American College of Physicians: Internal Medicine — Doctors for Adults ®

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ACP DiabetesMonthly



In the News for the month of December 2013




Highlights

Combined angiotensin inhibition increased risks of adverse events in diabetic nephropathy

Combination therapy with an angiotensin-converting enzyme inhibitor and angiotensin-receptor blocker in patients with diabetic nephropathy was associated with an increased risk of adverse events, including hyperkalemia and acute kidney injury, a study found. More...

Marked HDL reductions may occur with fenofibrate plus thiazolidinedione

Patients with type 2 diabetes taking fenofibrate plus a thiazolidinedione may experience significant reductions in high-density lipoprotein (HDL) cholesterol, according to a recent study. More...

Mail order pharmacy patients with diabetes less likely to visit ED than brick-and-mortar pharmacy users

Patients with diabetes who used a mail order pharmacy were less likely to visit the ED than patients who obtained medication in person from a pharmacy, a study found. More...


Test yourself

MKSAP Quiz: Abdominal pain in a type 1 diabetic

This month's quiz asks readers to evaluate a 40-year-old woman in the emergency department for a 7-hour history of gradually worsening generalized abdominal pain, hyperventilation, and lethargy. More...


From ACP InternistWeekly

Geriatrics society updates guideline for older diabetes patients

Several changes to recommended care for diabetes patients over age 65, including less use of aspirin therapy, were made in a guideline update from the American Geriatrics Society. More...

Chelation may reduce mortality, cardiovascular events in diabetics after MI

Chelation reduced cardiovascular disease events in patients with diabetes who had a previous myocardial infarction (MI), a recent study found. More...


Tool of the month

Advice on using oral therapy

When initiating oral therapy for patients in whom diet and exercise do not adequately control type 2 diabetes, consider some advice from ACP Smart Medicine and ACP DiabetesMonthly's physician editor. More...


Keeping tabs

Spotlight on diabetes medications and cancer risks

The risks of cancer in patients taking medication for diabetes were analyzed by 2 recent studies. More...


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



Highlights


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Combined angiotensin inhibition increased risks of adverse events in diabetic nephropathy

Combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor blocker (ARB) in patients with diabetic nephropathy was associated with an increased risk of adverse events, including hyperkalemia and acute kidney injury, a study found.

Researchers recruited patients from 32 Department of Veterans Affairs medical centers from July 2008 through September 2012. All patients had type 2 diabetes, a urinary albumin-to-creatinine ratio of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 mL/min/1.73 m2.

Researchers administered losartan, starting with 50 mg/d and increasing to 100 mg/d if the potassium level remained below 5.5 mmol/L and the creatinine level did not rise by more than 30%. After at least 30 days, patients were randomized to receive lisinopril, 10 to 40 mg/d, or placebo.

The primary end point was the first occurrence of a change in the estimated GFR of ≥30 mL/min/1.73 m2 if the initial estimated GFR was ≥60 mL/min/1.73 m2 or a decline of 50% or more if the initial estimated GFR was <60 mL/min/1.73 m2, end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia and acute kidney injury. Results were published Nov. 14 by the New England Journal of Medicine.

Among 1,448 patients with a median follow-up of 2.2 years, there were 152 primary end point events in the monotherapy group and 132 in the combination therapy group (21% vs. 18.2%; hazard ratio [HR], 0.88; 95% CI, 0.70 to 1.12; P=0.30). In October 2012, the data and safety monitoring committee recommended the study treatment be stopped, primarily due to rates of acute kidney injury. There were 190 acute kidney injury events in the combination therapy group (12.2 events per 100 person-years) compared to 105 acute kidney injury events in the monotherapy group (6.7 events per 100 person-years; HR, 1.7; 95% CI, 1.3 to 2.2; P<0.001). Researchers noted that the higher risk of acute kidney injury with combination therapy was evident from the start of treatment through 42 months of follow-up. Also, combination therapy was associated with more hyperkalemia (6.3 events per 100 person-years vs. 2.6 events with monotherapy; P<0.001).

While combination therapy did not provide a significant benefit for renal disease progression, mortality or cardiovascular disease, a benefit could not be ruled out since the trial was stopped early, the researchers wrote. However, conditional power calculations suggested that the observed effects on the primary end point would not have been significant even if the study had been completed.


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Marked HDL reductions may occur with fenofibrate plus thiazolidinedione

Patients with type 2 diabetes taking fenofibrate plus a thiazolidinedione may experience significant reductions in high-density lipoprotein (HDL) cholesterol, according to a recent study.

Researchers used data from the ACCORD Lipid Trial, a subset of the ACCORD Trial, to examine how frequently extremely low HDL levels occurred and whether they were associated with fenofibrate and thiazolidinedione treatment. The original objective of the ACCORD Lipid Trial was to test whether fenofibrate plus a statin would lower cardiovascular disease (CVD) event rates compared with a statin alone in high-risk patients with type 2 diabetes. Patients began taking open-label simvastatin at the randomization visit and began taking fenofibrate or placebo 1 month later.

The maximum dose of simvastatin was 40 mg/d; fenofibrate was initially administered at 160 mg/d, but the dose was decreased to 48 mg/d during the trial in patients whose estimated glomerular filtration rate was 50 mL/min/m2 or lower. Most of the patients in ACCORD were taking rosiglitazone as a thiazolidinedione, although a few were taking pioglitazone. The main outcome measure of the current study was occurrence of extremely low HDL cholesterol levels during the ACCORD Lipid Trial. An extremely low HDL level was defined as less than 25 mg/dL. The study results were published online Dec. 2 by Diabetes Care.

Of 10,251 ACCORD patients, 5,518 were included in the ACCORD Lipid Trial. Enrollment took place from Jan. 11, 2011, until Oct. 29, 2005, and patients were followed until March 1 and June 30, 2009 (mean follow-up, 4.7 years; range, 4 to 8 years). Six hundred twenty-seven of the 10,251 patients were reported to have an HDL level below 25 mg/dL at an annual follow-up visit. The researchers found that extremely low HDL cholesterol levels were much more common in patients who were randomly assigned to receive fenofibrate than in those who were randomly assigned to receive placebo (10.1% vs. 4.9%; P<0.001). In addition, extremely low HDL levels were associated with concurrent treatment with both fenofibrate and a thiazolidinedione, occurring in 7.2% of patients on both drugs at 24 months after randomization and 7.0% at 48 months compared with 2.2% and 3.6%, respectively, in those receiving only fenofibrate.

The authors extrapolated that according to their data, up to 5% of patients with type 2 diabetes treated with fenofibrate and a thiazolidinedione could develop iatrogenic, significant decreases in HDL cholesterol. They noted that they could not rule out the possibility of large HDL decreases in some patients treated with fenofibrate alone or a thiazolidinedione alone, but they pointed out that they had found no increased overall prevalence of low HDL cholesterol levels in patients who were not taking a thiazolidinedione versus baseline. The authors also stressed that their study was not designed or powered to determine the potential effect of the HDL reductions on mortality. However, they concluded that clinicians should be aware of the potential for marked HDL reductions in patients with type 2 diabetes taking fenofibrate, especially in combination with a thiazolidinedione.

"Although the mechanism of iatrogenic reduction in HDL-[cholesterol] with combined fenofibrate and [thiazolidinedione] treatment is unknown and there is as yet no definitive proof of lack of harm, if the magnitude of the reduction in HDL-[cholesterol] is significant it may be appropriate to discontinue either fenofibrate or the [thiazolidinedione], and monitor HDL-[cholesterol] levels to confirm return to baseline levels," the authors wrote.


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Mail order pharmacy patients with diabetes less likely to visit ED than brick-and-mortar pharmacy users

Patients with diabetes who used a mail order pharmacy were less likely to visit the ED than patients who obtained medication in person from a pharmacy, a study found.

Researchers performed a cross-sectional, observational study of 17,217 adult patients with diabetes who belonged to a Kaiser Permanente Northern California patient registry and who were prescribed new antiglycemic, antihypertensive or lipid-lowering medications in 2006. They used multivariate logistic regression to analyze the association between type of pharmacy use and outcomes, which included all-cause and preventable hospitalizations and ED visits.

For patients whose index drug was an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB) or a diuretic, the researchers also examined whether there was a lab test within 30 days after the index date. In addition, they looked at serious medication interactions, defined as 2 or more instances of overlapping supply days of contraindicated medications. Results were published online Nov. 20 by the American Journal of Managed Care.

About 34% of patients used a mail order pharmacy; these patients were more likely to be white and of higher socioeconomic status. After stratifying by age, the researchers found that patients younger than 65 who used mail order had fewer ED visits (33.8% vs 40.2%; P<0.001) and fewer preventable ED visits (7.7% vs 9.6%; P<0.01). They also had fewer serum creatinine lab monitoring tests after ACE/ARB or diuretic initiation (41.2% vs 47.2%; P<0.01). In patients who were 65 or older, mail order users also had fewer preventable ED visits (13.4% vs 16.3%; P<0.01) but slightly more instances when the supply of contraindicated medications overlapped (1.1% vs 0.7%; P<0.01).

Limitations of the study include its observational nature, which meant that the researchers couldn't control for differences in the kind of patients who use mail order pharmacies and the kind who don't. Also, the study was conducted in an integrated delivery system, "where patients access prescription medications differently than in many other settings," the authors noted.

Mail order pharmacy use doesn't appear to be negatively associated with patient safety outcomes on the whole and shouldn't serve as a barrier to care, the researchers concluded. The finding that younger patients who used a mail order pharmacy had lower rates of serum creatinine testing with ACE, ARB or diuretic use suggests in-person pharmacy use may make monitoring medications easier, they noted. As well, the finding that older mail order users are slightly more vulnerable to overlapping contraindicated drugs suggests patients on multiple medications may need extra monitoring, they added.

"System-level interventions to increase mail order pharmacy use may be an important strategy for improving processes and outcomes of care for patients with chronic illness; however, these interventions should use a patient-centered approach that does not increase risk in older patients and others who may be sensitive to primary and preventive care access," the authors wrote.



Test yourself


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MKSAP Quiz: Abdominal pain in a type 1 diabetic

A 40-year-old woman is evaluated in the emergency department at 1 a.m. for a 7-hour history of gradually worsening generalized abdominal pain, hyperventilation, and lethargy. Her husband reports difficulty awakening her on several occasions since onset of symptoms, both during the evening and at night. The patient has a 3-day history of nausea and anorexia. She has a 22-year history of type 1 diabetes mellitus treated with insulin. Because she has been unable to eat or drink for the past 3 days, she has reduced her dosage of basal insulin by half and taken no premeal rapid-acting insulin during this period. Her only other medical problem is hypertriglyceridemia. Medications before coming to the emergency department were insulin glargine, prandial insulin glulisine, gemfibrozil, niacin, and daily fish oil.

mksap.gif

Physical examination shows a lethargic but arousable woman. Temperature is 96.8 °C (36.0 °F), blood pressure is 105/70 mm Hg, pulse rate is 118/min, and respiration rate is 28/min; BMI is 36. Deep sighing respirations are noted, but the chest is clear to auscultation. She has a sweet smell on her breath. Abdominal examination reveals generalized abdominal tenderness with guarding but no rebound tenderness. Bowel sounds are heard in all four quadrants.

Laboratory studies show hemoglobin 14.7 g/dL (147 g/L), leukocyte count 23,000/µL (23 × 109/L) with 90% polymorphonuclear leukocytes, sodium 149 mEq/L (149 mmol/L), potassium 5.1 mEq/L (5.1 mmol/L), chloride 92 mEq/L (92 mmol/L), bicarbonate 4 mEq/L (4 mmol/L), fasting glucose 615 mg/dL (34.1 mmol/L), amylase 1168 units/L.

Urinalysis shows 4+ glucose, 4+ ketones, no bacteria or leukocytes. A chest radiograph is normal.

Besides administering intravenous fluids and insulin, which of the following is the most appropriate management?

A. Abdominal CT
B. Endoscopic retrograde cholangiopancreatography
C. Imipenem
D. Laparotomy
E. Serial abdominal examinations

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


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From ACP InternistWeekly


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Geriatrics society updates guideline for older diabetes patients

Several changes to recommended care for diabetes patients over age 65, including less use of aspirin therapy, were made in a guideline update from the American Geriatrics Society (AGS).

"The American Geriatrics Society Guidelines for Improving the Care of Older Adults with Diabetes Mellitus: 2013 Update" were based on high-quality research and developed by an expert panel of clinicians and researchers in the fields of medicine, nursing and pharmacy. An abridged version of the full guidelines was published in the Journal of the American Geriatrics Society on Nov. 12.

The update included several changes from the AGS's 2003 guideline. Aspirin is no longer recommended for the primary prevention of cardiovascular disease (CVD) in older diabetics, due to new evidence on the risk of bleeding. Daily aspirin therapy (81 mg to 325 mg) is still recommended for patients with diabetes and known CVD, however. Recommendations on using statins to treat dyslipidemia were revised to put less focus on targeting specific lipid levels.

The recommendations on glycemic control were also revised to encourage more personalization of blood glucose goals, based on patients' functional status, comorbidities and life expectancy. According to the update, hemoglobin A1c (HbA1c) targets for older adults should generally be 7% to 8%, but a lower target (7% to 7.5%) may be appropriate for healthier, more functional adults, and a higher target (8% to 9%) may be appropriate for less healthy patients with limited life expectancy. Lowering HbA1c to less than 6.5% using medical treatment is associated with potential harm in older adults with diabetes, the guideline update said.

The update also strengthened recommendations about lifestyle modification, calling for regular dietary counseling of all older diabetes patients and at least 150 minutes of moderate-intensity aerobic exercise per week, as well as resistance exercise, for older diabetes patients with normal cognition and functional status.

Other topics covered by the guideline update include smoking cessation, hypertension treatment, glycemic control monitoring and medications, and polypharmacy, as well as screening for foot problems, nephropathy, depression, cognitive impairment, urinary incontinence, fall risk and pain.


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Chelation may reduce mortality, cardiovascular events in diabetics after MI

Chelation reduced cardiovascular disease events in patients with diabetes who had a previous myocardial infarction (MI), a recent study found.

The Trial to Assess Chelation Therapy (TACT) included 1,708 patients age 50 or over with a history of MI, of whom 633 had diabetes mellitus. Patients were randomized to 40 infusions of either ethylene diamine tetraacetic acid (EDTA) chelation or placebo, and they were followed for a median of 55 months. Results were published by Circulation: Cardiovascular Quality and Outcomes on Nov. 19.

Patients without diabetes saw no significant benefit from the EDTA chelation therapy; however, patients with diabetes had a substantial reduction in cardiovascular events. In the diabetic subgroup, the study's primary end point (death, reinfarction, stroke, coronary revascularization or hospitalization for angina) was 25% in the active group versus 38% in the placebo group (hazard ratio [HR], 0.59; 95% CI, 0.44 to 0.79), a finding that remained significant after adjustment. The number needed to treat to reduce 1 primary end point over 5 years was 6.5.

The study authors concluded that EDTA chelation markedly reduced cardiovascular events in post-myocardial infarction patients age 50 and over with diabetes. They cautioned that these results were from a subgroup, although a prespecified one, of a larger trial, so they require replication. The authors speculated as to the possible mechanism of the effect, suggesting that metals bind to glycation end products, accumulating in tissue and promoting inflammation. The fact that the survival and event curves continued to separate long after the intervention stopped suggests that removal of the metals may have had long-term benefit for the patients.

The study was limited by an unexpectedly high dropout rate, but it was higher among placebo patients than intervention patients, which would cause an underestimation of the intervention's effect. The results support the initiation of more trials of chelation in patients with diabetes and vascular disease, the authors said. In the meantime, there is not yet sufficient evidence to support routine use of chelation for these patients, they concluded.



Tool of the month


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Advice on using oral therapy

For patients in whom diet and exercise do not adequately control type 2 diabetes, initiate oral therapy using the following principles:

  • Use metformin (unless contraindicated) as a first-line agent for most patients with type 2 diabetes who require medication, because it causes less hypoglycemia and weight gain and may reduce cardiovascular risk. Consider sulfonylureas as first-line agents in patients who are not obese.
  • Maximize dosage of an agent before adding additional agents, although escalating doses may be of limited effectiveness.
  • Add a sulfonylurea in most patients on metformin requiring a second agent; consider a thiazolidinedione or incretinomimetic drugs in those at risk for hypoglycemia.
  • Given minimal differences in efficacy and limited data about long-term outcomes, use combinations of oral agents based on patient preference, clinician familiarity, and consideration of issues such as side effect profiles and costs.
  • Consider pharmacologic therapy at the time of diagnosis in patients with severe hyperglycemia (fasting blood glucose >250 to 300 mg/dL) or marked symptoms.
  • Consider all of the following factors when making individual treatment decisions: minimization of weight gain, minimization of injections, minimization of patient effort, avoidance of hypoglycemia and minimization of cost.
  • Consider adding acarbose, a thiazolidinedione, or a GLP-1 agonist in patients who have not achieved adequate glycemic control on metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea.

This content is from ACP Smart Medicine, the College's new Web-based clinical decision support tool developed specifically for internal medicine physicians. Information about ACP Smart Medicine is online.

Commentary from ACP DiabetesMonthly's physician editor:

The research news in this month's ACP DiabetesMonthly provides even more support for choosing metformin as the initial pharmacologic therapy for type 2 diabetics. It is well established that metformin directly addresses insulin resistance in this population. In contrast to many diabetic therapies that are associated with weight gain, metformin therapy frequently leads to modest weight loss. Hypoglycemia is extremely rare when using metformin monotherapy. This is often an important consideration, particularly in older diabetics with comorbidities. Metformin appears to decrease cardiovascular events compared to other alternatives, and it is relatively well tolerated as long as therapy is started at a low dose and slowly titrated upward. Recent evidence suggests it may improve the prognosis of patients with cancer (see the "Keeping tabs" section in this issue). All this for a bargain-basement price. Can you imagine the direct-to-consumer advertisements we would see if this were a newly patented medication? We will not see these ads, but it is fun to speculate. So practice high-value care and pick metformin as first-line therapy for type 2 diabetics who do not have a contraindication to it.



Keeping tabs


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Spotlight on diabetes medications and cancer risks

The risks of cancer in patients taking medication for diabetes were analyzed by 2 recent studies.

In the first, a meta-analysis of 20 publications including more than 13,000 patients with cancer published in The Oncologist on Nov. 20, researchers compared the use of metformin with cancer-specific survival and overall survival. They found that patients taking metformin had significantly improved survival rates compared to those who didn't take metformin (hazard ratio, 0.66 for overall survival [95% CI, 0.55 to 0.79] and 0.62 for cancer survival [95% CI, 0.46 to 0.84]). The finding could be due to both the tumor-suppressing activities of metformin and the tumor-promoting effects of other diabetes medications, the authors suggested, concluding that metformin may be the drug of choice for patients with concurrent cancer and diabetes. The study was limited, however, by the fact that diabetes treatment often includes more than one drug and changes over time, the authors noted.

A second study looked at the cancer risks associated with some of those other diabetes medications. Published online Dec. 5 by Diabetes Obesity and Metabolism, the retrospective analysis included more than 25,000 patients from the Cleveland Clinic Diabetes Registry, studied over 8 years. Overall, 892 cancer cases were identified, and for men, no association was found between use of a particular oral diabetes therapy and cancer risk. However, women who used a thiazolidinedione had significantly lower risk of cancer than those taking a sulphonylurea (hazard ratio, 0.68; 95% CI, 0.48 to 0.97). In general, use of an insulin sensitizer (biguanide or thiazolidinedione) was associated with lower cancer risk than use of an insulin secretagogue (sulphonylurea or meglitinide), with a hazard ratio of 0.79 (95% CI, 0.64 to 0.98). The results are consistent with previous research finding a connection between elevated insulin levels and malignancy, the authors concluded, calling for further research on the topic, especially the apparent gender-specific effect.

In other good news for thiazolidinedione users, the FDA recently announced that updated data do not show an increased risk of heart attack with rosiglitazone compared to metformin or sulfonylureas. Therefore, the agency is removing the prescribing and dispensing restrictions that were put in place in 2010. Although some scientific uncertainty about the cardiovascular safety of rosiglitazone still remains, concern is substantially reduced, an FDA press release said.


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MKSAP Answer and Critique



The correct answer is E. Serial abdominal examinations. This item is available to MKSAP 16 subscribers as item 58 in the Endocrinology section. Information about MKSAP 16 is available online.

This patient should first be admitted to the intensive care unit for administration of intravenous fluids and insulin for management of severe diabetic ketoacidosis (DKA) and subsequently have serial abdominal examinations. She has reduced her insulin intake for the past 2 days while she was not feeling well. The insulin requirement usually is increased while a patient is under the stress imposed by illness. Her serum bicarbonate level is now substantially less than 15 mEq/L (15 mmol/L), and she has generalized abdominal pain in the absence of specific intra-abdominal findings on physical examination. These findings are common in DKA, with just under half of patients reporting abdominal pain. Serial abdominal examinations are necessary to determine if her abdominal symptoms improve as her ketoacidosis resolves.

The severity of the abdominal pain is related to the degree of metabolic acidosis. In the absence of localized findings, imaging with CT or other invasive procedures, such as laparotomy or endoscopic retrograde cholangiopancreatography, should be considered only if the patient's abdominal pain does not resolve with correction of the acidosis.

DKA also often causes an elevated leukocyte count, an elevated amylase level, and a less-than-normal temperature, all of which this patient has. However, none of these findings reliably suggests infection, and no obvious source of infection is evident. Imipenem thus should not be started.

Key Point

  • Diabetic ketoacidosis can cause generalized abdominal pain, leukocytosis, and hyperamylasemia.

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