Andrew J. Karter

Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus

CONTEXT Although acute hypoglycemia may be associated with cognitive impairment in children with type 1 diabetes, no studies to date have evaluated whether hypoglycemia is a risk factor for dementia in older patients with type 2 diabetes. OBJECTIVE To determine if hypoglycemic episodes severe enough to require hospitalization are associated with an increased risk of dementia in a population of older patients with type 2 diabetes followed up for 27 years. DESIGN, SETTING, AND PATIENTS A longitudinal cohort study from 1980-2007 of 16,667 patients with a mean age of 65 years and type 2 diabetes who are members of an integrated health care delivery system in northern California. MAIN OUTCOME MEASURE Hypoglycemic events from 1980-2002 were collected and reviewed using hospital discharge and emergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitive impairment, or general memory complaints as of January 1, 2003, were followed up for a dementia diagnosis through January 15, 2007. Dementia risk was examined using Cox proportional hazard regression models, adjusted for age, sex, race/ethnicity, education, body mass index, duration of diabetes, 7-year mean glycated hemoglobin, diabetes treatment, duration of insulin use, hyperlipidemia, hypertension, cardiovascular disease, stroke, transient cerebral ischemia, and end-stage renal disease. RESULTS At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia was diagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%). Results were not attenuated when medical utilization rates, length of health plan membership, or time since initial diabetes diagnosis were added to the model. When examining emergency department admissions for hypoglycemia for association with risk of dementia (535 episodes), results were similar (compared with patients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12-1.78) and for 2 or more episodes (HR, 2.36; 95% CI, 1.57-3.55). CONCLUSIONS Among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia. Whether minor hypoglycemic episodes increase risk of dementia is unknown.

The relation of body fat mass and distribution to markers of chronic inflammation

OBJECTIVE: To study the relation of fibrinogen and C-reactive protein (CRP) to various measures of body fat and body fat distribution and to investigate whether these relations were explained by differences in insulin sensitivity.DESIGN AND SUBJECTS: Cross-sectional analysis of the IRAS (Insulin Resistance Atherosclerosis Study), a large (n=1559) tri-ethnic population (non-Hispanic whites, African-Americans and Mexican-Americans) across different states of glucose tolerance.MEASUREMENTS: Glucose tolerance (oral glucose tolerance test), insulin sensitivity (frequently sampled intravenous glucose tolerance test and minimal model analysis), assessment of body fat mass and distribution (weight, girths, bioelectrical impedance), subclinical atherosclerosis (B-mode ultrasonography of carotid artery intima-media thickness, IMT), CRP (highly sensitive immunoassay), fibrinogen (standard assay).RESULTS: Both CRP and fibrinogen were related to all measures of body fat. Strong correlations (correlation coefficient r≥0.35) were found between CRP and body mass index (BMI), waist circumference and adipose body mass, respectively. The associations were consistent in non-diabetic and type-2 diabetic subjects, were generally stronger in women, and were only moderately attenuated by the prevailing insulin sensitivity (SI). In a multivariate linear regression model waist circumference explained 14.5% of the variability of circulating CRP levels (P=0.0001), BMI 0.4% (P=0.0067), and SI 1.7% (P=0.0001). Common carotid artery IMT was related to CRP and fibrinogen in men, but not in women, and was attenuated after adjusting for BMI or waist.CONCLUSION: Our findings show that measures of body fat are strongly associated with circulating levels of CRP and fibrinogen. These associations were not explained by lower SI in obese subjects. Chronic, subclinical inflammation may be one pathophysiological mechanism explaining the increased risk of atherosclerotic disease associated with adiposity.

Disparities in HbA1c levels between African-American and non-Hispanic white adults with diabetes: a meta-analysis.

OBJECTIVE—Among individuals with diabetes, a comparison of HbA1c (A1C) levels between African Americans and non-Hispanic whites was evaluated. Data sources included PubMed, Web of Science, the Cumulative Index to Nursing and Allied Health, the Cochrane Library, the Combined Health Information Database, and the Education Resources Information Center. RESEARCH DESIGN AND METHODS—We executed a search for articles published between 1993 and 2005. Data on sample size, age, sex, A1C, geographical location, and study design were extracted. Cross-sectional data and baseline data from clinical trials and cohort studies for African Americans and non-Hispanic whites with diabetes were included. Diabetic subjects aged <18 years and those with pre-diabetes or gestational diabetes were excluded. We conducted a meta-analysis to estimate the difference in the mean values of A1C for African Americans and non-Hispanic whites. RESULTS—A total of 391 studies were reviewed, of which 78 contained A1C data. Eleven had data on A1C for African Americans and non-Hispanic whites and met selection criteria. A meta-analysis revealed the standard effect to be 0.31 (95% CI 0.39–0.25). This standard effect correlates to an A1C difference between groups of ∼0.65%, indicating a higher A1C across studies for African Americans. Grouping studies by study type (cross-sectional or cohort), method of data collection for A1C (chart review or blood draw), and insurance status (managed care or nonmanaged care) showed similar results. CONCLUSIONS—The higher A1C observed in this meta-analysis among African Americans compared with non-Hispanic whites may contribute to disparity in diabetes morbidity and mortality in this population.

Prediction of Type 2 Diabetes Mellitus With Alternative Definitions of the Metabolic Syndrome The Insulin Resistance Atherosclerosis Study

Background— In addition to predicting cardiovascular disease (CVD) morbidity and mortality, the metabolic syndrome is strongly associated with the development of type 2 diabetes mellitus (DM), itself an important risk factor for CVD. Our objective was to compare the ability of various metabolic syndrome criteria (including those recently proposed by the International Diabetes Federation), markers of insulin resistance (IR) and inflammation, and impaired glucose tolerance (IGT) in the prediction of DM and to determine whether various proposed modifications to the National Cholesterol Education program (NCEP) metabolic syndrome definition improved predictive ability. Methods and Results— We examined 822 subjects in the Insulin Resistance Atherosclerosis Study aged 40 to 69 years who were nondiabetic at baseline. After 5.2 years, 148 individuals had developed DM. IGT, metabolic syndrome definitions, and IR markers all significantly predicted DM, with odds ratios ranging from 3.4 to 5.4 (all P<0.001), although there were no significant differences in the areas under the receiver operator characteristic (AROC) curves between the definitions. Modifying or requiring obesity, glucose, or IR components in NCEP-defined metabolic syndrome did not significantly alter the predictive ability of the definition under AROC curve criteria (all P>0.05). Similarly, although IR and inflammation variables were significantly associated with incident DM when included in multivariate models with NCEP-defined metabolic syndrome (all P<0.01), expanding the definition by adding these variables as components did not significantly alter the predictive ability of the definition under AROC curve criteria (all P>0.05). Conclusions— The International Diabetes Federation and NCEP metabolic syndrome definitions predicted DM at least as well as the World Health Organization definition, despite not requiring the use of oral glucose tolerance testing or measures of IR or microalbuminuria. Modifications or additions to the NCEP metabolic syndrome definition had limited impact on the prediction of DM.

Social disparities in internet patient portal use in diabetes: evidence that the digital divide extends beyond access

The authors investigated use of the internet-based patient portal, kp.org, among a well-characterized population of adults with diabetes in Northern California. Among 14,102 diverse patients, 5671 (40%) requested a password for the patient portal. Of these, 4311 (76%) activated their accounts, and 3922 (69%), logged on to the patient portal one or more times; 2990 (53%) participants viewed laboratory results, 2132 (38%) requested medication refills, 2093 (37%) sent email messages, and 835 (15%) made medical appointments. After adjustment for age, gender, race/ethnicity, immigration status, educational attainment, and employment status, compared to non-Hispanic Caucasians, African-Americans and Latinos had higher odds of never logging on (OR 2.6 (2.3 to 2.9); OR 2.3 (1.9 to 2.6)), as did those without an educational degree (OR compared to college graduates, 2.3 (1.9 to 2.7)). Those most at risk for poor diabetes outcomes may fall further behind as health systems increasingly rely on the internet and limit current modes of access and communication.

The Literacy Divide: Health Literacy and the Use of an Internet-Based Patient Portal in an Integrated Health System—Results from the Diabetes Study of Northern California (DISTANCE)

Internet-based patient portals are intended to improve access and quality, and will play an increasingly important role in health care, especially for diabetes and other chronic diseases. Diabetes patients with limited health literacy have worse health outcomes, and limited health literacy may be a barrier to effectively utilizing internet-based health access services. We investigated use of an internet-based patient portal among a well characterized population of adults with diabetes. We estimated health literacy using three validated self-report items. We explored the independent association between health literacy and use of the internet-based patient portal, adjusted for age, gender, race/ethnicity, educational attainment, and income. Among 14,102 participants (28% non-Hispanic White, 14% Latino, 21% African-American, 9% Asian, 12% Filipino, and 17% multiracial or other ethnicity), 6099 (62%) reported some limitation in health literacy, and 5671 (40%) respondents completed registration for the patient portal registration. In adjusted analyses, those with limited health literacy had higher odds of never signing on to the patient portal (OR 1.7, 1.4 to 1.9) compared with those who did not report any health literacy limitation. Even among those with internet access, the relationship between health literacy and patient portal use persisted (OR 1.4, 95% CI 1.2 to 1.8). Diabetes patients reporting limited health literacy were less likely to both access and navigate an internet-based patient portal than those with adequate health literacy. Although the internet has potential to greatly expand the capacity and reach of health care systems, current use patterns suggest that, in the absence of participatory design efforts involving those with limited health literacy, those most at risk for poor diabetes health outcomes will fall further behind if health systems increasingly rely on internet-based services.

Rates of Complications and Mortality in Older Patients With Diabetes Mellitus: The Diabetes and Aging Study

IMPORTANCE In the coming decades, the population of older adults with type 2 diabetes mellitus is expected to grow substantially. Understanding the clinical course of diabetes in this population is critical for establishing evidence-based clinical practice recommendations, identifying research priorities, allocating resources, and setting health care policies. OBJECTIVE To contrast the rates of diabetes complications and mortality across age and diabetes duration categories. DESIGN, SETTING, AND PARTICIPANTS This cohort study (2004-2010) included 72,310 older (≥ 60 years) patients with type 2 diabetes enrolled in a large, integrated health care delivery system. Incidence densities (events per 1000 person-years) were calculated for each age category (60-69, 70-79, and ≥ 80 years) and duration of diabetes (shorter [0-9 years] vs longer [≥ 10 years]). MAIN OUTCOMES AND MEASURES Incident acute hyperglycemic events, acute hypoglycemic events (hypoglycemia), microvascular complications (end-stage renal disease, peripheral vascular disease, lower limb amputation, and diabetic eye disease), cardiovascular complications (coronary artery disease, cerebrovascular disease, and congestive heart failure), and all-cause mortality. RESULTS Among older adults with diabetes of short duration, cardiovascular complications followed by hypoglycemia were the most common nonfatal complications. For example, among individuals aged 70 to 79 years with a short duration of diabetes, coronary artery disease and hypoglycemia rates were higher (11.47 per 1000 person-years and 5.03 per 1000 person-years, respectively) compared with end-stage renal disease (2.60 per 1000 person-years), lower limb amputation (1.28 per 1000 person-years), and acute hyperglycemic events (0.82 per 1000 person-years). We observed a similar pattern among patients in the same age group with a long duration of diabetes, with some of the highest incidence rates in coronary artery disease and hypoglycemia (18.98 per 1000 person-years and 15.88 per 1000 person-years, respectively) compared with end-stage renal disease (7.64 per 1000 person-years), lower limb amputation (4.26 per 1000 person-years), and acute hyperglycemic events (1.76 per 1000 person-years). For a given age group, the rates of each outcome, particularly hypoglycemia and microvascular complications, increased dramatically with longer duration of the disease. However, for a given duration of diabetes, rates of hypoglycemia, cardiovascular complications, and mortality increased steeply with advancing age, and rates of microvascular complications remained stable or declined. CONCLUSIONS AND RELEVANCE Duration of diabetes and advancing age independently predict diabetes morbidity and mortality rates. As long-term survivorship with diabetes increases and as the population ages, more research and public health efforts to reduce hypoglycemia will be needed to complement ongoing efforts to reduce cardiovascular and microvascular complications.

Glycemic Control, Complications, and Death in Older Diabetic Patients: The Diabetes and Aging Study

OBJECTIVE To identify the range of glycemic levels associated with the lowest rates of complications and mortality in older diabetic patients. RESEARCH DESIGN AND METHODS We conducted a retrospective cohort study (2004–2008) of 71,092 patients with type 2 diabetes, aged ≥60 years, enrolled in Kaiser Permanente Northern California. We specified Cox proportional hazards models to evaluate the relationships between baseline glycated hemoglobin (A1C) and subsequent outcomes (nonfatal complications [acute metabolic, microvascular, and cardiovascular events] and mortality). RESULTS The cohort (aged 71.0 ± 7.4 years [means ± SD]) had a mean A1C of 7.0 ± 1.2%. The risk of any nonfatal complication rose monotonically for levels of A1C >6.0% (e.g., adjusted hazard ratio 1.09 [95% CI 1.02–1.16] for A1C 6.0–6.9% and 1.86 [1.63–2.13] for A1C ≥11.0%). Mortality had a U-shaped relationship with A1C. Compared with the risk with A1C <6.0%, mortality risk was lower for A1C levels between 6.0 and 9.0% (e.g., 0.83 [0.76–0.90] for A1C 7.0–7.9%) and higher at A1C ≥11.0% (1.31 [1.09–1.57]). Risk of any end point (complication or death) became significantly higher at A1C ≥8.0%. Patterns generally were consistent across age-groups (60–69, 70–79, and ≥80 years). CONCLUSIONS Observed relationships between A1C and combined end points support setting a target of A1C <8.0% for older patients, with the caution that A1Cs <6.0% were associated with increased mortality risk. Additional research is needed to evaluate the low A1C–mortality relationship, as well as protocols for individualizing diabetes care.

Does literacy mediate the relationship between education and health outcomes? A study of a low-income population with diabetes

Objectives. We sought to determine whether literacy mediates the relationship between education and glycemic control among diabetes patients. Methods. We measured educational attainment, literacy using the Short Test of Functional Health Literacy in Adults (s-TOFHLA), and glycemic control (HbA1c) in 395 diabetes patients at a U.S. public hospital. We performed path analysis to compare two competing models to explain glycemic control. The direct effects model estimated how education was related to HbA1c; the mediational model estimated the strength of the direct relationship when the additional pathway from education to literacy to HbA1c was added. Results. Both the model with a direct effect of education on HbA1c and the model with literacy as a mediator were supported by good fit to observed data. The mediational model, however, was a significant improvement, with the additional path from literacy to HbA1c reducing the discrepancy from observed data (p<0.01). After including this path, the direct relationship between education and HbA1c fell to a non-significant threshold. Conclusions. In a low-income population with diabetes, literacy mediated the relationship between education and glycemic control. This finding has important implications for both education and health policy.

Barriers to Insulin Initiation The Translating Research Into Action for Diabetes Insulin Starts Project

OBJECTIVE Reasons for failing to initiate prescribed insulin (primary nonadherence) are poorly understood. We investigated barriers to insulin initiation following a new prescription. RESEARCH DESIGN AND METHODS We surveyed insulin-naïve patients with poorly controlled type 2 diabetes, already treated with two or more oral agents who were recently prescribed insulin. We compared responses for respondents prescribed, but never initiating, insulin (n = 69) with those dispensed insulin (n = 100). RESULTS Subjects failing to initiate prescribed insulin commonly reported misconceptions regarding insulin risk (35% believed that insulin causes blindness, renal failure, amputations, heart attacks, strokes, or early death), plans to instead work harder on behavioral goals, sense of personal failure, low self-efficacy, injection phobia, hypoglycemia concerns, negative impact on social life and job, inadequate health literacy, health care provider inadequately explaining risks/benefits, and limited insulin self-management training. CONCLUSIONS Primary adherence for insulin may be improved through better provider communication regarding risks, shared decision making, and insulin self-management training.