Rozalina G. McCoy

Increased Mortality of Patients With Diabetes Reporting Severe Hypoglycemia

OBJECTIVE Hypoglycemia is a cause of significant morbidity among patients with diabetes and may be associated with greater risk of death. We conducted a retrospective study to determine whether patient self-report of severe hypoglycemia is associated with increased mortality. RESEARCH DESIGN AND METHODS Adult patients (N = 1,020) seen in a specialty diabetes clinic between August 2005 and July 2006 were questioned about frequency of hypoglycemia during a preencounter interview; 7 were lost to follow-up and excluded from analysis. Mild hypoglycemia was defined as symptoms managed without assistance, and severe hypoglycemia was defined as symptoms requiring external assistance. Mortality data, demographics, clinical characteristics, and Charlson comorbidity index (CCI) were obtained from the electronic medical record after 5 years. Patients were stratified by self-report of hypoglycemia at baseline, demographics were compared using the two-sample t test, and risk of death was expressed as odds ratio (95% CI). Associations were controlled for age, sex, diabetes type and duration, CCI, HbA1c, and report of severe hypoglycemia. RESULTS In total, 1,013 patients with type 1 (21.3%) and type 2 (78.7%) diabetes were questioned about hypoglycemia. Among these, 625 (61.7%) reported any hypoglycemia, and 76 (7.5%) reported severe hypoglycemia. After 5 years, patients who reported severe hypoglycemia had 3.4-fold higher mortality (95% CI 1.5–7.4; P = 0.005) compared with those who reported mild/no hypoglycemia. CONCLUSIONS Self-report of severe hypoglycemia is associated with 3.4-fold increased risk of death. Patient-reported outcomes, including patient-reported hypoglycemia, may therefore augment risk stratification and disease management of patients with diabetes.

Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006-2013.

OBJECTIVE To examine temporal trends in utilization of glucose-lowering medications, glycemic control, and rate of severe hypoglycemia among patients with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS Using claims data from 1.66 million privately insured and Medicare Advantage patients with T2DM from 2006 to 2013, we estimated the annual 1) age- and sex-standardized proportion of patients who filled each class of agents; 2) age-, sex-, race-, and region-standardized proportion with hemoglobin A1c (HbA1c) <6%, 6 to <7%, 7 to <8%, 8 to <9%, ≥9%; and 3) age- and sex-standardized rate of severe hypoglycemia among those using medications. Proportions were calculated overall and stratified by age-group (18–44, 45–64, 65–74, and ≥75 years) and number of chronic comorbidities (zero, one, and two or more). RESULTS From 2006 to 2013, use increased for metformin (from 47.6 to 53.5%), dipeptidyl peptidase 4 inhibitors (0.5 to 14.9%), and insulin (17.1 to 23.0%) but declined for sulfonylureas (38.8 to 30.8%) and thiazolidinediones (28.5 to 5.6%; all P < 0.001). The proportion of patients with HbA1c <7% declined (from 56.4 to 54.2%; P < 0.001) and with HbA1c ≥9% increased (9.9 to 12.2%; P < 0.001). Glycemic control varied by age and was poor among 23.3% of the youngest and 6.3% of the oldest patients in 2013. The overall rate of severe hypoglycemia remained the same (1.3 per 100 person-years; P = 0.72), declined modestly among the oldest patients (from 2.9 to 2.3; P < 0.001), and remained high among those with two or more comorbidities (3.2 to 3.5; P = 0.36). CONCLUSIONS During the recent 8-year period, the use of glucose-lowering drugs has changed dramatically among patients with T2DM. Overall glycemic control has not improved and remains poor among nearly a quarter of the youngest patients. The overall rate of severe hypoglycemia remains largely unchanged.

Intensive Treatment and Severe Hypoglycemia Among Adults With Type 2 Diabetes.

IMPORTANCE Intensive glucose-lowering treatment among patients with non-insulin-requiring type 2 diabetes may increase the risk of hypoglycemia. OBJECTIVES To estimate the prevalence of intensive treatment and the association between intensive treatment, clinical complexity, and incidence of severe hypoglycemia among adults with type 2 diabetes who are not using insulin. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of administrative, pharmacy, and laboratory data from the OptumLabs Data Warehouse from January 1, 2001, through December 31, 2013. The study included nonpregnant adults 18 years or older with type 2 diabetes who achieved and maintained a hemoglobin A1c (HbA1c) level less than 7.0% without use of insulin and had no episodes of severe hypoglycemia or hyperglycemia in the prior 12 months. MAIN OUTCOMES AND MEASURES Risk-adjusted probability of intensive treatment and incident severe hypoglycemia, stratified by patient clinical complexity. Intensive treatment was defined as use of more glucose-lowering medications than recommended by practice guidelines at specific index HbA1c levels. Severe hypoglycemia was ascertained by ambulatory, emergency department, and hospital claims for hypoglycemia during the 2 years after the index HbA1c test. Patients were categorized as having high vs low clinical complexity if they were 75 years or older, had dementia or end-stage renal disease, or had 3 or more serious chronic conditions. RESULTS Of 31 542 eligible patients (median age, 58 years; interquartile range, 51-65 years; 15 483 women [49.1%]; 18 188 white [57.7%]), 3910 (12.4%) had clinical complexity. The risk-adjusted probability of intensive treatment was 25.7% (95% CI, 25.1%-26.2%) in patients with low clinical complexity and 20.8% (95% CI, 19.4%-22.2%) in patients with high clinical complexity. In patients with low clinical complexity, the risk-adjusted probability of severe hypoglycemia during the subsequent 2 years was 1.02% (95% CI, 0.87%-1.17%) with standard treatment and 1.30% (95% CI, 0.98%-1.62%) with intensive treatment (absolute difference, 0.28%; 95% CI, -0.10% to 0.66%). In patients with high clinical complexity, intensive treatment significantly increased the risk-adjusted probability of severe hypoglycemia from 1.74% (95% CI, 1.28%-2.20%) with standard treatment to 3.04% (95% CI, 1.91%-4.18%) with intensive treatment (absolute difference, 1.30%; 95% CI, 0.10%-2.50%). CONCLUSIONS AND RELEVANCE More than 20% of patients with type 2 diabetes received intensive treatment that may be unnecessary. Among patients with high clinical complexity, intensive treatment nearly doubles the risk of severe hypoglycemia.

Second-line Agents for Glycemic Control for Type 2 Diabetes: Are Newer Agents Better?

OBJECTIVE While metformin is generally accepted as the first-line agent in treatment of type 2 diabetes, there are insufficient evidence and extensive debate about the best second-line agent. We aimed to assess the benefits and harms of four commonly used antihyperglycemia treatment regimens considering clinical effectiveness, quality of life, and cost. RESEARCH DESIGN AND METHODS We developed and validated a new population-based glycemic control Markov model that simulates natural variation in HbA1c progression. The model was calibrated using a U.S. data set of privately insured individuals diagnosed with type 2 diabetes. We compared treatment intensification of metformin monotherapy with sulfonylurea, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, or insulin. Outcome measures included life-years (LYs), quality-adjusted life-years (QALYs), mean time to insulin dependence, and expected medication cost per QALY from diagnosis to first diabetes complication (ischemic heart disease, myocardial infarction, congestive heart failure, stroke, blindness, renal failure, amputation) or death. RESULTS According to our model, all regimens resulted in similar LYs and QALYs regardless of glycemic control goal, but the regimen with sulfonylurea incurred significantly lower cost per QALY and resulted in the longest time to insulin dependence. An HbA1c goal of 7% (53 mmol/mol) produced higher QALYs compared with a goal of 8% (64 mmol/mol) for all regimens. CONCLUSIONS Use of sulfonylurea as second-line therapy for type 2 diabetes generated glycemic control and QALYs comparable with those associated with other agents but at lower cost. A model that incorporates HbA1c and diabetes complications can serve as a useful clinical decision tool for selection of treatment options.

Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment

Objective To estimate the effectiveness and safety of thyroid hormone treatment among pregnant women with subclinical hypothyroidism. Design Retrospective cohort study. Setting Large US administrative database between 1 January 2010 and 31 December 2014. Participants 5405 pregnant women with subclinical hypothyroidism, defined as untreated thyroid stimulating hormone (TSH) concentration 2.5-10 mIU/L. Exposure Thyroid hormone therapy. Main outcome measure Pregnancy loss and other pre-specified maternal and fetal pregnancy related adverse outcomes. Results Among 5405 pregnant women with subclinical hypothyroidism, 843 with a mean pre-treatment TSH concentration of 4.8 (SD 1.7) mIU/L were treated with thyroid hormone and 4562 with a mean baseline TSH concentration of 3.3 (SD 0.9) mIU/L were not treated (P<0.01). Pregnancy loss was significantly less common among treated women (n=89; 10.6%) than among untreated women (n=614; 13.5%) (P<0.01). Compared with the untreated group, treated women had lower adjusted odds of pregnancy loss (odds ratio 0.62, 95% confidence interval 0.48 to 0.82) but higher odds of preterm delivery (1.60, 1.14 to 2.24), gestational diabetes (1.37, 1.05 to 1.79), and pre-eclampsia (1.61, 1.10 to 2.37); other pregnancy related adverse outcomes were similar between the two groups. The adjusted odds of pregnancy loss were lower in treated women than in untreated women if their pre-treatment TSH concentration was 4.1-10 mIU/L (odds ratio 0.45, 0.30 to 0.65) but not if it was 2.5-4.0 mIU/L (0.91, 0.65 to 1.23) (P<0.01). Conclusion Thyroid hormone treatment was associated with decreased risk of pregnancy loss among women with subclinical hypothyroidism, especially those with pre-treatment TSH concentrations of 4.1-10 mIU/L. However, the increased risk of other pregnancy related adverse outcomes calls for additional studies evaluating the safety of thyroid hormone treatment in this patient population.

Self-Report of Hypoglycemia and Health-Related Quality of Life in Patients with Type 1 and Type 2 Diabetes

OBJECTIVE To establish the prevalence of self-reported hypoglycemia among ambulatory patients with diabetes and assess its impact on health-related quality of life (HRQoL). METHODS This study was a cross-sectional analysis of a postal survey disbursed during the first quarter of 2010 to 875 adults with type 1 or 2 diabetes identified on the basis of an index clinical encounter for diabetes management between August 1, 2005 and June 30, 2006. The survey included questions regarding hypoglycemia, self-rating of health, and questions adapted from Confidence in Diabetes Self-Care, Generalized Anxiety Disorder-7, EuroQol5-D, and the Hypoglycemic Fear Survey. Data were analyzed using a two-sample t test for continuous variables and a chi-square test for categorical variables, with multivariate analysis to adjust for age, gender, diabetes duration, and Charlson comorbidity index. RESULTS The survey was completed by 418 patients (47.8% response rate). Of the respondents, 26 of 92 (28.3%) with type 1 and 55 of 326 (16.9%) with type 2 diabetes reported at least one episode of severe hypoglycemia within the previous 6 months. Fear of hypoglycemia, including engagement in anticipatory avoidance behaviors, was highest in patients with type 2 diabetes reporting severe hypoglycemia and all patients with type 1 diabetes (P<.001). HRQoL was lower in patients with type 2 (but not type 1) diabetes reporting severe hypoglycemia (P<.01). CONCLUSION Clinicians and health systems should incorporate screening for hypoglycemia into the routine health assessment of all patients with diabetes. Fear of hypoglycemia places patients at risk for counterproductive behaviors, impairs HRQoL, and should be considered in individualizing glycemic goals.

HbA1c overtesting and overtreatment among US adults with controlled type 2 diabetes, 2001-13: observational population based study

Study question What is the extent and effect of excessive testing for glycated hemoglobin (HbA1c) among adults with controlled type 2 diabetes? Methods A retrospective analysis of data from a national administrative claims database included commercially insured individuals in the USA, 2001-13. Study patients were aged 18 years or older, had type 2 diabetes with stable glycemic control (two consecutive tests showing HbA1c<7.0% within 24 months), did not use insulin, had no history of severe hypoglycemia or hyperglycemia, and were not pregnant. HbA1c testing frequency was measured within 24 months after the second (index) HbA1c test, and classified as guideline recommended (≤2 times/year), frequent (3-4 times/year), and excessive (≥5 times/year). Changes in treatment regimen were ascertained within three months of the index test. Study answer and limitations Of 31 545 patients in the study cohort (mean age 58 years; mean index HbA1c 6.2%), HbA1c testing frequency was excessive in 6% and frequent in 55%. Despite good glycemic control at baseline, treatment was further intensified by addition of glucose lowering drugs or insulin in 8.4% of patients (comprising 13%, 9%, and 7% of those tested excessively, frequently, and per guidelines, respectively; P<0.001). Compared with guideline recommended testing, excessive testing was associated with treatment intensification (odds ratio 1.35 (95% confidence interval 1.22 to 1.50)). Excessive testing rates remained unchanged in 2001-08, but fell significantly after 2009. The odds of excessive testing was 46% lower in 2011 than in 2001-02. The study population is not representative of all US patients with type 2 diabetes because it was restricted to commercially insured adults with stable and controlled diabetes not receiving insulin treatment. The study design did not capture the underuse of HbA1c testing. What this study adds In this US cohort of adults with stable and controlled type 2 diabetes, more than 60% received too many HbA1c tests, a practice associated with potential overtreatment with hypoglycemic drugs. Excessive testing contributes to the growing problem of waste in healthcare and increased patient burden in diabetes management. Funding, competing interests, data sharing NDS and RGM are funded partly by the Agency for Healthcare Research and Quality (R18HS18339) and AcademyHealth Delivery System Science Fellowship (2013), respectively. No competing interests declared. Additional data are available from mccoy.rozalina@mayo.edu.

Continuous subcutaneous insulin infusion versus multiple daily injections in individuals with type 1 diabetes: a systematic review and meta-analysis

The relative efficacy of continuous subcutaneous insulin infusion and multiple daily injections in individuals with type 1 diabetes is unclear. We sought to synthesize the existing evidence about the effect of continuous subcutaneous insulin infusion on glycosylated hemoglobin, hypoglycemic events, and time spent in hypoglycemia compared to multiple daily injections. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus from January 2008 through November 2015 for randomized controlled trials that enrolled children or adults with type 1 diabetes. Trials identified in a previous systematic review and published prior to 2008 were also included. We included 25 randomized controlled trials at moderate risk of bias. Meta-analysis showed a significant reduction in glycosylated hemoglobin in patients treated with continuous subcutaneous insulin infusion compared to multiple daily injections (mean difference 0.37; 95 % confidence interval, 0.24–0.51). This effect was demonstrated in both children and adults. There was no significant difference in minor or severe hypoglycemic events. Continuous subcutaneous insulin infusion was associated with lower incidence of nocturnal hypoglycemia. There was no significant difference in the time spent in hypoglycemia. In children and adults with type 1 diabetes and compared to multiple daily injections, continuous subcutaneous insulin infusion is associated with a modest reduction in glycosylated hemoglobin. There was no difference in severe or minor hypoglycemia, but likely a lower incidence of nocturnal hypoglycemia with continuous subcutaneous insulin infusion.

Hypoglycemia as an indicator of good diabetes care

Rene Rodriguez-Gutierrez and colleagues argue that more attention should be paid to hypoglycemia when assessing management of diabetes

The 2013 American Association of Clinical Endocrinologists’ Diabetes Mellitus Management Recommendations: Improvements Needed

For more than 20 years, the American Association of Clinical Endocrinologists (AACE) has been an authoritative source of advocacy and expertise in endocrinology. In line with its mission, the AACE recently introduced an update to their 2009 diabetes mellitus (DM) management algorithm,1 issuing an algorithm (April 2013),2 followed by a consensus statement (July2013).3 Management recommendations can be useful if they are based on evidence, developed through a readily understood process, and respectful of patients’ life circumstances and goals. A process that is easily understood is essential for physicians; other health care providers, such as physician assistants, nurse practitioners, and pharmacists; and patients to adequately judge the validity of management recommendations. Inclusion of patients’ values and preferences is important if the recommendations are to inform patient-centered care. In our view, the AACE’s DM algorithm and consensus statement do not meet these expectations and should not be used to guide clinical care in their current form. Algorithms and clinical guidelines should offer an assessment of the likely benefits and harms of treatments, and evaluate the quality of all of the relevant literature. The Institute of Medicine (IOM) has therefore proposed 8 standards for developing clinical practice guidelines to ensure “scientifically valid, transparent, and reproducible results.”4(p4) Although the AACE’s algorithm and consensus statement were not explicitly labeled as “guidelines,” they were “developed to provide clinicians with a practical guide”3(p3) to the management of type 2 DM, making them subject to the same general principles. The algorithm and consensus statement fall short on several of the 8 IOM standards. We are particularly concerned about the following.