A phase II, single center, randomized, double‐blind, placebo‐controlled study of the safety and therapeutic effectiveness of intranasal glulisine in amnestic mild cognitive impairment and probable mild Alzheimer’s disease

Abstract

Background IN insulin is a potential treatment for neurodegenerative disease shown to increase cerebral glucose update, reduce amyloid plaques and improve verbal memory in cognitively‐impaired as well as normal adults. Investigations have suggested that rapid‐acting (RA) insulins such as glulisine may result in superior cognitive benefits compared to regular insulin. Method We performed a single center, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy of IN glulisine versus placebo in N=35 memory impaired (MCI/AD) subjects. Subjects with non‐insulin dependent diabetes mellitus (NIDDM) were included in the study. IN administration utilized the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device. The ADAS‐Cog13, CDR global score, and FAQ were measured at baseline, 3, and 6 months. Secondary outcome measures included digit span forward/backwards, Trailmaking part A/B, COWAT, and WMS logical memory. Depression and suicidality were assessed using the GDS and C‐SSRS Results Subjects in the saline group were significantly older than those in the saline group (p=0.022). No significant differences in gender, education, ApoE4 status, and MOCA score existed between treatment groups. Overall, the number of adverse events per person was similar between groups (2.32 vs. 2.24, p=0.824); although subjects receiving IN glulisine had higher rates of nasal irritation (25.0% vs 13.9%) and respiratory symptoms (15.9% vs 8.3%) compared to placebo. Glucose<70 was observed in one subject receiving RA insulin, but otherwise, there were no other cases of hypoglycemia, including three NIDDM patients. Insulin levels and blood pressure was unaffected by treatment. No significant difference for ADAS‐Cog 13, CDR‐SOB or FAQ scores were found between treatment groups at 3 and 6 months. There was no impact of IN glulisine on depression or suicidality. Conclusion IN glulisine was safe and well‐tolerated and did not consistently impact peripheral glucose or insulin levels. There were no enhancing effects of IN glulisine on cognition, function, or mood, but the ability to detect significance was limited by number of subjects successfully enrolled and study duration. Additional investigations following a larger MCI/AD cohort inclusive of NIDDM subjects over a longer duration are necessary to better evaluate RA insulin efficacy in this population.

Efficacy of intranasal insulin in improving cognition in mild cognitive impairment or dementia: a systematic review and meta-analysis

“…Three crossover studies (Rosenbloom, 2011 ; Rosenbloom et al, 2014 ; Cha et al, 2017 ) out of the 16 papers we analyzed were included in our meta-analysis, Two studies used a parallel design (Craft, 2012a ; Craft et al, 2020 ). The follow-up period is from 1 day to 72 weeks.…”

“…The sample size ranged from 9 to 240. One study was HIV Dementia (Rubin, 2017 ), one was diagnosed with MDD(major depressive disorder) (Cha et al, 2017 ), and two studies enrolled patients with PDD (Parkinson's disease Dementia) (Novak et al, 2019 ; Yufeng, 2020 ), the others were about AD or MCI (Reger et al, 2006 , 2008a , b ; Rosenbloom, 2011 ; Craft, 2012a , b ; Claxton et al, 2013 , 2015 ; Rosenbloom et al, 2014 , 2021 ; Craft et al, 2017 ; Yufeng, 2020 ). These studies were conducted in the following regions: Canada ( n = 1), China ( n = 1), America ( n = 14).…”

Network medicine for disease module identification and drug repurposing with the NeDRex platform

“…Diabetes as original indication-Medications indicated for diabetes mellitus (DM) are potential treatments of AD since the glucose metabolism plays a key role in neural function 54,55 . Several drugs have been tested in vitro, in vivo and in clinical trials, where Insulin (DB00030), Insulin Detemir, Insulin Glulisine (insulin analogs) stand out [56][57][58] . These drugs interact with the insulin receptor (INSR) and are considered disease modifying drugs.…”

Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links

“…Furthermore, pharmacological preparations for insulin injections do not entirely cross the BBB, limiting its distribution in the CNS[ 136 ]. Therefore, intranasal insulin administration emerges as a highly viable alternative[ 137 - 143 ].…”