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ACP DiabetesMonthly



In the News for the month of July 2013




Highlights

Hypoglycemia may be increased by inpatient meal timing

Most episodes of inpatient hypoglycemia occurred between 9 p.m. and 9 a.m., one British hospital found in an analysis of hospitalized patients with diabetes. More...

Automatic insulin pump interruption reduced nocturnal hypoglycemia

Patients who used a pump that suspended insulin delivery when it sensed a low glucose threshold were less likely to experience hypoglycemia at night than those who used a pump without a threshold sensor, an industry-funded study found. More...

Scores may help predict renal risk in type 2 diabetes

Five-year models were useful in predicting renal risk among patients with type 2 diabetes, according to a recent study. More...


Test yourself

MKSAP Quiz: Type 1 diabetic with morning symptoms

This month's quiz asks readers to evaluate a 33-year-old woman for a 3-week history of fatigue, excessive sweating, and occasional headache on awakening. More...


From ACP InternistWeekly

Diabetes meeting features research on prevention, drug effects, complications

CHICAGO—Long-term effects of lifestyle modification and hospitalization rates for complications of diabetes and diabetes treatment were among the research findings presented at the American Diabetes Association's Scientific Sessions last month. More...

Salsalate lowered HbA1c, inflammatory markers but increased LDL, urinary albumin in type 2 diabetics

Salsalate improved glycemic control and showed anti-inflammatory effects compared to placebo in adult patients with type 2 diabetes, a recent study found. More...


From ACP Journal Club

Mediterranean diets reduced cardiovascular events more than a low-fat diet in high-risk persons

A randomized controlled trial (RCT) in Spain included older patients with type 2 diabetes mellitus or at least three major risk factors for cardiovascular disease. More...


Tool of the month

When should a patient be referred to a specialist?

Primary care physicians may consider referral to specialists when they need additional expertise or are out of their "comfort zone" in treating a patient with diabetes. More...


FDA update

Abbot FreeStyle Insulinx meters recalled

The Abbott FreeStyle Insulinx blood glucose meters were recently recalled because at extremely high blood glucose levels of 1,024 mg/dL and above, the meters will display and store in memory an incorrect test result that is 1,024 mg/dL below the measured result. More...


Keeping tabs

Spotlight on exercise

Two recent studies analyzed the effects of exercise on glycemic control in patients with type 2 diabetes or impaired glucose tolerance. More...


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



Highlights


.
Hypoglycemia may be increased by inpatient meal timing

Most episodes of inpatient hypoglycemia occurred between 9 p.m. and 9 a.m., one British hospital found in an analysis of hospitalized patients with diabetes.

Researchers did snapshot audits to capture all hypoglycemic results in inpatients receiving insulin or a sulfonylurea on two different days, six weeks apart. They identified a total of 109 patients who were hospitalized for at least 24 hours. For those patients who were hospitalized longer than a week, they reviewed only the last seven days' blood glucose logs. The researchers then compared the results of this snapshot audit with blood sugar measurements from all similar inpatients from a two-month period stored in a Web database (more than 15,000 blood glucose readings). Hypoglycemia was defined as severe if blood glucose was below 3.0 mmol/L (54 mg/dL) and mild if it was between 3.0 and 3.9 mmol/L (54 to 70 mg/dL). Results were published by Diabetic Medicine on June 29.

According to the bedside audit, 74% of the hospital's patients had a hypoglycemic event, and 83% of the events occurred between 9 p.m. and 9 a.m. Seventy percent of the severe hypoglycemia results were in this time period. The database showed similar timing: 771 hypoglycemic test results (4.9% of the total), 70% of them at night. Forty percent of the episodes were severe, and those mostly (66%) occurred between 9 p.m. and 9 a.m.

Inpatient hypoglycemia occurs more frequently between these hours, the study authors concluded, noting that their results may actually underestimate the phenomenon since glucose testing is less frequent overnight. The hypoglycemia may result from insufficient carbohydrate intake during the time period, because the hospital serves no food between the evening meal at 5 p.m. and breakfast at 8:30 a.m., they speculated.

To confirm this supposition, the authors also surveyed 18 diabetes inpatient nurses from other English hospitals and found that 14 nurses reported more hypoglycemia at night, and 12 of those said that bedtime snacks were never or only sometimes available to patients. Of the four that didn't report more hypoglycemia at night, three worked at hospitals where a snack was always available. The study authors planned to address the issue of prolonged fasting at their own hospital and suggested that other hospitals or clinicians similarly investigate their hypoglycemia trends and snack policies.


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Automatic insulin pump interruption reduced nocturnal hypoglycemia

Patients who used a pump that suspended insulin delivery when it sensed a low glucose threshold were less likely to experience hypoglycemia at night than those who used a pump without a threshold sensor, an industry-funded study found.

Researchers randomly assigned patients with type 1 diabetes and documented nocturnal hypoglycemia to receive sensor-enhanced insulin pump therapy with a threshold-suspend feature (n=121) or without a threshold-suspend feature (n=126) for three months. The threshold-suspend pump pauses insulin delivery for up to two hours, without confirmation needed by the user. In the study, the intervention group's pump was set to suspend insulin delivery at sensor glucose values of 70 mg/dL or less, after which the setting could range from 70 mg/dL to 90 mg/dL.

The study's main safety outcome was change in hemoglobin A1c (HbA1c) level, and the main efficacy outcome was area under the curve (AUC) for nocturnal hypoglycemic events. Such an event was defined as a sensor glucose value of 65 mg/dL or less between 10 p.m. and 8 a.m. for more than 20 consecutive minutes and with no pump interaction within 20 minutes. Results were published June 22 in the New England Journal of Medicine.

Changes in HbA1c were negligible and similar between groups. The mean AUC for nighttime hypoglycemic events was 37.5% lower in the threshold-suspend group than the control group (P<0.001); such events occurred 31.8% less frequently in the threshold-suspend group (P<0.001). Compared to the control group, the intervention group also had significantly lower percentages of nighttime sensor glucose values at less than 50 mg/dL (57.1% less than control), 50 to less than 60 mg/dL (41.9% less), and 60 to less than 70 mg/dL (26.8% less; P<0.001 for all three ranges). There were four severe hypoglycemic events in the control group and none in the intervention group.

Results were limited in that only hypoglycemia-prone patients were enrolled, the study lasted just three months, and low glucose values that lasted less than 20 minutes weren't analyzed. While the current study didn't show differences between groups in quality of life—possibly because the study was too short—it does show that the threshold-suspend feature can lower hypoglycemia episodes, particularly at night, "without any apparent loss in overall glucose control," the researchers concluded.

The study was funded by Medtronic MiniMed, which manufactures the pump with the suspend feature used in the study. The product is currently under review by the FDA.


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Scores may help predict renal risk in type 2 diabetes

Five-year models were useful in predicting renal risk among patients with type 2 diabetes, according to a recent study.

Researchers developed risk models for predicting end-stage renal disease (ESRD) events in type 2 diabetes and used patients in the nationwide New Zealand Diabetes Cohort Study as the derivation cohort. The New Zealand Diabetes Cohort Study included patients with type 2 diabetes, excluding those with ESRD, who were first assessed in 2000 to 2006 and were then followed until December 2010. The main outcome of the New Zealand Diabetes Cohort Study was a fatal or nonfatal ESRD event, that is, peritoneal dialysis or hemodialysis for ESRD, renal transplant, or ESRD death. The researchers developed risk models with Cox proportional hazards models and assessed them in a separate validation cohort, which included 5,877 patients with type 2 diabetes in the Diabetes Care Support Services audit database who had been followed for at least five years. Results were published online June 25 by Diabetes Care.

A total of 25,736 patients were included in the derivation cohort and were followed for up to 11 years; 86% were followed for more than five years. Mean patient age at baseline was 62 years, and the median diabetes duration was five years. Median hemoglobin A1c level and median estimated glomerular filtration rate were 7.2% and 77 mL/min/1.73 m2, respectively, and 37% of patients had albuminuria. Six hundred thirty-seven ESRD events occurred during follow-up in the derivation cohort, and 121 renal events occurred during five-year follow-up in the validation cohort. The authors found that models including sex, ethnicity, age, diabetes duration, albuminuria, serum creatinine level, systolic blood pressure, hemoglobin A1c, smoking status, and history of cardiovascular disease did well at predicting renal risk in both the derivation and validation cohorts and that their predictive performance was better than in previous models.

Complete data were not available for analysis in all patients, and data on diet and physical activity were not accessible for any patients, the authors noted. In addition, they said, risk was predicted using only baseline data, and many of the patients at high risk for renal problems died of other causes before having an ESRD event. However, the authors concluded that the models assessed in their study performed well in predicting renal risk among patients with type 2 diabetes treated in primary care. They called for further studies to continue to refine risk assessment in this population. "Being able to enumerate the risk will also be important in treatment pathways, and the use of (externally validated) risk models will be able to be incorporated to ensure [that] escalation of care…can be based on risk rather than clinical factors, (in)equities, or less precise clinical descriptions," they wrote.



Test yourself


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MKSAP Quiz: Type 1 diabetic with morning symptoms

A 33-year-old woman is evaluated for a 3-week history of fatigue, excessive sweating, and occasional headache on awakening. The patient has had type 1 diabetes mellitus since age 18 years. Her blood glucose log for the past 2 weeks shows fasting blood glucose levels ranging between 125 and 146 mg/dL (6.9 to 8.1 mmol/L) (average, 135 mg/dL [7.5 mmol/L]) and an average predinner level of 176 mg/dL (9.8 mmol/L). She does not check her level at other times during the day but occasionally experiences hypoglycemic symptoms around lunchtime, especially if she does not eat enough. She lives alone and usually exercises 1 hour each evening. Her diabetes regimen is premixed 70/30 insulin (neutral protamine Hagedorn [NPH] insulin/regular insulin) before breakfast and before dinner.

mksap.gif

Physical examination shows a slim but well-appearing woman. Temperature is 36.6 °C (97.9 °F), blood pressure is 104/63 mm Hg, pulse rate is 66/min, and respiration rate is 14/min; BMI is 18. Other physical examination findings are unremarkable. Results of laboratory studies show a hemoglobin A1c value of 5.7% (estimated average plasma glucose level, 120 mg/dL [6.7 mmol/L]).

Which of the following is the most likely cause of her symptoms?

A. Dawn phenomenon
B. Nocturnal hypoglycemia
C. Sleep apnea
D. Somogyi phenomenon

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


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From ACP InternistWeekly


.
Diabetes meeting features research on prevention, drug effects, complications

CHICAGO—Long-term effects of lifestyle modification and hospitalization rates for complications of diabetes and diabetes treatment were among the research findings presented at the American Diabetes Association's Scientific Sessions last month.

Final results from the Look AHEAD trial, presented at the meeting and published in the New England Journal of Medicine on June 24, showed that an intensive lifestyle intervention for overweight and obese type 2 diabetics reduced weight, hemoglobin A1c and some cardiovascular risk factors but had no impact on the primary outcome of cardiovascular-related death, myocardial infarction, stroke or angina hospitalization.

An analysis of Medicare fee-for-service beneficiaries with type 2 diabetes between 1999 and 2007 revealed that rates of hospital admission for hyperglycemia have declined (from 114 per 100,000 person-years in 1999 to 70 per 100,000 person-years in 2007) while hospitalizations for hypoglycemia have risen (94 per 100,000 person-years in 1999 up to a peak of 130 per 100,000 in 2007 back down to 105 per 100,000 in 2011). The findings should draw attention to the risks of increasing use of antihyperglycemic medications, said the Yale researchers who conducted the study.

Focusing on similar concerns, CDC researchers presented data on rates of emergency department (ED) visits and hospitalizations for insulin-related adverse events. In 2007-2009, insulin was responsible for 5.1% of all adverse drug event-related ED visits, and hypoglycemia occurred in 91.8% of those cases. Patients age 80 and over were significantly more likely to have an ED visit or hospitalization related to insulin (9.6 ED visits per 100 diabetic patients over 80 vs. 4.3 among younger diabetic patients, and 4.1 hospitalizations vs. 1.0 per 100 younger diabetic patients). The most common causes were not eating when expected and taking the wrong insulin or wrong dose.

Finally, an analysis of hospitalizations for diabetic foot infections from 2001-2010 found that the hospitalizations increased at the same pace as diabetes cases overall. The hospitalizations were associated with an average 8.2-day length of stay and $46,107 in hospital charges, as well as serious complications. Mortality occurred in 2.0% of hospitalizations, sepsis occurred in 9.6%, surgical complications occurred in 8.0% and amputation occurred in 10.5%. The statistics raise questions about whether greater efforts need to be made in the outpatient setting to prevent these hospitalizations, said study authors from the University of Arizona.

By Stacey Butterfield, Associate Editor


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Salsalate lowered HbA1c, inflammatory markers but increased LDL, urinary albumin in type 2 diabetics

Salsalate improved glycemic control and showed anti-inflammatory effects compared to placebo in adult patients with type 2 diabetes, a recent study found.

The randomized trial included 286 patients ages 18 to 75 with hemoglobin A1c (HbA1c) levels of 7.0% to 9.5%, recruited from three private practices and 18 academic centers in the U.S. For 48 weeks, patients added either 3.5 g of salsalate per day or placebo to their current diabetes regimens. Results were published in the July 2 Annals of Internal Medicine.

annals.jpg

The mean HbA1c was 0.37% lower in the salsalate group than in the placebo group over the course of the study (95% CI, −0.53% to −0.21%; P<0.001). This reduction in HbA1c was achieved despite overall reductions in other diabetes medications in the salsalate group and medication increases in the placebo group. The salsalate also showed anti-inflammatory effects: lower circulating leukocyte, neutrophil and lymphocyte counts in patients taking it compared to those on placebo. Salsalate patients also had greater increases in adiponectin and hematocrit levels and decreases in fasting glucose, uric acid and triglycerides.

However, they also had increases in weight, low-density lipoprotein (LDL) cholesterol and urinary albumin levels. The clinical relevance of the albumin increase is unclear, the study authors said, since the increase reversed after discontinuation of the medication and patients' estimated glomerular filtration rates were unchanged. Continued, longer-term evaluation of the effects of salsalate on renal function and LDL cholesterol is warranted before it can be widely recommended for type 2 diabetes patients, the authors said.

The study was limited by its small size and short duration, but salsalate was well tolerated and showed glucose-lowering effects similar to other typical second-line oral diabetes therapies, the study authors concluded.



From ACP Journal Club


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Mediterranean diets reduced cardiovascular events more than a low-fat diet in high-risk persons

A randomized controlled trial (RCT) in Spain included older patients with type 2 diabetes mellitus or at least three major risk factors for cardiovascular disease. They were assigned to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). The trial was stopped after a median follow-up of 4.8 years, when the two Mediterranean diet groups had significantly lower rates of cardiovascular events.

The study was published in the April 4 New England Journal of Medicine. The following commentary by Paul Glasziou, RACGP, PhD, was published in the ACP Journal Club section of the June 18 Annals of Internal Medicine.

Interest in the possible benefits of a Mediterranean diet was boosted in 1994 when a large French trial found that it reduced mortality in patients after myocardial infarction. The large RCT by Estruch and colleagues provides replication and has the power to examine effects on CV events. The results echo the earlier French study and extend the findings to persons at high risk for CV disease. If we accept that the diet is effective, clinicians and patients will have questions, including: What is a Mediterranean diet? How does it work? What are the important components?

The small improvements in weight, blood pressure, glucose, and C-reactive protein shown in a meta-analysis of the effects of the Mediterranean diet on risk factors are not enough to explain the results. Perhaps it was antiarrhythmic effects of omega-3 fatty acids, but a meta-analysis of omega-3 supplements was disappointing and could not explain the effects. One simplification is that there was no difference between the olive oil– and nut-enhanced diets, so we would be free to choose either. But without knowing what the other effective elements were, we will need to use the whole intervention package, which included individual assessment and tailoring by a nutritionist, with both individual and group sessions. The appendices and Web site of the PREDIMED trial provide many needed details but are largely in Spanish. Considerable enthusiasm and work by clinicians will be needed to implement the intervention! It is certainly more than a handful of free mixed nuts but might be worth the (tasty) effort.



Tool of the month


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When should a patient be referred to a specialist?

All patients with diabetes should be referred to an ophthalmologist for a dilated eye exam. Primary care physicians may consider referral to an endocrinologist when they are out of their "comfort zone" in terms of therapeutic options or practice resources.

Consider referral to the appropriate subspecialists when a patient:

  • Fails to reach target hemoglobin A1c within a reasonable time period (six months).
  • Develops diabetic complications including nephropathy, cardiovascular disease, gastroparesis, etc.
  • Suffers unexplainable blood sugar fluctuations.
  • Has severe or recurrent hypoglycemia.

Excellent communication is key for successful collaboration between generalists and specialists in diabetic care. When a referral is made, remember to clearly define the question/problem that should be addressed. The specialist should, in turn, provide clear documentation about what changes in management have been recommended. If a specialist makes a change in medication that requires laboratory follow-up, the specialist should make sure that the appropriate tests are ordered and completed and that the results are followed up with the patient. If specialist resources are scarce, innovative models have been successful, such as having a specialist provide assistance and additional expertise as part of a diabetes expert care team (e.g., a diabetologist and a nurse-certified diabetes educator) that sees patients jointly with primary care team.



FDA update


.
Abbot FreeStyle Insulinx meters recalled

The Abbott FreeStyle Insulinx blood glucose meters were recently recalled because at extremely high blood glucose levels of 1,024 mg/dL and above, the meters will display and store in memory an incorrect test result that is 1,024 mg/dL below the measured result.



Keeping tabs


.
Spotlight on exercise

Two recent studies analyzed the effects of exercise on glycemic control in patients with type 2 diabetes or impaired glucose tolerance.

In the first study, published by JAMA Internal Medicine on July 1, 105 overweight or obese older patients (mean age, 61) with impaired glucose tolerance or type 2 diabetes had aerobic exercise training for 12 to 16 weeks. On average, the patients lost weight and improved their body composition, aerobic fitness, fasting plasma glucose and two-hour oral glucose tolerance test (OGTT) levels. However, patients with OGTT levels of 236 mg/dL or higher at the start of the study showed less improvement in their OGTT by the end. Patients who started with a hemoglobin A1c (HbA1c) above 6.2% also saw less improvement in their HbA1c and aerobic fitness from the exercise, leading the study authors to conclude that patients with chronic hyperglycemia may not respond as well to exercise, so using exercise to treat poorly controlled diabetes may have limited chances of success.

The other study, published by Diabetes Care on June 11, included 10 inactive adults, age 60 or over, with fasting blood glucose concentrations between 105 and 125 mg/dL, who were studied for multiple 48-hour periods. They spent the first day being inactive as a control period and then the next day walked for 45 minutes at either 10:30 a.m. or 4:30 p.m. or took a 15-minute walk half an hour after each meal. The morning walk and the post-meal walking both improved 24-hour glucose control, but the post-meal walks were most effective at lowering the glucose concentration measured three hours after dinner. The researchers concluded that the timing of exercise may be as important as volume and intensity and speculated that shorter bouts may be better tolerated by older patients, who could even incorporate this exercise into common daily activities, such as dog walking.


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MKSAP Answer and Critique



The correct answer is B. Nocturnal hypoglycemia. This item is available to MKSAP 16 subscribers as item 31 in the Endocrinology section. Information about MKSAP 16 is available online.

This patient's symptoms are most likely caused by nocturnal hypoglycemia. Her hemoglobin A1c value is lower than what her blood glucose log averages suggest. Frequent episodes of significant hypoglycemia for several hours each night would explain this discrepancy. The 70/30 insulin she takes twice daily gives a single large peak 6 to 8 hours after taking it. This patient exercises every evening, which means that her muscles will continue to remove glucose from her blood to replenish their glycogen stores for several hours afterward. This occurrence could cause her blood glucose to decrease to very low levels while she sleeps. Given the duration of her diabetes mellitus, the appropriate adrenergic counterregulatory response may be adequately blunted to not cause her to awaken from sleep but can lead to fatigue, sweating, and headache when she awakens.

The dawn phenomenon is defined as an elevation in blood glucose levels during the early morning hours (4 a.m. to 8 a.m.) that is thought to be related to the increased physiologic release of cortisol and growth hormone that occur during this time period. The dawn phenomenon is typically identified by persistent significant elevations of morning blood glucose levels, which were not seen in this patient.

Although sleep apnea may be a cause of fatigue and early morning headache, it is more often seen in obese patients with type 2 diabetes who have an associated high hemoglobin A1c value.

The "Somogyi phenomenon" is a phrase used to describe the theoretical concept that the lower the blood glucose level decreases during the night, the higher it increases the next morning because of increasingly severe rebound hyperglycemia. This idea, however attractive on a theoretical level, has been disproven as a cause of fasting hyperglycemia.

Key Point

  • Frequent nocturnal hypoglycemia may cause morning fatigue, sweating, and headache in patients with type 1 diabetes mellitus.

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Test yourself

A 50-year-old man is evaluated in follow-up for a recent diagnosis of cirrhosis secondary to nonalcoholic steatohepatitis. He has a history of asthma, type 2 diabetes mellitus, hyperlipidemia, and obesity. His current medications are inhaled fluticasone, montelukast, insulin glargine, insulin lispro, simvastatin, and lisinopril. Following a physical exam, lab studies, and upper endoscopy, what is the most appropriate treatment?

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