With Valentin A. Pavlov, PhD and J. Michael Gonzalez-Campoy, MD, PhD
A common Alzheimer’s medication, galantamine, appears to reduce inflammation and insulin resistance in patients with metabolic syndrome (MetS), according to findings published in JCI Insight.1 Currently prescribed to patients with mild to moderate vascular dementia and Alzheimer’s disease, galantamine is a centrally acting acetylcholinesterase inhibitor with anti-inflammatory properties.
There is evidence to suggest that Inflammation can foster dyslipidemia, excessive abdominal adiposity, increased fasting glucose levels, and high blood pressure, all typical characteristics present in MetS.2, 3
In the first randomized trial to examine the potential role of galantamine in treating MetS, 60 eligible men and women received galantamine or a placebo (1:1) for 12 weeks.1 Of note, a clinical trial examining the potential improvement in insulin sensitivity from administration of this anti-inflammatory medication in obese, African American women is currently recruiting subjects.
Since MetS is an obesity-related condition that may increase the risk of type 2 diabetes (T2D) as well as cardiovascular disease (CVD), the researchers chose to take a closer look at galantamine based on prior pre-clinical work.4-6
“My colleagues and I had discovered that galantamine has powerful anti-inflammatory properties. It stems from our research on inflammation and the nervous system, specifically the vagus nerve in controlling inflammation. We have seen these anti-inflammatory properties in a very relevant model to what we did clinically, a model of high-fat diet-induced obesity and MetS in mice.6 We treated these mice with galantamine, and we saw a reduction in inflammation and a resolution of metabolic derangements, including decreased insulin resistance,” senior author Valentin A. Pavlov, PhD, told EndocrineWeb.
“Additionally, galantamine is clinically approved to treat Alzheimer’s such that we could more easily study galantamine in a clinical setting in humans,” said Dr. Pavlov.
In this trial, patients with MetS were evenly randomized to receive oral galantamine (n = 30) at 8 mg per day for four weeks followed by 16 mg per day for eight weeks or to receive placebo (n=30).1 The study was conducted over two years, from March 2013 and March 2015. The dosage of galantamine used was considered low since the usual level prescribed for dementia is 24 and tested in trials up to 32 mg.
The primary outcome was inflammation as evaluated by plasma levels of cytokines and adipokines associated with MetS.1 Patients in the galantamine arm experienced reduced levels of pro-inflammatory, tumor necrosis factor molecules by 2.57 pg/mL (95% confidence interval [CI], -4.96 to -0.19; P = .035) and leptin by 12.02 ng/mL (95% CI, -17.71 to -6.33; P < .0001) as compared with placebo.1 The galantamine arm also experienced increased levels of the anti-inflammatory molecules adiponectin by 2.71 μg/mL (95% CI, 1.93 to 3.49; P < .0001) and IL-10 by 1.32 pg/mL (95% CI, 0.29 to 2.38; P = .002) as compared with placebo.1
Secondary endpoints that were evaluated were: body weight, insulin, plasma glucose, a homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL, triglycerides), fat tissue depots, blood pressure, heart rate, and heart rate variability (HRV).1
HOMA-IR is a method for determining insulin resistance and beta cell function. HRV describes variation in the interval of time between heartbeats and might associate with physiological health parameters. Autonomic tone, including vagal nerve tone, controls HRV.
The galantamine arm experienced significantly decreased plasma insulin and HOMA-IR and changes to HRV. 1 Insulin levels in the galantamine arm were reduced 0.57 mU/L (95% CI, 0.37 to 0.87; P = .010) compared to the placebo arm. HOMA-IR was reduced in the galantamine arm (log scale 0.55 [95% CI, 0.36 to 0.85]; P = .008) compared with the placebo arm.1
Four different measures of HRV—low frequency (LF) power, LF in normalized units, high frequency (HF) in normalized units, and the LF/HF ratio—were significantly different in the galantamine arm compared with the placebo arm, suggesting differences in autonomic tone associated with inflammation.1
No significant differences occurred between the two arms in measures of adiposity, body weight, waist circumference, blood lipids, blood pressure, or heart rate, said Dr. Pavlov, and “another thing to keep in mind is our treatment was relatively short at just 12 weeks.”
“Notably, the inflammatory improvements came even with a small does over a brief time frame,” Dr. Pavlov said.
“This paper is the first to my knowledge that intervenes in patients with obesity to treat the inflammatory milieu that is associated with increasing fat mass and adiposopathy. It is not surprising that treating inflammation has little effect on the measures of adiposity, or other complications of adiposopathy,” said J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO of the Minnesota Center for Obesity, Metabolism, and Endocrinology in Eagan, MN. “However, treating a complication of obesity does not treat obesity itself.”
“We didn’t use the highest dose (24 mg) that is approved for Alzheimer’s disease. Rather, we used 16 mg, so it didn’t surprise us when we didn’t see any effect on fat depots, body weight, waist circumference, blood lipids, or blood pressure,” Dr. Pavlov said,” and the lack of any effect of galantamine on heart rate is a good thing as it means we did not see any abnormal effects.
Galantamine was well tolerated; only three adverse events occurred in each arm, and these side effects were mild (grade 1-2) in nature.1
“These results suggest that treating inflammation helps return adipose tissue function toward normal, and with this comes insulin sensitization. This should help return metabolism to normal, but this will remain one aspect of patient care. Treating inflammation will not likely improve fat mass. The lifestyle that leads to the accumulation of fat mass remains a primary target for intervention,” Dr. Gonzalez-Campoy told EndocrineWeb.
Overall, the findings support the need to use therapeutics in MetS that specifically addresses inflammation to decrease the risk of developing CVD and T2D, and demonstrates the value for further research into the therapeutic use of galantamine in MetS,1 said Dr. Gonzalez-Campoy.
“This proof of concept paper will now need to be tested in larger numbers of patients over a longer period of time to see if decreasing inflammatory markers improves cardiovascular risk,” he said.
“Obesity is a complex, chronic disease. Adiposopathy, or sick fat, includes the development of inflammation in adipose tissue. This trial opens an exciting area of investigation and documents that galantamine returns adipose tissue function toward normal,” said Dr. Gonzalez-Campoy.