Kasia J. Lipska

Use of Metformin in the Setting of Mild-to-Moderate Renal Insufficiency

A common clinical conundrum faces all U.S. practitioners treating patients with type 2 diabetes. Today’s U.S. Food and Drug Administration prescribing guidelines for metformin contraindicate its use in men and women with serum creatinine concentrations ≥1.5 and ≥1.4 mg/dL (≥132 and ≥123 µmol/L), respectively. In a patient tolerating and controlled with this medication, should it automatically be discontinued as the creatinine rises beyond these cut points over time? Stopping metformin often results in poorly controlled glycemia and/or the need for other agents with their own adverse-effect profiles. Moreover, is the now widespread use of estimated glomerular filtration rate (eGFR) in lieu of serum creatinine levels creating even more confusion, especially in those with abnormalities in one but not the other indirect measure of renal function? Indeed, more than a decade and a half after metformin became available in the U.S., debate continues over the best approach in these settings (1–3). How many patients are unable to receive this medication on the basis of guidelines which, although well intentioned, are somewhat arbitrary and outdated based on modern assessments of renal status? There is some evidence that early treatment with metformin is associated with reduced cardiovascular morbidity and total mortality in newly diagnosed type 2 diabetic patients (4). However, the data come from a small subgroup of a much larger trial. In contrast, despite multiple trials of intensive glucose control using a variety of glucose-lowering strategies, there is a paucity of data to support specific advantages with other agents on cardiovascular outcomes (5–7). In the original UK Prospective Diabetes Study (UKPDS), 342 overweight patients with newly diagnosed diabetes were randomly assigned to metformin therapy (8). After a median period of 10 years, this subgroup experienced a 39% ( P = 0.010) risk reduction for myocardial infarction and a …

Metformin in Patients With Type 2 Diabetes and Kidney Disease: A Systematic Review

IMPORTANCE Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. OBJECTIVE To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. EVIDENCE ACQUISITION In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. RESULTS Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100,000 person-years to 10 per 100,000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus--use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. CONCLUSIONS AND RELEVANCE Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.

National Trends in US Hospital Admissions for Hyperglycemia and Hypoglycemia Among Medicare Beneficiaries, 1999 to 2011

IMPORTANCE The increasing intensity of diabetes mellitus management over the past decade may have resulted in lower rates of hyperglycemic emergencies but higher rates of hospital admissions for hypoglycemia among older adults. Trends in these hospitalizations and subsequent outcomes are not known. OBJECTIVE To characterize changes in hyperglycemia and hypoglycemia hospitalization rates and subsequent mortality and readmission rates among older adults in the United States over a 12-year period, and to compare these results according to age, sex, and race. DESIGN, SETTING, AND PATIENTS Retrospective observational study using data from 33,952,331 Medicare fee-for-service beneficiaries 65 years or older from 1999 to 2011. MAIN OUTCOMES AND MEASURES Hospitalization rates for hyperglycemia and hypoglycemia, 30-day and 1-year mortality rates, and 30-day readmission rates. RESULTS A total of 279,937 patients experienced 302,095 hospitalizations for hyperglycemia, and 404,467 patients experienced 429,850 hospitalizations for hypoglycemia between 1999 and 2011. During this time, rates of admissions for hyperglycemia declined by 38.6% (from 114 to 70 admissions per 100,000 person-years), while admissions for hypoglycemia increased by 11.7% (from 94 to 105 admissions per 100,000 person-years). In analyses designed to account for changing diabetes mellitus prevalence, admissions for hyperglycemia and hypoglycemia declined by 55.2% and 9.5%, respectively. Trends were similar across age, sex, and racial subgroups, but hypoglycemia rates were 2-fold higher for older patients (≥75 years) when compared with younger patients (65-74 years), and admission rates for both hyperglycemia and hypoglycemia were 4-fold higher for black patients compared with white patients. The 30-day and 1-year mortality and 30-day readmission rates improved during the study period and were similar after an index hospitalization for either hyperglycemia or hypoglycemia (5.4%, 17.1%, and 15.3%, respectively, after hyperglycemia hospitalizations in 2010; 4.4%, 19.9%, and 16.3% after hypoglycemia hospitalizations). CONCLUSIONS AND RELEVANCE Hospital admission rates for hypoglycemia now exceed those for hyperglycemia among older adults. Although admissions for hypoglycemia have declined modestly since 2007, rates among black Medicare beneficiaries and those older than 75 years remain high. Hospital admissions for severe hypoglycemia seem to pose a greater health threat than those for hyperglycemia, suggesting new opportunities for improvement in care of persons with diabetes mellitus.

Potential Overtreatment of Diabetes Mellitus in Older Adults With Tight Glycemic Control

IMPORTANCE In older adults with multiple serious comorbidities and functional limitations, the harms of intensive glycemic control likely exceed the benefits. OBJECTIVES To examine glycemic control levels among older adults with diabetes mellitus by health status and to estimate the prevalence of potential overtreatment of diabetes. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional analysis of the data on 1288 older adults (≥65 years) with diabetes from the National Health and Nutrition Examination Survey (NHANES) from 2001 through 2010 who had a hemoglobin A1c (HbA1c) measurement. All analyses incorporated complex survey design to produce nationally representative estimates. EXPOSURES Health status categories: very complex/poor, based on difficulty with 2 or more activities of daily living or dialysis dependence; complex/intermediate, based on difficulty with 2 or more instrumental activities of daily living or presence of 3 or more chronic conditions; and relatively healthy if none of these were present. MAIN OUTCOMES AND MEASURES Tight glycemic control (HbA1c level, <7%) and use of diabetes medications likely to result in hypoglycemia (insulin or sulfonylureas). RESULTS Of 1288 older adults with diabetes, 50.7% (95% CI, 46.6%-54.8%), representing 3.1 million (95% CI, 2.7-3.5), were relatively healthy, 28.1% (95% CI, 24.8%-31.5%), representing 1.7 million (95% CI, 1.4-2.0), had complex/intermediate health, and 21.2% (95% CI, 18.3%-24.4%), representing 1.3 million (95% CI, 1.1-1.5), had very complex/poor health. Overall, 61.5% (95% CI, 57.5%-65.3%), representing 3.8 million (95% CI, 3.4-4.2), had an HbA1c level of less than 7%; this proportion did not differ across health status categories (62.8% [95% CI, 56.9%-68.3%]) were relatively healthy, 63.0% (95% CI, 57.0%-68.6%) had complex/intermediate health, and 56.4% (95% CI, 49.7%-62.9%) had very complex/poor health (P = .26). Of the older adults with an HbA1c level of less than 7%, 54.9% (95% CI, 50.4%-59.3%) were treated with either insulin or sulfonylureas; this proportion was similar across health status categories (50.8% [95% CI, 45.1%-56.5%] were relatively healthy, 58.7% [95% CI, 49.4%-67.5%] had complex/intermediate health, and 60.0% [95% CI, 51.4%-68.1%] had very complex/poor health; P = .14). During the 10 study years, there were no significant changes in the proportion of older adults with an HbA1c level of less than 7% (P = .34), the proportion with an HbA1c level of less than 7% who had complex/intermediate or very complex/poor health (P = .27), or the proportion with an HbA1c level of less than 7% who were treated with insulin or sulfonylureas despite having complex/intermediate or very complex/poor health (P = .65). CONCLUSIONS AND RELEVANCE Although the harms of intensive treatment likely exceed the benefits for older patients with complex/intermediate or very complex/poor health status, most of these adults reached tight glycemic targets between 2001 and 2010. Most of them were treated with insulin or sulfonylureas, which may lead to severe hypoglycemia. Our findings suggest that a substantial proportion of older adults with diabetes were potentially overtreated.

The idolatry of the surrogate.

Easier to measure surrogate outcomes are often used instead of patient important outcomes such as death, quality of life, or functional capacity when assessing treatments. John Yudkin, Kasia Lipska, and Victor Montori argue that our obsession with surrogates is damaging patient care

HbA1c and Risk of Severe Hypoglycemia in Type 2 Diabetes: The Diabetes and Aging Study

OBJECTIVE We examined the association between HbA1c level and self-reported severe hypoglycemia in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Type 2 diabetic patients in a large, integrated healthcare system, who were 30–77 years of age and treated with glucose-lowering therapy, were asked about severe hypoglycemia requiring assistance in the year prior to the Diabetes Study of Northern California survey conducted in 2005–2006 (62% response rate). The main exposure of interest was the last HbA1c level collected in the year preceding the observation period. Poisson regression models adjusted for selected demographic and clinical variables were specified to evaluate the relative risk (RR) of severe hypoglycemia across HbA1c levels. We also tested whether the HbA1c-hypoglycemia association differed across potential effect modifiers (age, diabetes duration, and category of diabetes medication). RESULTS Among 9,094 eligible survey respondents (mean age 59.5 ± 9.8 years, mean HbA1c 7.5 ± 1.5%), 985 (10.8%) reported experiencing severe hypoglycemia. Across HbA1c levels, rates of hypoglycemia were 9.3–13.8%. Compared with those with HbA1c of 7–7.9%, the RR of hypoglycemia was 1.25 (95% CI 0.99–1.57), 1.01 (0.87–1.18), 0.99 (0.82–1.20), and 1.16 (0.97–1.38) among those with HbA1c <6, 6–6.9, 8–8.9, and ≥9%, respectively, in a fully adjusted model. Age, diabetes duration, and category of diabetes medication did not significantly modify the HbA1c-hypoglycemia relationship. CONCLUSIONS Severe hypoglycemia was common among patients with type 2 diabetes across all levels of glycemic control. Risk tended to be higher in patients with either near-normal glycemia or very poor glycemic control.

Identifying Dysglycemic States in Older Adults: Implications of the Emerging Use of Hemoglobin A1c

CONTEXT Hemoglobin A1c (A1c) was recently added to the diagnostic criteria for diabetes and prediabetes. OBJECTIVE Our objective was to examine performance of A1c in comparison with fasting plasma glucose (FPG) in diagnosing dysglycemia in older adults. DESIGN AND SETTING We conducted a cross-sectional analysis of data from the Health, Aging, and Body Composition study at yr 4 (2000-2001) when FPG and standardized A1c measurements were available. PARTICIPANTS Of 3075 persons (aged 70-79 yr, 48% men, 42% Black) at study entry, 1865 participants without known diabetes who had appropriate measures were included. MAIN OUTCOME MEASURES Sensitivity and specificity of A1c-based diagnoses were compared with those based on FPG and the proportion of participants identified with dysglycemia by each measure. RESULTS Of all participants, 2.7 and 3.1% had undiagnosed diabetes by FPG≥126 mg/dl and A1c≥6.5%, respectively. Among the remaining participants, 21.1% had prediabetes by impaired fasting glucose (≥100 mg/dl) and 22.2% by A1c≥5.7%. Roughly one third of individuals with diabetes and prediabetes were identified by either FPG or A1c alone and by both tests simultaneously. Sensitivities and specificities of A1c compared with FPG were 56.9 and 98.4% for diabetes and 47.0 and 84.5% for prediabetes, respectively. Blacks and women were more likely to be identified with dysglycemia by A1c than FPG. CONCLUSIONS In this older population, we found considerable discordance between FPG- and A1c-based diagnosis of diabetes and prediabetes, with differences accentuated by race and gender. Broad implementation of A1c to diagnose dysglycemic states may substantially alter the epidemiology of these conditions in older Americans.

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.

Polypharmacy in the Aging Patient: A Review of Glycemic Control in Older Adults With Type 2 Diabetes

IMPORTANCE There is substantial uncertainty about optimal glycemic control in older adults with type 2 diabetes mellitus. OBSERVATIONS Four large randomized clinical trials (RCTs), ranging in size from 1791 to 11,440 patients, provide the majority of the evidence used to guide diabetes therapy. Most RCTs of intensive vs standard glycemic control excluded adults older than 80 years, used surrogate end points to evaluate microvascular outcomes and provided limited data on which subgroups are most likely to benefit or be harmed by specific therapies. Available data from randomized clinical trials suggest that intensive glycemic control does not reduce major macrovascular events in older adults for at least 10 years. Furthermore, intensive glycemic control does not lead to improved patient-centered microvascular outcomes for at least 8 years. Data from randomized clinical trials consistently suggest that intensive glycemic control immediately increases the risk of severe hypoglycemia 1.5- to 3-fold. Based on these data and observational studies, for the majority of adults older than 65 years, the harms associated with a hemoglobin A1c (HbA1c) target lower than 7.5% or higher than 9% are likely to outweigh the benefits. However, the optimal target depends on patient factors, medications used to reach the target, life expectancy, and patient preferences about treatment. If only medications with low treatment burden and hypoglycemia risk (such as metformin) are required, a lower HbA1c target may be appropriate. If patients strongly prefer to avoid injections or frequent fingerstick monitoring, a higher HbA1c target that obviates the need for insulin may be appropriate. CONCLUSIONS AND RELEVANCE High-quality evidence about glycemic treatment in older adults is lacking. Optimal decisions need to be made collaboratively with patients, incorporating the likelihood of benefits and harms and patient preferences about treatment and treatment burden. For the majority of older adults, an HbA1c target between 7.5% and 9% will maximize benefits and minimize harms.

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.