Disclosures 9/25/18 OBJECTIVES I DO NOT HAVE ANY DISCLOSURES TO MAKE AND AM RECEIVING NO FUNDING FROM ANY PHARMACEUTICAL COMPANY FOR THIS PROGRAM

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1 David Joffe, BSPharm, CDE Editor-in Chief, Diabetes in Control National Manager Pharmacy Accounts- Arbor Pharma Disclosures I DO NOT HAVE ANY DISCLOSURES TO MAKE AND AM RECEIVING NO FUNDING FROM ANY PHARMACEUTICAL COMPANY FOR THIS PROGRAM I MAY MAKE OFF LABEL REFERENCES TO MEDICATIONS OR DEVICES IN THIS PRESENTATION 2 OBJECTIVES Identify the connections between diabetes and dementia related diseases Describe physiologically how these patient s brain function diseases affect glucose levels and how glucose levels affect brain function Identify the effects of diabetes mediations on dementia Identify the challenges associated with diabetes care in these patients Understand the development of glucose goals and targets Identify medications choices and regimens to reduce the risk of hypo or hyperglycemia in these patients Develop medication plans for these patients 3 1

2 Question 1 Patients With Diabetes Are More Likely To Develop Alzheimer s And Dementia? True False 4 D2 DEMENTIA AND DIABETES UNCONTROLLED BLOOD GLUCOSE SEEMS TO INCREASE THE RISK OF BRAIN TROUBLES THERE IS A POSITIVE RELATIONSHIP BETWEEN HBA1C AND THE RISK OF DEMENTIA IN THE AVERAGE TYPE 2 DIABETES POPULATION HBA1C >10% INCREASED THE RISK FOR DEMENTIA IN THE MAJORITY OF PATIENTS. Maintaining an active lifestyle and continuous monitoring of blood sugar are key in avoiding developing dementia. Diabetologia. Improving blood sugar control could help prevent dementia in patients with type 2 diabetes, study suggests. Piela, Rita. Type 2 Diabetes, APOE Gene, and the Risk for Dementia and Related Pathologies. American Diabetes Association YEAR DEMENTIA RISK SCORE FOR TYPE 2 DIABETES PATIENTS A NEW 20 POINT DIABETES-SPECIFIC DEMENTIA RISK SCORE" COULD PAVE THE WAY FOR SELECTING "HIGH-RISK PATIENTS FOR EARLY INTERVENTION STUDIES AND FOR MANY APPLICATIONS OF PERSONALIZED MEDICINE" A NEW RISK SCORE HAS BEEN DEVELOPED BY RESEARCHES AT KAISER PERMANENTE AND THE UNIVERSITY OF MEDICAL CENTRE UTRECHT IN ORDER TO DETERMINE THE 10-YEAR DEMENTIA RISK FOR PATIENTS WITH TYPE 2 DIABETES PATIENTS ASSOCIATED WITH THE LEAST RISK FOR DEMENTIA BASED ON RISK SCORE, HAD A 5.3% CHANCE OF DEVELOPING DEMENTIA OVER THE NEXT TEN YEARS, THOSE ON THE HIGHEST RISK SIDE HAD A 73% CHANGE OF DEVELOPING DEMENTIA. "Risk score for prediction of 10 year dementia risk in individuals with type 2 diabetes: a cohort study" published in The Lancet Diabetes and Endicronology, 20 August

3 ELEVATED GLUCOSE A RISK FOR COGNITIVE DECLINE AND DEMENTIA Glucose peaks tied to greater cognitive decline for those with diabetes and A1c 7.0 percent. Glucose peaks are a risk factor for cognitive decline and dementia Targeting glucose peaks, in addition to average glycemia, may be an important avenue for prevention. Low levels of 1,5-AG, indicative of glycemic peaks, were associated with an increased risk of dementia and greater cognitive decline over 20 years. Andreea M. Rawlings, A. Richey Sharrett, Thomas H. Mosley, Shoshana H. Ballew, Jennifer A. Deal and Elizabeth Selvin; Diabetes Care 2017 Apr; dc ALZHEIMER S AND DIABETES LINKED Elevated glucose in the blood can rapidly increase levels of amyloid beta, a key component of brain plaques The buildup of plaques is thought to be an early driver of the complex set of changes that Alzheimer s causes in the brain Elevated blood glucose may also be responsible for aging the brain and causing memory dysfunction Open KATP channels are responsible for increased levels of amyloid beta in the brain without increased production. Elevated glucose increases opening of KATP channels Macauley SL. Hyperglycemia modulates extracellular amyloid beta concentrations and neuronal activity in vivo. The Journal of Clinical Investigation, online May 4, J Clin Invest. doi: /jci From Washington University in St. Louis, Dept. of Genetics, website info. 8 Diabetes May Be An Early Indicator Of Alzheimer s Disease Smaller total brain volume is associated with diabetes, this size loss affects brain memory retrieval as well as emotional and social behavior. Lower cognitive test scores correlated with lower brain volumes in each area and also suggests that diminished hippocampal and precuneus volumes may be risk indicators for cognitive decline in patients 50 years and older. Srinivasa RN, Rossetti HC, Gupta MK, et al. Cardiovascular Risk Factors Associated with Smaller Brain Volumes in Regions Identified as Early Predictors of Cognitive Decline. Radiology. 2015;

4 Hyperglycemia s Effect on Alzheimer Toxicity Tulane university has published data linking high blood glucose to increasing toxicity of the beta-amyloid plaques that are seen in Alzheimer's Studies indicate that damaged blood vessels subjected to high blood glucose and beta-amyloid protein showed decreased cell viability and worsened alzheimer s. Diabetic blood vessels were at greater susceptibility to damage and death due to beta-amyloid even in the presence of normal blood glucose levels. JOURNAL OF ALZHEIMER S DISEASE, OCTOBER Alzheimer s and Low Blood Sugar Can Trigger a Vicious Cycle Low blood sugar episodes can increase the incidence of developing dementia, while dementia may increase the risk of having low blood sugar, creating a vicious cycle. Elderly patients who were hospitalized for episodes of extreme hypoglycemia were twice as likely to develop dementia. Diabetic patients with dementia were twice as likely to have a severe hypoglycemia episode. Kristine Yaffe et al. Association Between Hypoglycemia and Dementia in a Biracial Cohort of Older Adults With Diabetes MellitusHypoglycemia and Dementia in Older Adults With DM. JAMA Internal Medicine, 2013; 1 DOI: /jamainternmed Insulin Resistance in Middle-aged Patients Increases Atrophy of Brain in Alzheimer s High Insulin resistance corresponds to lower hippocampal volume Researchers found that higher insulin resistance predicted less gray matter at baseline and at the 4-year follow-up in the medial temporal lobe, prefrontal cortices, precuneus and other parietal gyri. All 372 participants, higher [homeostasis model assessment of insulin resistance] was significantly associated with less gray matter at baseline in several regions implicated in early Alzheimer's disease," 12 Diabetes Care published ahead of print October 15, 2012, doi: /dc

5 Evidence Links Alzheimer s and Diabetes Type 2 diabetes is known to increase the risk for Alzheimer's disease. Recent research has found that insulin resistance also develops in the brains of patients with Alzheimer's, which scientists sometimes call brain diabetes. This brain insulin signaling deficit results in learning and memory disability and could potentially be known as type 3 diabetes. Brain levels of insulin and insulin receptor (IR) are lower in AD and insulin signaling impairments have been documented in human postmortem analysis and in animal models. Journal of Clinical Investigation. (2012, March 21). Alzheimer s Disease And Diabetes Linked By New Evidence. 13 Diabetes Drug, Metformin, May Protect the Brain from Dementia Over a five-year study period, patients taking metformin had a 20 percent reduced risk of developing dementia compared to those taking sulfonylureas. Based on animal research, metformin may play a role in the development of new brain cells. It has also been linked to reduced inflammation. Presented at the Alzheimer s Association International Conference in Boston, July Diabetes Drug, Victoza, Could Combat Dementia The drug can enhance brain cell growth and protect memory formation in mice, as well as reducing levels of amyloid a hallmark protein in Alzheimer s in the brain. GLP-1 also improves insulin production in the pancreas, so it is thought that it may also improve insulin signaling in the hippocampus which helps improve cognition Press Release, University of Ulster,June Journal of Clinical Investigation. (2012, March 21). Alzheimer s Disease And Diabetes Linked By New Evidence. 15 5

6 Dementia Meds Increase Risk for Hyperglycemia in Older Diabetics The use of both atypical antipsychotics(aripiprazole, risperidone, olanzapine and quetiapine) and typical antipsychotic(haloperidol, thioridazine and fluphenazine) was associated with a significant increase in hospitalizations for hyperglycemia, which appeared independent of baseline diabetes treatment and was strikingly high during the initial period of antipsychotic therapy. The neurotransmitter dopamine has a role in keeping blood glucose levels under control. The researchers noted that firsttime antipsychotic users may get a disruption in this system and 76 hyperglycemia episodes may result. JAMA/archives journals, news release, july 27, Alzheimer s Plaques Reduced by Diabetes Therapy Patients who had Alzheimer's disease and diabetes and were treated with insulin and oral hypoglycemic drugs had lower densities of neural plaques in the brain, a hallmark of this dementia, than did other diabetes patients or those without diabetes. Insulin use alone reduces density of plaques. There is increased reduction with the use of oral anti-diabetes medication such as metformin, pioglitazone or glyburide with insulin 17 NEUROLOGY, SEPTEMBER 2, Evidence Suggests Pioglitazone Reduces Dementia Risk 42% The risk for developing dementia was about 47 percent lover in diabetes patient taking pioglitazone when compared to non-diabetics. Evidence suggested that pioglitazone inhibits the deposition of harmful proteins in the brain thus they appear to havea neuroprotective effect. The longer the pioglitazone treatment the lower the risk for developing dementia. Michael T. Heneka, Anne Fink, Gabriele Doblhammer. Effect of pioglitazone medication on the incidence of dementia. Annals of Neurology, 2015; DOI: /ana

7 The Effects of Naturally Occurring and Synthetic Amylin on the Development and Progression of Alzheimer s Disease. Endogenous amylin has the tendency to fold over on itself and oligemerize into amyloid which is insoluble and makes plaque. Symlin, a synthetic human amylin, has Proline substitutions to help prevent oligemerization and would likely not have a negative effect on a patient s AD. Symlin could cause negative feedback on the pancreas to slow/stop the release of endogenous amylin and subsequent plaque formation. Jonathan Afiat and Leslie Kutner PharmD Candidates University of Florida College of Pharmacy, Copyright 2013 Diabetes In Control, Inc 19 Glucagon like peptide-1 (GLP-1) likes Alzheimer's disease. The restoration of brain glucose availability and neuronal. metabolism with GLP-1 or an analog potentially protects against cognitive impairment in Alzheimer s disease. Scientific Reportsvolume 7, Article number: (2017) We conclude that the GLP-1 analogue treatment prevented the decline of CMRglc that signifies cognitive impairment, synaptic dysfunction, and disease evolution In Alzheimer s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial Request PDF. 1_Analog_Prevents_Decline_of_Brain_Glucose_Metabolism_Randomized_Placebo-Controlled_Double-Blind_Clinical_Trial 20 Medication Adherence, Lifestyle, and Monitoring Patients with Dementia or Alzheimer s are challenged with the simple tasks associated with diabetes care. Testing Glucose Taking medications Injecting medications Physical Activity Food consumption They often become agitated and frustrated when someone attempts to help them. These efforts are difficult for caregivers as well 21 7

8 How many times a day to test? What times of day to test? What to do with information? Testing Glucose 22 Continuous Glucose Monitoring Wearable devices for 24/7 readings 23 Oral Medications Large pill size, inability to crush tablet or capsules 24 8

9 Injectable medications Insulin, GLP-1 analogs, Amylin analogs 25 Physical Activity Difficult and Frustrating Wheelchair yoga, light weights, group exercise 26 Food consumption Inability to self-feed, difficulty swallowing, taste challenges, decreased or increased hunger. 27 9

10 Development Of Glucose Goals And Targets Why Are These Patients Different? -Poorer socioeconomic situation -Greater social isolation and loneliness -Nursing home residency -Polypharmacy increases the risk of drug side effects and drug-to-drug interactions -Higher frequency of depressive illness or cognitive impairment -Higher risk of mortality 28 Development Of Glucose Goals And Targets Why Are These Patients Different? -Poorer socioeconomic situation -Greater social isolation and loneliness -Nursing home residency -Polypharmacy increases the risk of drug side effects and drug-to-drug interactions -Higher frequency of depressive illness or cognitive impairment -Higher risk of mortality -Decreased renal & hepatic function -Increased risk of hypoglycemia -Presence of a geriatric syndrome: confused state, depression, falls, incontinence, immobility, pressure sores -Presence of disabilities resulting from lower-limb vascular disease or neuropathy requiring a rehabilitation program 29 Development Of Glucose Goals And Targets ADA Guidelines Treatment goals for older adults are the same as younger adults if they have: 1. Physical and cognitive functionality 2. Adequate life expectancy to see the benefits -May widen glycemic goals if individual criteria is not met in older adults caution: avoid hyperglycemia-related complications and hypoglycemia AMERICAN DIABETES ASSOCIATION. STANDARDS OF MEDICAL CARE IN DIABETES DIABETES CARE. 2016;35(SUPPL 1):S11- S

11 Development Of Glucose Goals And Targets What would you consider a good A1c for your Alzheimer s Patient A. 5.7 B. 6.5 C. 7.9 D Development Of Glucose Goals And Targets Clinical Pearls of Wisdom -Insulin requires good visual, motor, and cognitive skills -Metformin is contraindicated in renal insufficiency and significant heart failure -TZDs can cause fluid retention may exacerbate or lead to heart failure -Sulfonylureas can cause hypoglycemia -DPP-4 inhibitors may increase risk of heart failure hospitalization -SGLT-2 inhibitors may increase UTI and frequency of urination -Hypoglycemia can increase falls and can be caused by meds such as beta blockers, insulin dosing, failure to eat. This must be watched carefully, 32 Development Of Glucose Goals And Targets Glycemic Control and Medications in T2DM Elderly with Dementia -Older veterans with T2DM and dementia may need to decrease intensity of diabetes medications -Studies have observed that dementia affects up to 16% of diabetic patients aged 65 years and 24% aged 75 years. Some data has shown that the two conditions may share a pathophysiological link -The present findings highlight the need for initiatives to support safer antidiabetic prescribing choices for patients with dementia. -The relationship between glycemic control levels and the progression of dementia is unknown as of right now and further studies may be needed. CAROLYN T. THORPE, WALID F. GELLAD, SIJIAN ZHANG, ET AL. TIGHT GLYCEMIC CONTROL AND USE OF HYPOGLYCEMIC MEDICATIONS IN OLDER VETERANS WITH TYPE 2 DIABETES AND COMORBID DEMENTIA. DIABETES CARE. APRIL 2015;38:

12 Medications Choices And Regimens Patient Case Mrs. Smith is an 84 y/o patient with dementia. She currently lives at home with an extended family and they take care of her. She is on Metformin and Glyburide for her diabetes care and has had some recent issues with low glucose and dizziness. What questions would you ask the family? Would you make changes to her medication? 34 Medications Choices And Regimens Patient Case Dr. Johnson is at his wit s end with his patient Thomas who has mild dementia and memory loss. Thomas takes insulin and he either has high glucose or extreme lows. She has asked you to figure out what is wrong and what you might possibly do. What questions would you ask What devices might you use Would you make changes to his medication? 35 Medications Choices And Regimens Patient Case A metformin using type 2 diabetes patient has been diagnosed with new onset dementia and has been placed on olanzapine for treatment, A1c has increased from 7.1 to 8.6 What questions would you ask the patient Would you make medication changes or additions? 36 12

13 Conclusion With all the knowledge, treatments, and technology available, there is no reason why anyone should have elevated blood sugars above normal for their age and condition. QUESTIONS AND COMMENTS 37 13