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ACP DiabetesMonthly



In the News for the month of March 2013




Highlights

GLP-1 drugs associated with hospitalizations for pancreatitis

Sitagliptin and exenatide were associated with increased risk of hospitalization for acute pancreatitis, according to a recent study of patients with type 2 diabetes. More...

Hyperbaric oxygen fails to improve wound healing or prevent amputation

Hyperbaric oxygen therapy didn't improve the likelihood that a wound would heal or prevent amputation in diabetes patients compared to other conventional therapies, a new study found. More...

Study examines heterogeneity of type 2 diabetes

Type 2 diabetes appears to have different subtypes based on how it is diagnosed, according to a recent study. More...


Test yourself

MKSAP Quiz: muscle weakness and uncontrolled diabetes

A 67-year-old woman is evaluated for a 2-day history of severe muscle weakness. The patient experienced significant weight gain and developed hypertension and type 2 diabetes mellitus 2 years ago. She also reports developing muscle weakness of the lower extremities 6 months ago. Her diabetes is only partially controlled by metformin. Following a physical exam and lab results, what tests should be performed to reveal the cause of her diabetes? More...


From ACP InternistWeekly

Angina not associated with mortality in diabetes patients with coronary artery disease

Patients with type 2 diabetes and stable coronary artery disease (CAD) had similar risk of cardiovascular events and death, regardless of whether they had angina or angina-like symptoms, a study found. More...


From ACP HospitalistWeekly

Similar glycemic control found with basal bolus and basal plus regimens

For hospitalized patients with type 2 diabetes, a regimen of daily glargine supplemented with corrective doses of glulisine controlled blood glucose as well as a standard basal bolus regimen, a new study found. More...


Tool of the month

Tips to help patients manage type 1 diabetes when they're sick

Key messages for patients about sick days include five recommendations. More...


Keeping tabs

Spotlight on diabetes knowledge and practice

Knowledge among U.S. patients and clinicians about recommended care for diabetes is good but could still use improvement, one can conclude from studies published this month. More...

Editorial note: ACP DiabetesMonthly will not be published in April due to Internal Medicine 2013, ACP's annual scientific meeting.


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



Highlights


.
GLP-1 drugs associated with hospitalizations for pancreatitis

Sitagliptin and exenatide were associated with increased risk of hospitalization for acute pancreatitis, according to a recent study of patients with type 2 diabetes.

The population-based, case-control study used an administrative database to identify 1,269 patients with type 2 diabetes who were hospitalized with acute pancreatitis between 2005 and 2008. They were matched to 1,269 control subjects based on age, sex, enrollment pattern and diabetes complications. The study was published online by JAMA Internal Medicine on Feb. 25.

After adjustment for confounders, including metformin use, the study found that patients who had taken one of these glucagonlike peptide-1 (GLP-1)-based therapies in the prior 30 days were significantly more likely to be hospitalized with acute pancreatitis (adjusted odds ratio [AOR], 2.24; 95% CI, 1.36 to 3.68). Taking the drugs more than 30 days but less than two years prior was also associated with increased risk (AOR, 2.01; 95% CI, 1.37 to 3.18). The study also found a number of other factors more common in GLP-1 patients than controls, including hypertriglyceridemia, alcohol use, gallstones, tobacco use, obesity, biliary and pancreatic cancer, cystic fibrosis and any neoplasm.

The study authors concluded that sitagliptin and exenatide were associated with increased odds of hospitalization for acute pancreatitis. They noted that this finding supports previous mechanistic studies and reports to the FDA, although overall the evidence on GLP-1 drugs and pancreatitis is mixed. This study was limited by the possibility of additional confounders and the exclusion of patients over age 64. In addition, data on the long-term risk of pancreatic cancer and newer GLP-1-based therapies were not available.

The authors called for future studies to clarify the findings, particularly whether patients with certain genetic mutations or pancreatic risks, such as obesity, are at elevated risk. Another open research question is whether monitoring of serum enzyme levels might predict acute pancreatitis in patients on GLP-1 drugs.


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Hyperbaric oxygen fails to improve wound healing or prevent amputation

Hyperbaric oxygen therapy didn't improve the likelihood that a wound would heal or prevent amputation in diabetes patients compared to other conventional therapies, a new study found.

In a longitudinal observational study, researchers followed 6,259 patients who had diabetes, adequate lower-extremity arterial flow as determined by a clinician, and a wound on the plantar foot, hindfoot, midfoot or forefoot. Patients also experienced failure to heal during the first four weeks of wound center care and didn't see a decrease in wound size by at least 40% during that time. Eighty-three wound care centers in 31 states provided data for the study from November 2005 to May 2011.

Researchers compared the effectiveness of hyperbaric oxygen with that of other conventional therapies. The outcomes—healed wound and lower-extremity amputation—were assessed 16 weeks after a subject became eligible for the study or 20 weeks after enrollment at a wound care center. Propensity scores were used to determine the likelihood that an individual was selected to receive hyperbaric oxygen. Results were published online Feb. 19 by Diabetes Care.

Hyperbaric oxygen was administered to 12.7% of subjects, most often to a depth of 2.0 atm (88.5% of treatments) five days per week (88%) and for 90-minute sessions (99.5%). In propensity analysis, subjects who received hyperbaric oxygen were less likely to have healing of their foot ulcer (hazard ratio [HR], 0.68; 95% CI, 0.63 to 0.73) and more likely to have amputation (HR, 2.37; 95% CI, 1.84 to 3.04) than those who didn't have this therapy. Additional analyses, aimed at assessing the robustness of results to confounding, also found that hyperbaric oxygen didn't improve the likelihood that a wound would heal or decrease the likelihood of amputation.

Indeed, using multiple analytic approaches, the study found that patients who received hyperbaric oxygen were 1.5 to three times more likely to have an amputation than those who didn't receive hyperbaric oxygen and were 1.2 to three times less likely to heal a foot ulcer, researchers said. About a third of subjects they studied who got hyperbaric oxygen received more than the recommended maximum of 40 treatments, they noted. The authors speculated that hyperbaric oxygen may only enhance a specific aspect of wound repair and may be part of the answer rather than a therapy that should be used until a wound fully heals. The authors concluded by calling for a randomized, controlled trial to help answer this question.


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Study examines heterogeneity of type 2 diabetes

Type 2 diabetes appears to have different subtypes based on how it is diagnosed, according to a recent study.

Researchers used prospectively collected data from the Whitehall II study and performed a retrospective analysis of the trajectory of cardiovascular risk factors and 10-year cardiovascular risk in patients identified as diabetic by a 75-g oral glucose tolerance test (OGTT). The Whitehall II study is a longitudinal study done in the United Kingdom in adults who were 35 to 55 years of age in 1985-1988 and have undergone eight phases of follow-up through 2009. For this study, participants who were diagnosed with type 2 diabetes on the OGTT were divided into three subgroups: those who at time of diagnosis had fasting hyperglycemia, those who had elevated 2-hour glucose concentrations and those who had both fasting hyperglycemia and elevated 2-hour glucose concentrations. The goal of the study was to determine whether patients diagnosed with type 2 diabetes by these three methods differed in pathogenesis or in cardiovascular risks. The results were published online Feb. 21 by The Lancet Diabetes & Endocrinology.

Patients were followed for a median of 14.2 years from 1991 to 2009, with 15,826 person-examinations. Of 10,308 individuals in the Whitehall II study, 6,843 met criteria for inclusion in this analysis (patients with diabetes diagnosed before the OGTT and diagnosed outside the study were excluded). A total of 274 patients developed type 2 diabetes, and of these, 55 had high fasting glucose concentrations, 148 had high 2-hour glucose concentrations and 71 had both. Patients with high concentrations on both measures had a higher mean body mass index at diagnosis than those who had only high fasting glucose concentrations (P=0.0009) or high 2-hour concentrations (P<0.0001). The first group also had higher mean glycated hemoglobin A1c levels (7.4% vs. 5.9% vs. 5.9%; P<0.0001 for both comparisons), a larger proportion of patients with moderate to high risk for cardiovascular disease and a more substantial acceleration of glucose levels and insulin resistance, plus classic β-cell compensation before diagnosis.

The authors noted that their results may not be generalizable to all patients and that their study included few women (<30%) and few minorities, among other limitations. However, they concluded that the natural history and pathogenesis of type 2 diabetes appear to differ depending on how the disorder is diagnosed. For example, patients with high concentrations on only the fasting or two-hour glucose test showed no increase in β-cell function before diagnosis, as has been considered typical in type 2 diabetes. "Future studies should establish whether glycaemic control, drug needs, and the incidence of cardiovascular disease and microvascular complications differ between patients with different subgroups of disease," the authors wrote.



Test yourself


.
MKSAP Quiz: muscle weakness and uncontrolled diabetes

A 67-year-old woman is evaluated for a 2-day history of severe muscle weakness. The patient experienced significant weight gain and developed hypertension and type 2 diabetes mellitus 2 years ago. She also reports developing muscle weakness of the lower extremities 6 months ago. Her diabetes is only partially controlled by metformin; her blood glucose measurements at home are usually greater than 250 mg/dL (13.9 mmol/L). Other medications are hydrochlorothiazide, lisinopril, amlodipine, and metoprolol.

mksap.gif

Physical examination shows a woman who appears chronically ill. Blood pressure is 154/92 mm Hg, and other vital signs are normal; BMI is 40. Skin examination is notable for facial hirsutism. Central obesity, mild proximal muscle weakness, and 2+ peripheral edema are noted.

Results of laboratory studies show a serum creatinine level of 1.3 mg/dL (115 µmol/L), a plasma glucose level of 144 mg/dL (8.0 mmol/L), and a serum potassium level of 2.9 mEq/L (2.9 mmol/L).

Which of the following tests should be performed to reveal the cause of her diabetes?

A. Adrenal CT
B. C-peptide measurement
C. Glutamic acid decarboxylase antibody titer
D. Pancreatic MRI
E. 24-Hour urine free cortisol excretion

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


.

From ACP InternistWeekly


.
Angina not associated with mortality in diabetes patients with coronary artery disease

Patients with type 2 diabetes and stable coronary artery disease (CAD) had similar risk of cardiovascular events and death, regardless of whether they had angina or angina-like symptoms, a study found.

Researchers performed a post hoc analysis in 2,364 patients with diabetes and CAD enrolled in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial to determine the occurrence of death and a composite outcome of death, myocardial infarction and stroke during a five-year follow-up.

Results appeared in the Journal of the American College of Cardiology on Feb. 11.

There were 1,434 patients with angina, 506 with angina equivalents and 424 with neither condition. All patients received optimal medical therapy of lifestyle management and medication to maintain hemoglobin A1c levels less than 7%, low-density lipoprotein less than 100 mg/dL, and blood pressure of 130/80 mm Hg or less. The cumulative five-year death rates (total deaths, 316) were 12% in patients with angina, 14% in angina equivalents and 10% in neither (P=0.3), and composite cardiovascular outcome rates (total events, 548) were 24% in angina, 24% in angina equivalents and 21% in neither (P=0.5).

Compared to patients who had neither condition, the hazard ratios (HRs) for death, adjusted for confounders, were not different in the groups with angina (HR, 1.11; 99% CI, 0.81 to 1.53) and angina equivalents (HR, 1.17; 99% CI, 0.81 to 1.68). The same was true of cardiovascular events in patients with angina (HR, 1.17; 99% CI, 0.92 to 1.50) and angina equivalents (HR, 1.11; 99% CI, 0.84 to 1.48). Researchers noted that these findings suggest that these patients can be similarly managed in terms of risk stratification and preventive therapies.

An editorialist noted that given rising rates of diabetes and of health care costs, clinicians should carefully assess the risk, benefit and cost of widespread screening for CAD.

"Given the rapidly escalating epidemic of type 2 diabetes, the costs of widespread CAD screening of low-risk asymptomatic patients with diabetes would likely outweigh the minor clinical benefit," stated the editorial. "For now, we should certainly optimize risk factor management for all patients with diabetes, and we will need more prospective cost-effectiveness studies to determine an optimal risk stratification strategy for patients with diabetes at risk for CAD."



From ACP HospitalistWeekly


.
Similar glycemic control found with basal bolus and basal plus regimens

For hospitalized patients with type 2 diabetes, a regimen of daily glargine supplemented with corrective doses of glulisine controlled blood glucose as well as a standard basal bolus regimen, a new study found.

The multicenter trial included 375 medical or surgical patients with type 2 diabetes usually treated with diet, oral antidiabetic agents or insulin at a dose of 0.4 unit/kg/day or less. During hospitalization, they were randomized to a basal bolus regimen (glargine once daily and glulisine before meals), a basal plus regimen (glargine once daily and corrective doses of glulisine given by sliding scale), or sliding-scale regular insulin.

Noting that clinicians have been reluctant to follow recommendations to switch from sliding scale to basal bolus, probably because of complexity and hypoglycemia risks, the authors hypothesized that a single daily dose of basal insulin might provide similar glucose control and lower hypoglycemia rates than a basal bolus regimen. The results were published by Diabetes Care on Feb. 22.

The study found that the basal bolus and basal plus regimens improved mean daily blood glucose after the first day of therapy by about the same amount. Both basal groups also had significantly lower mean daily blood glucose than the sliding-scale group. There were also significantly fewer patients with more than two consecutive glucose measurements above 240 mg/dL: 0% of the basal bolus group, 2% of the basal plus group and 19% of the sliding-scale group. Hypoglycemia (blood glucose under 70 mg/dL) occurred in 16% of basal bolus patients, 13% of basal plus patients and 3% of sliding-scale patients. The groups had similar rates of severe hypoglycemia (under 40 mg/dL).

Basal plus and basal bolus resulted in similar glycemic control, superior to that found with sliding scale, the study authors concluded. Based on these results, basal plus is an effective alternative to basal bolus for patients similar to those in this trial. The study was limited by its exclusion of ICU patients and those who had hepatic disease, creatinine ≥3.0 mg/dL, severe hyperglycemia or a usual insulin dose of more than 0.4 unit/kg/day. Higher insulin doses or a standard basal bolus regimen might be best for those patients, the authors noted.



Tool of the month


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Tips to help patients manage type 1 diabetes when they're sick

Key messages for patients about sick days include the following recommendations:

  1. Never omit diabetes medication.
  2. Self-monitor blood glucose every 3 to 4 hours and perform ketone testing when two blood glucose readings are greater than 250 mg/dL.
  3. If blood glucose readings are greater than 250 mg/dL, supplemental corrective short-acting insulin is recommended.
  4. Drink 6 to 8 ounces of fluids each hour while awake.
  5. Call a clinician if vomiting or diarrhea persists more than 8 hours, the ketone value is moderate to large, blood glucose values greater than 250 mg/dL do not decrease with extra insulin, blood glucose values are low, or the appropriate action is unknown.


Keeping tabs


.
Spotlight on diabetes knowledge and practice

Knowledge among U.S. patients and clinicians about recommended care for diabetes is good but could still use improvement, one can conclude from studies published this month.

The knowledge of clinicians was assessed by a survey of almost 1,000 endocrinologists, primary care physicians and non-physician providers conducted in 2011. According to the results, published in the Winter 2013 Clinical Diabetes, about 70% of endocrinologists and diabetes educators were very familiar with guidelines compared to about 40% of the other clinicians. The survey found several specific gaps in internists' and family physicians' knowledge, including management of insulin regimens other than long-acting basal analog. About half of surveyed primary care clinicians also fell short in their understanding of the differences between glucagonlike peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. The authors called for clinician education to fill these gaps.

Among the general U.S. population, about 21% of non-diabetics and more than two-thirds of diabetics are very knowledgeable about the disease, according to their self-reports in a Harris Interactive/HealthDay poll. Most of the respondents knew the common risk factors and complications of diabetes, with the exception of stroke, which only 39% of the overall survey population and 56% of type 2 diabetics knew was a potential consequence of the disease. The survey also asked diabetic patients about how well they and their physicians control their diabetes and found that 35% reported it was only somewhat controlled and another 5% said "not at all."

A more precise evaluation of U.S. patients' diabetes control was provided by National Health and Nutrition Examination Survey (NHANES) data published by Diabetes Care on Feb. 15. The data showed that 52.5% of people with diabetes achieved a hemoglobin A1c (HbA1c) level less than 7% in 2007-2010, compared to 44% in 1988-1994 and 57% in 2003-2006. The percentage with a blood pressure below 130/80 mm Hg was 51.1% in the most recent survey, 29% in 1999-2002 and 46% in 2003-2006. Control of cholesterol (low-density lipoprotein cholesterol level below 100 mg/dL) steadily improved from 36% to 46% to 56.2%. In the 2007-2010 data, 18.8% of diabetic patients achieved all three of these "ABC" goals, compared to 7% and 12% in earlier time periods.

The results show significant improvement in diabetes control but also room for more, the study authors concluded. "Access to care, education, and self-management support; personal knowledge, behavior, and adherence to therapy; healthy environments; as well as variation in the pathophysiology underlying diabetes all play important roles in achieving diabetes management goals that can improve long-term health of individuals with diabetes," they wrote.


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MKSAP Answer and Critique



The correct answer is E. 24-Hour urine free cortisol excretion. This item is available to MKSAP 16 subscribers as item 6 in the Endocrinology section. Part A of MKSAP 16 was released on July 31, 2012, and Part B was released on Feb. 1, 2013. More information is available online.

Measurement of the 24-hour excretion of urine free cortisol is the most appropriate next test in this patient to determine the cause of her diabetes mellitus. Various secondary causes of diabetes exist, most involving other endocrinopathies, effects of medications, pancreatic diseases, or genetic conditions. Cushing syndrome is one of these secondary causes of diabetes. The most common cause of Cushing syndrome is corticosteroid therapy, followed by the secretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma (Cushing disease) and the hyperfunctioning of an adrenocortical adenoma. In this patient, the combination of diabetes, hypertension, central obesity, hypokalemia, proximal muscle weakness, and edema strongly suggests the presence of Cushing syndrome. The diagnosis can be confirmed by several tests, including measurement of 24-hour excretion of urine free cortisol, an overnight dexamethasone suppression test, or a midnight salivary cortisol measurement.

Adrenal CT is appropriate after Cushing syndrome is diagnosed, especially when it is non–ACTH dependent, to identify the type of adrenal condition responsible. This test would be premature in this patient in whom the diagnosis has not been confirmed.

Residual beta-cell function can be assessed by measuring the C-peptide level, which is often high-normal in early type 2 diabetes because of insulin resistance. Similarly, measuring the glutamic acid decarboxylase antibody titer is useful to confirm the presence of autoimmune (type 1) diabetes when no other evidence exists. However, the C-peptide level will not indicate the cause of diabetes in this patient, and measuring the glutamic acid decarboxylase level also is unlikely to be helpful because she does not have type 1 diabetes.

Pancreatic imaging could be considered when signs and symptoms (such as abdominal or back pain, jaundice, or chronic diarrhea) suggest that an underlying pancreatic disorder is the cause of diabetes. This patient has none of these signs or symptoms, and thus a pancreatic MRI is unlikely to be revealing.

Key Point

  • Cushing syndrome is a likely cause of diabetes mellitus in a patient with hypertension, central obesity, and hypokalemia.

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A 66-year-old man is evaluated for vague abdominal pain of several months' duration and a 10-kg (22-lb) weight loss. He drinks alcohol socially but does not smoke. The patient is otherwise well, has good performance status, and takes no medications. Following a physical exam, lab studies, and a CT scan, what is the most appropriate initial management of this patient?

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