelines for glycemic control and blood pressure control,” advised Doria, also of the Joslin Diabetes Center.

However, because ACCORD was not designed to study CAN risk, the findings of the current posthoc analysis must be interpreted with caution, he stressed, and the benefits must be balanced against the risks because, overall, excess mortality was observed in the intensive glycemic control group of ACCORD.

Pat Attention to CAN, Which Predicts CV Events in Both Diabetes Types

CAN is relatively common in type 1 and type 2 diabetes, and about 20% of patients in ACCORD had the complication. CAN is asymptomatic in the early stages, and the only finding may be changes in heart rate variability on ECG (which is picked up using special software).

Later CAN symptoms include orthostatic hypotension (feeling dizzy when getting up), hypoglycemia (without the usual racing heartbeat), asymptomatic heart attack, resting tachycardia, exercise intolerance, and syncope.

Autonomic neuropathy also involves the gastrointestinal, urinary, and genital tracts, Doria pointed out, so it can manifest, for example, as gastroparesis (with symptoms such as vomiting, inability to eat big meals, or diarrhea).    

Known risk factors for CAN include long diabetes duration, severe hyperglycemia, obesity, dyslipidemia, hypertension, and smoking.

Clinicians should pay attention to CAN — an often overlooked, serious complication of diabetes tied to a greater risk of cardiovascular events, and death in some cases — said senior coauthor Rodica Pop-Busui, MD, PhD, University of Michigan, Ann Arbor.

“These findings have high clinical care relevance, as we have previously demonstrated that CAN, even in earlier stages, independently predicts cardiovascular and all-cause mortality in type 2 diabetes, and major cardiovascular events and heart failure in type 1 diabetes,” he noted.

Aim for A1c Below 7%, Document CAN as Early as Possible  

According to Doria, “It’s unclear right now whether the increase in mortality with intensive glycemic control [observed in the original ACCORD trial] was a fluke (a chance event) or was real; there’s still a lot of debate.” And if it was a real finding, the biological explanation is unknown.

Nevertheless, “These [current] results provide us with definitive proof that these [intensive] treatments can be used to prevent this serious complication of diabetes [CAN],” he stressed in a statement from the Joslin Diabetes Center.

“My take is we implement intensive glycemic control but do not push it as low as they were trying in the clinical trial, in ACCORD,” he elaborated.

“I would say A1c below 7% [which is basically the current guideline] should be okay” for lowering CAN risk “and should not increase mortality.”  

The researchers also stress the importance of early detection: “As CAN presentation varies, from subclinical cardiovascular autonomic nerve dysfunction, presenting with asymptomatic changes in [heart rate variability] that may be reversible, to more advanced [disease], it is important and clinically relevant to document presence of CAN as early as possible.”

The current study reveals that intensive glycemic therapy was only associated with a significantly lower risk of CAN in patients without prior cardiovascular disease, and intensive blood pressure lowering was only associated with a significantly lower risk of CAN in patients aged 65 years and older. However, these findings are from a subgroup of a posthoc analysis, so again, they need to be interpreted with caution, Doria emphasized.

However, the findings also indicate some degree of personalization of risk reduction might be advised, the researchers note.

Other study limitations are that none of the patients received sodium-glucose cotransporter 2 (SGLT2) inhibitors and only a few received glucagon-like peptide-1 (GLP-1) receptor agonists; CAN status was based on heart rate variability determined from short ECG tracings; and the impact of reduced CAN on mortality or hypoglycemia could not be assessed.

Postoc Analysis of ACCORD Trial

Tang and colleagues decided to analyze 7275 patients out of the original 10,251 in ACCORD who had data on CAN at baseline and follow-up because the Steno-2 trial, published in 2003, showed intensive multifactorial interventions targeting hyperglycemia, hypertension, dyslipidemia, and lifestyle lowered the rate of progression to CAN by 63% in those with type 2 diabetes.

In the current analysis, about half of patients received intensive glycemic control and half received standard glycemic control.

Patients were further subdivided to receive intensive or standard blood pressure lowering therapy, or simvastatin plus fenofibrate or placebo.

In the original ACCORD trial, patients in the intensive glycemic control group had higher mortality, so they were switched to standard glycemic therapy after a mean of 3.7 years.

At baseline, patients were an average age of 62 years and approximately 40% were women. Median A1c was 8.1% and mean systolic blood was around 135 mmHg.  

Intensive glucose-lowering therapy was more effective than standard therapy in reducing the risk of CAN (odds ratio [OR], 0.83; P = .002), after adjusting for multiple confounders — but was only significant in patients without cardiovascular disease at baseline.

Intensive blood pressure lowering therapy was also more effective than standard therapy in reducing the risk of CAN (OR, 0.78; P = .004) after multivariable adjustment — but was only significant in patients at least 65 years old.

Fenofibrate did not have a significant effect on CAN (OR, 0.87; P = .078). 

Intensive glycemic control on top of intensive blood pressure control did not provide added reduction in risk of CAN.

Doria has reported receiving funding from Sanofi. Pop-Busui has reported receiving grants from AstraZeneca and personal fees from Bayer, Boehringer Ingelheim, and Novo Nordisk. Tang has reported no relevant financial relationships. Disclosures for the other authors are listed in the article.

Diabetes Care. 2021;44:164-173. Abstract

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