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ACP DiabetesMonthly



In the News for the month of May 2014




Highlights

ACE inhibitors improved all-cause mortality, cardiovascular outcomes versus ARBs

Angiotensin-converting enzyme (ACE) inhibitors improved all-cause mortality, cardiovascular mortality, and major cardiovascular events compared with angiotensin II receptor blockers (ARBs) in patients with diabetes, a new study found. More...

Studies suggest no elevated risk of pancreatitis with incretin-based drugs

A study and a meta-analysis suggest incretin-based drugs don't increase the risk of pancreatitis in patients with type 2 diabetes. More...

Novel algorithms could help individualize HbA1c goals

Two novel algorithms to individualize glycemic control targets would allow clinicians to set HbA1c goals, reclassify from one-quarter to one-third of patients as controlled instead of uncontrolled, and possibly improve treatment of certain patient populations, a study found. More...


Test yourself

MKSAP quiz: Checking kidney function

This month's quiz asks readers to evaluate a 59-year-old woman recently diagnosed with type 2 diabetes mellitus and hyperlipidemia during a routine follow-up visit. More...


From Annals of Internal Medicine

Albuminuria can be ruled out with quantitative point-of-care tests

To screen at-risk patients for albuminuria, quantitative tests can be used effectively at the point of care, but semiquantitative tests are not sufficiently accurate, a recent meta-analysis found. More...


From ACP Journal Club

Adding lisinopril to losartan increased hyperkalemia and acute kidney injury in type 2 diabetes and proteinuria

In a trial of more than 1,000 diabetic patients with proteinuria, adding an ACE inhibitor to an ARB didn't improve estimated glomerular filtration rate and increased risk for hyperkalemia and acute kidney injury, so the trial was halted early. More...


From ACP Hospitalist

Patients with pumps

As insulin pumps become more common, hospitalists need plans to manage them. Learn about the issues that can arise, including potentially difficult negotiations with patients, in the April ACP Hospitalist. More...


FDA update

New GLP-1 receptor agonist approved

Albiglutide (Tanzeum), a glucagon-like peptide-1 (GLP-1) receptor agonist, was recently approved by the FDA to treat type 2 diabetes in adults, along with diet and exercise. More...


Keeping tabs

Spotlight on trends in diabetes prevalence and outcomes

Several recent analyses of national health care data assessed the prevalence of diabetes and its complications in the U.S. More...


Physician editor: David V. O'Dell, MD, FACP



Highlights


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ACE inhibitors improved all-cause mortality, cardiovascular outcomes versus ARBs

Angiotensin-converting enzyme (ACE) inhibitors improved all-cause mortality, cardiovascular mortality, and major cardiovascular events compared with angiotensin II receptor blockers (ARBs) in patients with diabetes, a new study found.

Researchers performed a meta-analysis to examine how ACE inhibitors and ARBs affect all-cause mortality, cardiovascular deaths, and major cardiovascular events in diabetic patients. Randomized clinical trials that were published between 1966 and 2012, reported the effects of both classes of drugs on these outcomes, and had an observation period of 12 months or longer were included.

The researchers analyzed dichotomous outcomes data from individual trials by using risk ratios (RRs) and 95% CIs and random-effects models, and differences between subgroup estimates were calculated with tests for interactions. Heterogeneity was identified via meta-regression analyses. The study's primary end points were all-cause and cardiovascular mortality, while secondary end points were effects of both drug classes on cardiovascular events. The study results were published online March 31 and in the May issue of JAMA Internal Medicine.

Of the trials identified and included in the study, 23 compared ACE inhibitors with control therapy (n=32,827 patients) and 13 compared ARBs with control therapy (n=23,867 patients). ACE inhibitors reduced all-cause mortality by 13% (20 trials; RR, 0.87; 95% CI, 0.78 to 0.98), cardiovascular deaths by 17% (13 trials; RR, 0.83; 95% CI, 0.70 to 0.99), and major cardiovascular events by 14% (14 trials; RR, 0.86; 95% CI, 0.77 to 0.95) compared with control therapy. ARBs, in contrast, did not appear to significantly affect any of the study end points besides heart failure events (4 trials; RR, 0.70; 95% CI, 0.59 to 0.82). Neither class of drugs appeared to reduce stroke risk in diabetics.

The authors noted that their study compared ACE inhibitors and ARBs only indirectly, that the populations of the included studies varied significantly, and that the trials examining each class of drug were not equivalent. However, they concluded that ACE inhibitors decrease all-cause mortality, cardiovascular mortality, and major cardiovascular events in patients with diabetes while ARBs appear to have no similar effects. Based on their findings, they concluded, "ACE [inhibitors] should be considered as first-line therapy to limit the excess mortality and morbidity in this population."


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Studies suggest no elevated risk of pancreatitis with incretin-based drugs

A study and a meta-analysis suggest incretin-based drugs don't increase the risk of pancreatitis in patients with type 2 diabetes.

In a population-based cohort study in the U.K., researchers compared 20,748 new users of incretin-based drugs with 51,712 users of sulfonylureas. Incretin-based drugs included exenatide, liraglutide, sitagliptin, saxagliptin, vildagliptin, and linagliptin, alone or in combination. Sulfonylureas also were used alone or in combination. Patients had started the drugs sometime between Jan. 1, 2007, and March 31, 2012, and were followed until March 31, 2013, or until they were diagnosed with acute pancreatitis, died, or left the practice. The crude incidence rate for acute pancreatitis was 1.45 per 1,000 patients per year for incretin-based drug users and 1.47 for sulfonylurea users (adjusted hazard ratio, 1.00; 95% CI, 0.59 to 1.70), suggesting that incretin-based drugs are not associated with a higher risk of acute pancreatitis than sulfonylureas in type 2 diabetics. Results were published online April 24 by BMJ.

A systematic review and meta-analysis of 60 studies also didn't find an elevated risk of pancreatitis with incretin-based treatment. The researchers analyzed 55 randomized, controlled trials (RCTs) and 5 observational studies (n=353,639) that compared treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo, lifestyle modification, or other active antidiabetic drugs. Pooled estimates of the RCTs suggested no higher risk of pancreatitis with incretins versus control (odds ratio, 1.11; 95% CI, 0.57 to 2.17). In addition, 4 of the 5 observational studies also showed no increased risk, but one of the case-control studies (n=2,538) did indicate that taking exenatide or sitagliptin was associated with higher odds of acute pancreatitis (adjusted odds ratio, 2.07; 95% CI, 1.36 to 3.13). The authors warned the results "should be interpreted cautiously," noting that many of the trials had fairly small sample sizes and short follow-up periods and that most patients had less comorbidity than is observed in actual practice. Results were published online by BMJ April 15.

An editorialist wrote that the results of these 2 studies suggest "with low to moderate confidence" that there is no significant increased risk of pancreatitis from incretin-based drugs. Clinicians should share this evidence with patients as part of their decision-making process on drug treatment but should not necessarily assume incretin-based drugs are the "next step" after metformin, he said. The editorial was published online April 24 by BMJ.


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Novel algorithms could help individualize HbA1c goals

Two novel algorithms to individualize glycemic control targets would allow clinicians to set HbA1c goals, reclassify from one-quarter to one-third of patients as controlled instead of uncontrolled, and possibly improve treatment of certain patient populations, a study found.

Researchers conducted a cross-sectional, observational study of 12,199 adult patients with diabetes in an 18-practice primary care network affiliated with an academic medical center, measuring HbA1c during calendar year 2011. The algorithms applied 4 patient factors—age, duration of diabetes, presence of macrovascular or microvascular complications, and Charlson comorbidity score—to set 1 of 3 HbA1c goals: <6.5%, <7.0%, or <8.0%. Each patient's HbA1c was compared with these targeted goals and to the standard goal of <7%.

Under both algorithms, patients 75 years and over were assigned a goal of <8%. Looking at duration of diabetes, having been diagnosed within 5 years contributed (but was not sufficient) to having an assigned goal of <6.5%, while patients with long duration (15 years under the first algorithm, 10 years under the second) had a goal of <8%. Any macrovascular or advanced microvascular conditions also led to a goal of <8%. Finally, significant comorbidity (Charlson score of <6 under the first algorithm, <4 under the second) put patients in the <8% group. Results were published by Diabetic Medicine on April 11.

The first algorithm assigned 23.8% of patients a goal HbA1c of <6.5%, 29.7% a goal of <7.0%, and 46.5% a goal of <8.0%. The second algorithm assigned 17.7% of patients a goal HbA1c of <6.5%, 14.4% a goal of <7.0%, and 67.9% a goal of <8.0%. Overall, 55.7% of patients were considered controlled under the standard approach, 61.2% were considered controlled using the first algorithm, and 67.5% were considered controlled under the second algorithm.

The authors noted that the algorithms combine multiple sources of readily available patient information to provide a starting point for decision-making about glycemic goals, although clinicians in practice should consider factors that were not available in this electronic health record-based study, including risk and riskiness of hypoglycemia, social circumstances, and patient preferences. They also acknowledged that the 6.5% goal is controversial and should be based on the interventions required to achieve it or could be left out of the system entirely.

However, the lowered goal could improve existing disparities in diabetes outcomes affecting minority patients. "As a result of younger age and less co-morbidity, individualized algorithms would reclassify slightly more non-Hispanic black and Hispanic patients to more stringent goals. Because these groups have increased prevalence of diabetes complications and diabetes mortality, partially attributable to inadequate glycemic control, the targeted algorithms may help focus attention on glycemic control early in the disease course," the authors noted.

Overall, the algorithm-based approach could help health systems meet performance requirements without overtreating by reclassifying a quarter to a third of patients from uncontrolled to controlled without adversely affecting vulnerable subgroups, the authors concluded.



Test yourself


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MKSAP quiz: Checking kidney function

A 59-year-old woman is evaluated during a routine follow-up visit. She was recently diagnosed with type 2 diabetes mellitus and hyperlipidemia. She feels well. Medications are metformin, atorvastatin, and aspirin.

mksap.gif

Physical examination findings and vital signs are normal. BMI is 27.

Laboratory studies reveal a serum creatinine level of 0.9 mg/dL (79.6 µmol/L), an estimated glomerular filtration rate of >60 mL/min/1.73 m2, and normal urinalysis results.

Which of the following is the most appropriate diagnostic test to perform next?

A. 24-Hour urine collection for protein
B. Kidney ultrasonography
C. Spot urine albumin–creatinine ratio
D. No additional testing

Click here or scroll to the bottom of the page for the answer and critique.


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From Annals of Internal Medicine


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Albuminuria can be ruled out with quantitative point-of-care tests

To screen at-risk patients for albuminuria, quantitative tests can be used effectively at the point of care (POC), but semiquantitative tests are not sufficiently accurate, a recent meta-analysis found.

annals.jpg

Researchers included 16 studies with more than 3,000 patients that compared semiquantitative or quantitative machine-read POC tests of urinary albumin-creatinine ratio to laboratory measurements. Results were published in the April 15 Annals of Internal Medicine.

According to a bivariate random-effects model, the semiquantitative tests had a sensitivity of 76% (95% CI, 63% to 86%) and a specificity of 93% (CI, 84% to 97%), while the quantitative tests had a sensitivity of 96% (CI, 78% to 99%) and a specificity of 98% (CI, 93% to 99%). The negative likelihood ratios were 0.26 (CI, 0.16 to 0.40) for semiquantitative tests and 0.04 (CI, 0.01 to 0.25) for quantitative.

The American Diabetes Association and the American Association for Clinical Chemistry have suggested that such screening tests should have sensitivity exceeding 95%, the study authors noted. Thus, based on the results, only the quantitative tests, not the semiquantitative tests, should be used to rule out albuminuria. Sensitivity is more important than specificity in albuminuria testing, because a diagnosis requires 2 out of 3 samples collected during a 6-month period to be positive.

The ability to get a rapid result from POC testing is useful because patients with negative results can be sent on their way and those with positive results can be told immediately about the need for further testing. There may also be potential cost savings in transport and laboratory testing, the study authors said.

Annals of Internal Medicine's Diabetes Collection is available online.



From ACP Journal Club


.
Adding lisinopril to losartan increased hyperkalemia and acute kidney injury in type 2 diabetes and proteinuria

In a randomized, controlled trial (RCT) of more than 1,000 diabetic patients with proteinuria, adding an angiotensin-converting enzyme (ACE) inhibitor to an angiotensin II receptor blocker (ARB) didn't improve estimated glomerular filtration rate (eGFR) and increased risk for hyperkalemia and acute kidney injury, so the trial was halted early.

The study was published in the New England Journal of Medicine on Nov. 14, 2013. A summary of the study was published in the December 2013 ACP DiabetesMonthly. The following commentary by Catherine M. Clase, MB, BChir, and Johannes F.E. Mann, MD, was published in the ACP Journal Club section of the March 18 Annals of Internal Medicine.

Previous RCTs in patients with overt proteinuria have shown that blockade of the renin–angiotensin system (RAS) using a single agent prevents clinically important renal outcomes. Dual inhibition (ACE inhibitors plus ARBs) reduced proteinuria more than a single agent alone, making this an attractive strategy. The VA NEPHRON-D study assessed whether dual blockade of the RAS improves clinically important outcomes compared with losartan alone in patients with diabetes, low eGFR, and proteinuria. The methodologically rigorous trial was stopped early because of increased harm without evidence of benefit. Recent randomized trials have shown similar results. Similarly, a meta-analysis of 33 RCTs with >68,000 patients found no benefit with dual blockade and increased risk for renal failure, hyperkalemia, and adverse effects in patients with or without heart failure. Dual RAS blockade is consistently harmful. There are no data to support the idea that the results of VA NEPHRON-D do not generalize to nondiabetic kidney disease.

What is the next step for improving outcomes in patients with diabetic nephropathy? It is unlikely that the harmful and potentially beneficial effects of more intense RAS inhibition could be dissociated given that both result from the same renal physiologic events. Such novel agents as bardoxolone have also been disappointing. New therapies are needed.



From ACP Hospitalist


.
Patients with pumps

As insulin pumps become more common, hospitalists need plans to manage them. Learn about the issues that can arise, including potentially difficult negotiations with patients, in the April ACP Hospitalist.



FDA update


.
New GLP-1 receptor agonist approved

Albiglutide (Tanzeum), a glucagon-like peptide-1 (GLP-1) receptor agonist, was recently approved by the FDA to treat type 2 diabetes in adults, along with diet and exercise.

The safety and effectiveness of this subcutaneous injection were evaluated in 8 trials involving more than 2,000 patients, in which patients taking the drug showed improvements in their HbA1c levels. Albiglutide has been studied as a stand-alone therapy and in combination with other drugs, including metformin, glimepiride, pioglitazone, and insulin. It should not be used to treat people with type 1 diabetes or diabetic ketoacidosis, or as a first-line therapy.

Albiglutide carries a boxed warning to warn that thyroid C-cell tumors have been observed in rodent studies with some GLP-1 receptor agonists but that it is unknown whether the drug causes such tumors, including medullary thyroid carcinoma (MTC), in humans. It should not be used in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2. The FDA is requiring postmarketing studies related to pediatric use, risks of MTC, and cardiovascular outcomes.

The most common side effects are diarrhea, nausea, and injection site reactions, according to an FDA press release.

The FDA also recently approved a new indication for the Dexcom G4 Platinum Continuous Monitoring System for patients with diabetes who are 2 to 17 years of age. The system, which monitors blood glucose levels, had already been approved for patients ages 18 and older.



Keeping tabs


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Spotlight on trends in diabetes prevalence and outcomes

Several recent analyses of national health care data assessed the prevalence of diabetes and its complications in the U.S.

In the first study, in the April 15 Annals of Internal Medicine, researchers compared National Health and Nutrition Examination Surveys from 1988-1994 and 1999-2010. They found that confirmed diabetes (either self-reported or elevated HbA1c and fasting glucose) increased from 5.5% in 1988-1994 to 7.6% in 1999-2004 to 9.3% in 2005-2010. The change is mainly explained by increases in obesity, the researchers stated. Prediabetes, defined as an HbA1c between 5.7% and 6.4%, increased from 5.8% of the population in 1988-1994 to 12.4% in 2005-2010.

In children, both type 1 and type 2 diabetes have been on the rise, according to an analysis of selected U.S. geographic areas published in the May 7 Journal of the American Medical Association. Between 2001 and 2009, prevalence of type 1 diabetes in 0- to 19-year-olds increased from 1.48 to 1.93 per 1,000, a 21.1% rise. In the same time, type 2 diabetes increased in 10- to 19-year-olds from 0.34 to 0.46 per 1,000, a 30.5% rise. The study authors noted that similar trends have been observed around the world and called for further research to investigate the causes.

On a positive note, the proportion of diabetes cases that were undiagnosed decreased from 16% in 1988-1994 to 11% in 2005-2010, the study in Annals found. Control of diabetes also improved, with the proportion of diabetes patients having an HbA1c under 7% increasing from 50.9% in 1988-1994 to 58.8% in 2005-2010. This improvement in control was not seen in minority groups, however. The increase in overall glycemic control can probably be attributed to improvements in diagnosis, screening, and care, the authors said, but the results show that many patients, especially non-Hispanic blacks and Mexican-Americans, still have high HbA1c levels. "Clinical inertia is still a problem," noted an accompanying editorial.

Complication rates among diabetic patients have also declined in recent decades, according to another study, published in the New England Journal of Medicine on April 17. Researchers used several national surveys to compare rates of 5 common diabetes complications between 1990 and 2010. Among diabetics, acute myocardial infarction declined by 67.8% during the time period, deaths from hyperglycemia crisis declined 64.4%, stroke declined 52.7%, lower-extremity amputation declined 51.4%, and end-stage renal disease declined 28.3%. Rates of these problems declined among non-diabetic adults, too, but to a lesser degree. Because the overall prevalence of diabetes increased during the time period, only myocardial infarction and death from hyperglycemic crisis declined overall in the population (2.7 and 0.1 fewer cases per 10,000, respectively). The study authors attributed the gains to improvements in clinical care, the health care system, and health promotion efforts but noted that the total burden of complications is likely to increase if diabetes rates continue to rise.


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MKSAP Answer and Critique



The correct answer is C. Spot urine albumin–creatinine ratio. This item is available to MKSAP 16 subscribers as item 73 in the Nephrology section. Information about MKSAP 16 is available online.

A spot urine albumin–creatinine ratio is indicated to evaluate this patient for chronic kidney disease (CKD). She has type 2 diabetes mellitus, a population that is at risk for CKD, and testing for microalbuminuria is appropriate. The National Kidney Foundation and the American Diabetes Association recommend annual testing to assess urine albumin excretion in patients with type 1 diabetes of 5 years' duration and in all patients with type 2 diabetes starting at the time of diagnosis by measuring the albumin–creatinine ratio. Microalbuminuria is defined as an albumin–creatinine ratio of 30 to 300 mg/g; diagnosis requires an elevated albumin–creatinine ratio on two of three random samples obtained over 6 months. Patients with diabetes and microalbuminuria are at increased risk for progression of CKD and cardiovascular disease. Use of ACE inhibitors or angiotensin receptor blockers delays progression in patients with proteinuric kidney disease or in patients with diabetes and microalbuminuria, underscoring the importance of early detection.

The gold standard for measuring urine protein excretion is a 24-hour urine collection. However, this test is cumbersome and unreliable if not collected correctly. Patients have a difficult time accurately collecting urine for 24 hours, in addition to keeping it on ice. Therefore, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) recommends use of urinary ratios on random urine samples as an alternative method of estimating proteinuria in the clinical assessment of kidney disease. Furthermore, a 24-hour urine collection may not diagnose low-grade microalbuminuria.

Kidney ultrasonography can be performed once a diagnosis of CKD is made but should not be used to screen for CKD.

Although this patient has an estimated glomerular filtration rate of >60 mL/min/1.73 m2 and normal urinalysis results, she has diabetes and should therefore be evaluated for CKD.

Key Point

  • The National Kidney Foundation and the American Diabetes Association recommend annual testing to assess urine albumin excretion in patients with type 1 diabetes mellitus of 5 years' duration and in all patients with type 2 diabetes starting at the time of diagnosis by measuring the albumin–creatinine ratio.

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Test yourself

A 38-year-old man is evaluated for a mass in his right neck that he first noticed 2 weeks ago while shaving. The patient also reports experiencing a pressure sensation when swallowing solid foods for the past year and daily diarrhea for the past 2 months. His personal medical history is unremarkable. His younger brother has nephrolithiasis, and his father died of a hypertensive crisis and cardiac arrest at age 62 years while undergoing anesthesia induction to repair a hip fracture. Following a physical exam, lab studies, and a chest radiograph, what is the most likely diagnosis?

Find the answer

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