Epidemiology of Diabetes mellitus in Puerto Rico Efraín Rodríguez Vigil, MD FACP, FACE Medical Director Center for Diabetes Control Inc.

Objetives Discuss new diagnostic test and classification for diabetes mellitus Discuss the epidemiologic data for diabetes mellitus in PR Discuss the role of diabetes mellitus in cognitive disorders

Disclosures Nothing to disclose

Types of Diabetes Type 1: Autoimmune Type 2: Insulin Resistance   Type 1: Autoimmune Type 2: Insulin Resistance Gestational: Insulin resistance Secondary Diabetes: Tumors, medication, etc.

Five Clusters of Diabetes N (%) Characteristics Name 1 577 (6.4) Early disease onset (at a young age), essentially corresponds with type 1 diabetes and LADA, relatively low BMI, poor metabolic control, insulin deficiency (impaired insulin production), GADA+ Severe autoimmune diabetes (SAID) 2 1575 (17.5) Similar to cluster 1 but GADA–, high HbA1c, highest incidence of retinopathy Severe insulin-deficient diabetes (SIDD) 3 1373 (15.3) Insulin resistance, high BMI, highest incidence of nephropathy Severe-insulin resistant diabetes (SIRD) 4 1942 (21.6) Obesity, younger age, not insulin resistant Mild obesity-related diabetes (MOD) 5 3513 (39.1) Older age, modest metabolic alterations Mild age-related diabetes (MARD)  

Criteria for the Diagnosis of Diabetes Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) OR 2-h plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT A1C ≥6.5% Classic diabetes symptoms + random plasma glucose ≥200 mg/dL (11.1 mmol/L) Fasting plasma glucose, the 2 hour plasma glucose after a 75-g oral glucose tolerance test, and A1C are equally appropriate diagnostic tests for diabetes. These diagnostic criteria are: Fasting plasma glucose (FPG) ≥126 mg/dL OR 2-hour plasma glucose ≥200 mg/dL during an OGTT A1C ≥6.5% Or in a patient with classic symptoms of hyperglycemia a random plasma glucose ≥ 200 can also be used. In the absence of unequivocal hyperglycemia, the result should be confirmed by repeat testing. [SLIDE] American Diabetes Association Standards of Medical Care in Diabetes. Classification and diagnosis of diabetes. Diabetes Care 2017; 40 (Suppl. 1): S11-S24 Reference American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014;37(suppl 1):S15; Table 2 6

Criteria for the Diagnosis of Diabetes Mellitus Fasting Glucose 2-h Glucose Tolerance Test HbA1c Diabetes Diabetes Diabetes 126 mg/dL Impaired Fasting Glucose 200 mg/dL Impaired Glucose Tolerance Increased risk for diabetes 6.5% 100 mg/dL Healthy 140 mg/dL Healthy Healthy 5.7% Diabetes Care 2010;34:Supp1:S1. 7

Glucose Tolerance Test Oral Tolerance Test: 8 hours fasting 75 gms of Glucola™ Blood sample at: 0 min 30 min 60 min 120 min 180 min

Epidemiology Definition Epidemiology is the branch of medical science that deals with the incidence, distribution, and control of disease in a population. Is considered  the sum of the factors controlling the presence or absence of a disease or pathogen.

Important Definitions Incidence: Number of new cases/ period of time Mortality: Number of deaths/ period of time Prevalence: Number of cases at a given point in time Population at risk: comprises the total number of individuals in original population that are considered capable of acquiring the particular disease or disease characteristic being studied. Trend: A pattern of gradual change in a condition, output, or process, or an average or general tendency of a series of data points to move in a certain direction over time, represented by a line or curve on a graph.

Types of Risk Factors Factors Causally Associated with Factors that are Prime Targets for Major Population Policies Factors Causally Associated with Increased Diabetes Incidence in Individuals Modifiable and Prime Targets for Individual-Level Interventions Factors Explaining Population Trends in the Disease Structured, multi-disciplinary lifestyle Metformin and other drugs Nutrition / education referral Brief Counseling Food policy incentives and restrictions; Crop subsidy policies Incentives / restrictions related to built environment Youth-targeted obesity prevention

Risk Factors for Diabetes mellitus Development Non Modifiable Genetics Age Sex Ethnicity Poor fetal growth High birth weight Modifiable Weight Obesity * Physical inactivity* Smoke Unhealthy diet* * Strongest risk factor

Normal BMI by Height If you are not Asian American or Pacific Islander If you are Asian American If you are Pacific Islander  At-risk BMI ≥ 25  At-risk BMI ≥ 23  At-risk BMI ≥ 26 Height Weight  4'10" 119 110 124  4'11" 114 128  5'0" 118 133  5'1" 132 122 137  5'2" 136 126 142  5'3" 141 130 146  5'4" 145 134 151  5'5"  150 138 156  5'6" 155 161  5'7" 159 166  5'8" 164 171  5'9"  169 176  5'10"  174 160 181  5'11"  179 165 186  6'0"  184 169 191  6'1"  189 174 197  6'2"  194 179 202  6'3"  200 184 208  6'4"  205 189 6'4" 213

Body Mass Index and 1-year Risk of Diabetes (Ford ES et al. AJE 1997;146:214-22) %- Point Absolute Increase 0.031 0.204 0.315 0.329 0.675 0.850 1.256 1.668 2.237 Increase per 100,000 31 204 315 329 675 850 1,256 1,668 2,237 Cumulative Increase BMI <22 22-<23 23-<24 24-<25 25-<27 27-<29 29-<31 31-<33 33-<35 35+ 1-y Risk (%) 0. 224 0. 255 0. 428 0. 539 0. 553 0. 899 1.074 1.480 1.892 2.461 RR 1 1.18 2.44 2.97 3.04 5.07 5.70 8.21 10.89 14.64 550 1,554 7,565

Diabetes mellitus Prevalence in PR 2000 - 2015

Prevalence of Diabetes mellitus by Year and Sex

Prevalence of Diabetes mellitus in Puerto Rico by Sex

Prevalence of Diabetes mellitus in PR by Age Group

Prevalence of Diabetes mellitus in PR Adjusted by Income

Prevalence of Diabetes mellitus in PR by Education Attained

Prevalence of Obesity in PR

Obesity in PR by Household Income

How are we doing?

Distribution by Sex and Age Groups Female Male Total 18 – 29 4 30 – 39 15 19 40 – 49 28 38 66 50 – 59 73 55 128 60 – 69 129 71 200 70 – 79 95 63 158 > 80 10 25 344 256 600 * 85% are > 50 years, 90% female are > 50 years and 78% male are > 50 years

Diabetes and Obesity 2011

Diabetes and Obesity Prevalence in PR

Prevalence of Hypertension and Hypercholesterolemia (2011) in a Diabetic Population

Diabetes mellitus Control

Blood Pressure

Lipids Control (Calculated LDL)

Eye Examination, Monitoring, Education and A1c Monitoring http://apps.nccd.cdc.gov/DDTSTRS/default.aspx

Diabetes Foot Examination http://apps.nccd.cdc.gov/DDTSTRS/default.aspx

Influenza and Pneumococcus Vaccination http://apps.nccd.cdc.gov/DDTSTRS/default.aspx

Diabetes Preventive Measures

A1c Measure, Self Monitoring Blood Glucose and Education

Risk Factor Control in Adults With Diabetes (PRADCO)

Diabetes mellitus Chronic Complications (2012) Retinopathy 20% Cardiovascular Disease 14% Peripheral Neuropathy 67% Depression 18.2%

Cognitive Dysfunction in Diabetes mellitus CDC, Inc.

Cognitive Impairment in Diabetes mellitus Affected Areas: Attention Learning and memory Mental flexibility Psychomotor efficiency Speed and executive functions CDC, Inc.

Diabetes and Dementia Type 1 Diabetes: mild to moderate slowing of mental speed and diminished mental flexibility Type 2 Diabetes: cognitive changes affect learning, memory, mental flexibility and mental speed The rate of cognitive decline is accelerated in elderly people with type 2 diabetes T2 DM or impaired fasting glucose may be present in 80% of people with Alzheimer’s disease (Janson et al, Diabetes 2004;83)

Emerging complications of diabetes Improvement in management of microvascular complications (due to improved glycemic, blood pressure control ) and macrovascular complications (improved lipid control) People with diabetes are living longer Emergence of novel complications such as cognitive impairment and dementia Mediated by mechanisms not addressed by conventional therapies

Center for Disease Control database for deaths in 2010. Aging Drives Disease Center for Disease Control database for deaths in 2010.

Alzheimer’s Disease Prevalence is increasing especially in those age 85+

Diabetes mellitus and Depression Prevalence

Metanalysis of 16 studies assessing the risk of dementia with diabetes Incidence of any dementia was increased in people with diabetes in 5 of 7 studies Overall, the incidence of dementia was increased by 50-100% relative to people without diabetes (CV factors not controlled in all) Increased risk of Alzheimer's disease 50-100% (7 of 11 studies) Increase in risk of vascular dementia of 100-150% (6 of 7 studies) Biessels et al. Lancet Neurology 5(1); Jan 2006

Accelerated Progression from Mild Cognitive Impairment to Dementia in People with Diabetes Weili Xu et al. Diabetes. 2010;59(11):2928-2935

Predictors of cognitive impairment and dementia in older people with diabetes Surviving participants of the Fremantle Diabetes Study (FDS), who were aged 70 years Of 302 participants, 28 (9.3%) had dementia (16 with probable Alzheimer’s disease) and 60 (19.9%) had cognitive impairment without dementia The major independent longitudinal predictors of dementia were older age (per decade; odds ratio 4.0) diabetes duration (for each 5 years; odds ratio 1.69) peripheral arterial disease (odds ratio 5.35) exercise (which was protective; odds ratio 0.26) For Alzheimer’s disease, diabetes duration was an independent predictor in addition to age and diastolic blood pressure Bruce et al. Diabetologia Feb 2008

Determinants of the risk of dementia in individuals with diabetes. Biessels et al. Lancet Neurology 5(1); Jan 2006

Mechanisms that may link diabetes and dementia Exalto et al. Exp Gerontol. 47 (11) Nov 2012

Potential mediators of cognitive impairment in patients with type 2 diabetes mellitus. Nature Endo Rev 7; Feb 2011

The role of inflammation Inflammation is now thought to be involved in insulin resistance and the development of diabetes Human studies point towards increased inflammatory biomarkers (IL-6 and TNF) and age-related cognitive impairment One cross-sectional study in T2DM suggests association between cognitive ability and Il-6

T2DM is associated with the development of vascular dysfunction in the brain. T2DM is a risk factor for microvascular complications as well as macrovascular defects such as stroke Chap 16; Mental and Behavioral disorders; Diseases of the Nervous System Feb 2013

Hypothalamic-pituitary-adrenal dysregulation in diabetes People with T2DM have activation of the hypothalamic-pituitary-adrenal (HPA) axis Raised levels of cortisol and adrenocorticotrophic hormone (ACTH) Increased cortisol levels are associated with increased heart disease and diabetic complications Dysregulation of the HPA axis may be associated with accelerated cognitive decline and mood disturbances in patients with T2DM

Glucocorticoids and cognitive decline Chronic exposure of the hippocampus to high levels of glucocorticoids (cortisol) thought to contribute to age-related cognitive decline Patients with Alzheimer’s have high cortisol levels and low hippocampal volumes Studies in T2DM suggest high cortisol levels are associated with accelerated cognitive decline, reduced working memory, processing speed, mental flexibility, immediate and delayed memory (Edinburgh Type 2 Diabetes Study)

Glucocorticoids and depression Depression is a well-established risk factor for cognitive impairment Depression and its symptoms are more common in people with diabetes mellitus One study in participants both with and without T2DM, reported high cortisol levels and more depressive symptoms were associated with high blood glucose levels This effect was stronger in African American participants (who have a high incidence of both diabetes and depression) than in white individuals Boyle, S. H. et al. Diabetes Care 30, 2484-2488 (2007)

What can be done to reduce the development of dementia in diabetes Blood pressure control? Better control of diabetes? Avoidance of hypoglycemia Statins? Treat depression?

Does treatment of diabetes make a difference? Prospective study of type 2 diabetes and cognitive decline in women aged 70-81 years. Nurses' health study in the US; two cognitive interviews were carried out by telephone during 1995-2003 Women with type 2 diabetes performed worse on all cognitive tests than women without diabetes at baseline (odds ratios 1.34) In contrast, women with diabetes who were on oral hypoglycemic agents performed similarly to women without diabetes (OR 1.06 and 0.99) Women not using any medication had the greatest odds of poor performance (OR 1.74 and 1.45) Women with type 2 diabetes have about 30% greater odds of poor cognitive function than those without diabetes, with a 50% increase after 15 years' of diabetes (Logroscino et al. BMJ 2004, Mar 6)

Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND) Participants (aged 55–80 years) with T2DM, high HbA 1c concentrations (>7·5%; >58 mmol/mol), and a high risk of cardiovascular events: The Digit Symbol Substitution Test (DSST) score, at baseline and at 20 and 40 months and total brain volume (TBV) by MRI, as a primary brain structure outcome There was no significant treatment difference in mean 40-month DSST score (difference in mean 0·32, 95%;p=0·2997) The intensive-treatment group had a greater mean TBV than the standard-treatment group (4·62, 2·0 to 7·3; p=0·0007) Lancet Neurology, The, 2011-11-01, Volume 10, Issue 11

Cognitive impairment affects management of diabetes and treatment-related complications Less involvement on diabetes self-care and monitoring Increased likelihood of severe hypoglycemia Increased risk of major cardiovascular events and death Increased risk of injurious falls

Copyright © 2012 American Medical Association. All rights reserved. Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus JAMA. 2009;301(15):1565-1572. doi:10.1001/jama.2009.460 Date of download: 5/7/2013 Copyright © 2012 American Medical Association. All rights reserved.

Risk Factors For Severe Hypoglycemia Age Unawareness of, or previous severe hypoglycemia High doses of insulin or sulfonylureas Recent hospitalization or intercurrent illness Polypharmacy (>5 prescribed meds) “Tight control” of diabetes Poor nutrition or fasting Chronic liver, renal or cardiovascular disease Vigorous sustained exercise Endocrine deficiency (thyroid, adrenal, or pituitary) Alcohol use Loss of normal counter-regulation Chelliah. Drugs aging 2004:21

Screening Persons with diabetes are screened for retinopathy, neuropathy, microalbuminuria Screening for peripheral arterial or cardiovascular disease if symptomatic Cognitive impairment or dementia is often undiagnosed Perceived lack of benefit of early diagnosis How does this translate to persons with T2 DM?

Diagnosis Work-up of any patient with T2DM and cognitive dysfunction is the same as any other patient with cognitive complaints Behavior, mood and personality changes should be addressed Assess diabetes management and support system Serum chemistry, thyroid, B12, HIV, RPR as indicated Neuroimaging (MRI if possible)

Cognitive trajectories in T2DM Modest decline in cognition over time even in people without dementia This affects verbal memory, information processing speed, attention and executive function Modest decrements affect all age groups and are slowly progressive over time These are NOT early manifestations of dementia Dementia only affects a subset; possible added effect of Alzheimer’s or severe cerebrovascular disease?

What about MRI? Multiple white matter areas of ischemia

Functional MRI showing less brain activation in diabetic subject Gail Munsen PhD. Joslin Diabetes Center 2011 Diabetic subject Control subject

Treatment As yet there are no diabetes-specific therapies with proven efficacy in preventing or ameliorating cognitive decline Cognitive function is being included as an outcome measure in more therapeutic trials Glucose lowering does not show consistent benefit on cognition The large ACCORD-MIND study showed that intensive glucose lowering treatment over 40 mth in people over 55 with T2DM did not benefit cognitive performance

Conclusion Diabetes mellitus prevalence in PR has increased during the last decades This correlated with an increase in obesity prevalence Preventive measures has failed in improving stablished goals Cognitive impairment or dementia is often undiagnosed Education measure has to be changed if we want a real advance in the prevention of diabetes morbidity and mortality

Questions? Thanks