Diabetes Drugs Tied to Less Amyloid, Slowed Cognitive Decline

Among patients with cognitive impairment, those with diabetes who took dipeptidyl peptidase-4 (DPP-4) inhibitors had less amyloid beta (Aβ) in the brain compared to the patients with diabetes who did not take these medications and to the patients without diabetes, new research shows. DPP-4 inhibitors are a class of oral hypoglycemic agents.

The analysis also showed that the patients with diabetes who took a DPP-4 inhibitor experienced slower cognitive decline over time compared to those who did not take the drug.

Dr Seong Ho Jeong

"This study provides evidence that diabetic patients with comorbid Alzheimer's disease can benefit from a DPP-4i," study investigator Seong Ho Jeong, MD, clinical professor at Inje University College of Medicine and Sanggye Paik Hospital, Seoul, South Korea, told Medscape Medical News.

The results highlight the need to study these drugs in patients with Alzheimer's disease (AD) who do not have diabetes, said Jeong.

The study was published online August 11 in Neurology.

Neuroprotective Effect

DPP-4 inhibitors, which block the enzyme dipeptidyl peptidase-4, are often prescribed for patients with diabetes mellitus (DM) whose conditions have not responded well to other antidiabetes drugs, such as metformin and sulfonylureas. They may also be a preferred agent for elderly patients, those with chronic renal failure, and patients vulnerable to hypoglycemia, said Jeong.

This class of drugs, also called gliptins, has proven glycemic properties. Jeong and his colleagues previously showed that these agents also have a neuroprotective effect for patients with Parkinson's disease. In addition, preclinical studies showed an association of DPP-4 inhibitors with Aβ burden.

"So we decided to study whether DPP-4 inhibitors have a protective effect on patients with Alzheimer's disease as well," said Jeong.

The study included 282 patients with AD-related cognitive impairment. The mean age of the patients was about 76.6 years, and about 60% were women. The researchers divided these patients into three groups: 70 diabetic patients with diabetes who were treated with a DPP-4 inhibitor; 71 patients with diabetes who did not take a DPP-4 inhibitor; and 141 patients without diabetes who were matched for age, sex, education, and cognitive status.

About 42.6% in the nondiabetes group, 45.1% among those not taking a DPP-4 inhibitor, and 41.4% of patients who took this drug were considered to probably have AD. The others were categorized as having preclinical AD or prodromal AD.

Co-prescription of other antidiabetes drugs, such as metformin, sulfonylureas, thiazolidinedione, alpha-glucosidase, and insulin, did not differ between the two diabetes groups.

Researchers obtained ¹⁸F-florbetaben (¹⁸F-FBB) positron-emission tomography scans, a widely used Aβ imaging biomarker. Study participants were confirmed to be amyloid positive, as determined by the Alzheimer's Disease Neuroimaging Initiative (global standardized uptake value ratios [SUVRs] >1.08).

Investigators calculated global SUVRs as well as regional SUVRs for four predefined cortical regions of interest: frontal, lateral temporal, lateral parietal, and anterior/posterior cingulate cortices. These are the main brain structures involved in AD.

The primary outcome was the difference of global and regional SUVRs among study groups. Researchers adjusted for age at ¹⁸F-FBB scan, sex, education, cognitive status, and APOE4 carrier status.

Compared to the group not taking a DPP-4 inhibitor, those taking these agents had significantly lower global SUVRs (1.33 vs 1.41; P = .001). These patients also had significantly lower regional Aβ SUVRs (frontal:1.33 vs 1.41; lateral parietal: 1.34 vs 1.42; lateral temporal: 1.33 vs 1.41; and anterior cingulate/posterior cingulate cortices: 1.43 vs 1.53; all P = .002).

More Definitive Data Needed

In addition, those taking DPP-4 inhibitors had lower Aβ burden globally and in two regional cortices ― the lateral parietal and lateral temporal ― compared to the nondiabetes group.

This addresses "a very important question" of whether the beneficial effects of DPP-4 inhibitors on Aβ burden "may extend to AD patients without diabetes," said Jeong.

He noted that more definitive data are needed from a randomized trial to show the neuroprotective properties of DPP-4 inhibitors.

The researchers assessed general cognition using the Korean version of the Mini–Mental State Examination (MMSE). They divided MMSE scores into subscores for orientation, memory registration, memory recall, attention, language, and construction.

A longitudinal assessment of changes to MMSE scores and subscores included 108 patients (56 not taking a DDP-4 inhibitor and 52 taking this drug) who were followed for a median of 30 months. For these patients, the researchers had at least two MMSE scores with a 1-year interval.

Among the patients with diabetes who took a DPP-4 inhibitor, there was an average annual decline of 0.87 points on MMSE score. Among patients with diabetes who did not take a DPP-4 inhibitor, there was an average annual decline of 1.65 points.

"After adjusting for other factors that could affect test scores, we found that the scores of the patients taking a DPP-4i declined by 0.77 points per year more slowly than the patients who did not take a DPP-4i," said Jeong.

Among MMSE subscores, the group x time interaction term was significant only for memory recall after adjustments. The authors note that this subscore is the one mainly affected in AD pathology.

At this point, the potential protective mechanism of DPP-4 inhibitors is unclear, but some studies suggest a direct effect of DPP-4 inhibitors on AD pathology. However, because these agents can't cross the blood-brain barrier, their protective role may be through an indirect mechanism, said Jeong.

He speculated that this could be via an increase in levels of glucogon-like peptide-1 in the peripheral blood or modulation of peripheral inflammation.

"Many studies have shown that DPP-4 inhibitors have an anti-inflammatory effect," he said.

The current study does not definitively answer the question of whether DM is a risk factor for AD, said Jeong. Although many nationwide cohort studies have demonstrated that DM is a risk factor for all-cause dementia, this study and others "failed to demonstrate the association between the presence of DM and amyloid burden," he said.

He noted that although AD is the most common cause of dementia, vascular dementia accounts for a significant proportion of dementia cases.

Early Days

Commenting on the study, Maria C. Carrillo, PhD, the chief science officer of the Alzheimer's Association, told Medscape Medical News that "there's some rationale" behind studying DPP-4 inhibitors for patients with AD.

"There's a well-known though largely undefined connection between diabetes and Alzheimer's, and other diabetes drugs have been and are being investigated in people with cognitive decline and Alzheimer's," she said.

The new findings "may throw some additional light onto the diabetes/Alzheimer's relationship," said Carrillo.

However, she noted that because the study is not a randomized controlled clinical trial, it's impossible to draw firm conclusions about this type of drug and Alzheimer's.

"No causal relationship can be shown in this study design," she noted.

Carrillo also pointed out that key data are missing from the analysis, including amyloid accumulation over time and sequential and baseline A1c levels that indicate blood sugar control.

In addition, she noted, the authors admit that they don't know why the use of these diabetes drugs was associated with slower cognitive decline on a cognitive test.

The study was supported by a grant from the Korea Health Technology R&D Project through the Korean Healthy Industry Development Institute), funded by the Ministry of Health and Welfare, Republic of Korea. The authors have disclosed no relevant financial relationships.

Neurology. Published August 11, 2021

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