Is Strict Glycemic Control Meaningless for the Elderly?

BUSAN, South Korea ― Whether or not strict glycemic control is appropriate for older adults was the subject of a debate between two experts here at the IDF Congress 2019: International Diabetes Federation.

Current guidelines from the Endocrine Society addressing diabetes management in older adults call for shared decision making and individualized approaches, taking into account comorbidities, complications, and special situations.

Here, on December 6, Medha Munshi, MD, and Ryo Suzuki, MD, PhD, took differing approaches to the risk-vs-benefit equation in the elderly.

Munshi: Strict Glycemic Control Is Too Risky in the Elderly

Munshi, director of the Joslin Geriatric Diabetes Program at Beth Israel Deaconess Medical Center, Boston, started the debate by stating, "Yes, strict glycemic control in the elderly is meaningless."

She based this on two main points: the benefits of strict glycemic control in older adults are not clear, whereas the risks are "catastrophic and well documented."

The first problem, Munshi said, is the dearth of data in older adults. In a 2013 review of 2484 diabetes-focused studies registered on clinicaltrials.gov, just 0.6% included participants who were older than 65 years, whereas 30.8% specifically excluded that age group, and 54.9% excluded people older than 70 years.

Another analysis of 440 studies that investigated treatments for type 2 diabetes showed that of trials that did include older adults, more than three quarters (76.8%) excluded those with comorbidities, nearly a third (29.5%) excluded people with polypharmacy or specific drugs, and 18.4% excluded those with cognitive impairment.

"So, the trials are not targeted toward older adults, and those which are exclude people with multiple comorbidities, so the ones who are left in the trials are not the ones we see in the clinic," Munshi emphasized.

Among the major trials that evaluated intensive treatment vs usual care in type 2 diabetes ― including the UK Prospective Diabetes Study (UKPDS), the Veterans Administration Diabetes Trial (VADT), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial ― no macrovascular benefits were found except in UKPDS, and evidence of harm was found in ACCORD.

What those trials suggested, Munshi said, is that the patients who do better with intensive glycemic control are younger, have a shorter duration of disease, fewer complications and comorbidities at baseline, better overall health, and longer life expectancy.

In contrast, those at greater risk from the hypoglycemia associated with intensive glycemic control are people who are older and frail, have longer duration of diabetes, have macro- and microvascular complications and comorbidities, those unable to safely follow complex regimens, and those with shorter life expectancy.

She also pointed to a 2010 retrospective cohort study that identified a U-shaped curve relationship between hemoglobin A1c and all-cause mortality and cardiac events, suggesting that "there is a threshold beyond which, if the control is tighter, then the risk of mortality increases."

Medications used by older adults with diabetes also pose risks, as shown in a 2011 study of 99,628 emergency hospitalizations for adverse drug events among US adults aged 65 and older conducted between 2007–2009.

Warfarin topped the list, but insulin was the second most common, and oral hypoglycemic agents were also in the top 5.

And those episodes of emergency hospitalization, another study found, were associated with a 3.4-fold increased risk for 5-year mortality.

"Hypoglycemia actually has an impact on people over and above the risk of hospitalization. It increases the risk of cognitive decline; depression; frailty; falls and fractures; functional decline; anxiety; and fear of hypoglycemia; and it lowers quality of life," she explained.

Other unintended consequences of strict glycemic control in older adults include difficulty coping with complex regimens, increased caregiver burden, loss of independence, and increased financial burden.

But Is Tight Control Appropriate for the Healthy Elderly?

A valid question, Munshi said, is whether strict glycemic control might be appropriate for older adults who are still healthy.

She responded to that by explaining that there is a phenomenon of aging called homeostenosis, a physical limit beyond which homeostasis can't be restored in the presence of stressors, such as hypoglycemia leading to a fall, hospitalization, delirium, and poor outcome.

Another reasonable question is whether strict glycemic control in older adults could be achieved more safely and with greater benefit by using newer agents with lower risks for hypoglycemia that have been found to have cardiovascular and renal benefits.

To that, she noted that it's unclear whether those benefits are a result of glycemic control, that the duration of the trials has been short (2–3 years), and drug interactions and side effects in populations with multiple morbidities haven't been studied. Moreover, "cost and availability need consideration."

And so, she concluded, "Is strict glycemic control in the elderly really worth the risk? My answer would be no."

Suzuki: No Consensus on What Constitutes "Elderly"

Suzuki, professor in the Division of Diabetes, Metabolism, Endocrinology, Rheumatology, and Collagen Diseases at Tokyo Medical University, Japan, took the opposing position, that strict glycemic control in the elderly isn't "meaningless."

He began by pointing out that his country is "one of the most highly aging societies in the world."

His arguments were based on three points: The elderly population is "full of diversity," that A1c is "not a perfect marker of glycemic control," and that new glucose-lowering drug classes may have benefits beyond blood glucose reduction.

He also noted that there isn't consensus on the definition of "elderly."

Most developed countries use age 65 and older, but the United Nations defines it as 60 and above, whereas the IDF's guideline for manging older people with type 2 diabetes uses 70 and older, "emphasizing the difficulty to generalize the gap between calendar age and biological age."

Suzuki also pointed out that the American Diabetes Association's Standards of Medical Care in Diabetes 2019 doesn't mention age as a consideration in individualizing glycemic targets.

Instead, factors such as risk for hypoglycemia, disease duration, life expectancy, comorbidities, established vascular complications, patient preference, and resources/support systems are listed. "We need to evaluate and assess these factors individually for every patient," he asserted.

"Older age is very heterogeneous. Some people are very robust and active, while others are sick and frail.... We need to be careful about the active, healthy people because sometimes they need more intensified treatment to prevent complications of diabetes."

Suzuki also pointed out that people hold important positions that require good health well into their 60s and 70s.

He showed a slide with photos of US President Donald Trump, age 73, Russian President Vladimir Putin, age 67, and China's leader Xi Jinping, 66.

"In many countries, many older individuals with or without diabetes have responsibilities and play important roles in their societies. Diabetes can be a big barrier for them.... Sometimes it requires hospitalizations and they need to stop business."

He cited an observational study from a Swedish national database showing a significant difference in hospitalizations for heart failure for older adults with diabetes and A1c between 6% and 7%, vs 7% to 8%, among both men and women aged 71–75 and 61–65 years.

"This is of course an observational study, so we cannot draw a conclusion, but still, it strongly suggests that lower than 7% may prevent hospitalization for heart failure in elderly people."

Many Drug Trials Show Benefits in Subgroup Analysis in Elderly

Another point is that A1c doesn't reflect glycemic variability, so it's impossible to tell just from that measure the extent to which an individual is experiencing hypoglycemia ― that is, two people can have the same A1c level, yet one experiences frequent hypoglycemia whereas the other never does.

"So, determining treatment based solely on A1c may be risky," Suzuki noted.

And recently, the availability of continuous glucose monitoring is shifting the definition of "strict" glycemic control from "average" glucose to "time-in-range," which also allows for a determination of the key metric "time below range."

Recent international guidelines advise that for older adults, fewer than 1% of readings should be below 70 mg/dL (3.9 mmol/L), compared to fewer than 4% for most other individuals with diabetes.

Thus, "In terms of avoiding hypoglycemia, older adults have a 'stricter' range. In other words, less stringency for high-risk people does not always mean broader allowance range in any glycemic profiles," Suzuki noted.

But of course, newer drugs are available for patients with type 2 diabetes that don't increase the risk for hypoglycemia.

Suzuki pointed to his own 2018 study demonstrating that the dipeptidyl peptidase‐4 (DPP-4) inhibitor sitagliptin had a greater ability to reduce daily glucose fluctuations compared to the sulfonylurea glibenclamide in drug-naive Japanese patients with type 2 diabetes.

Similarly, in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), the DPP-4 inhibitor did not increase severe hypoglycemia in the subgroup of participants aged 75 years and older.

And in several of the recent cardiovascular outcomes trials demonstrating cardiovascular benefit for type 2 diabetes agents, those benefits have been just as robust among older participants, he stressed.

These include the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial, in which those aged above and below 66 years experienced similar results with dulaglutide, a GLP-1 agonist.

And the landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), which actually showed even greater protection against cardiovascular events among subjects aged 65 and older (hazard ratio, 0.86).

Also in the Dapagliflozin-Heart Failure (Dapa-HF) study, the SGLT-2 inhibitor reduced worsening of heart failure in patients with heart failure with reduced ejection fraction, regardless of age or presence of diabetes.

"I argue that older patients have rights to receive appropriate and effective treatment to prevent diabetes complications," Suzuki concluded.

Munshi is a consultant for Sanofi and Lilly. Suzuki has received honoraria from MSD KK, Novo Nordisk Pharma Ltd, Novartis Pharma KK, Takeda Pharmaceutical Co, Ltd, Mitsubishi Tanabe Co, and Eli Lilly Japan KK.

IDF Congress 2019: International Diabetes Federation: Debate presented December 6, 2019.

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