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

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ACP DiabetesMonthly



In the News for the month of March 2014




Highlights

FDA finds no link between incretin-based drugs, pancreatic complications

Data do not support a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, concluded a review by U.S. and European regulatory agencies. More...

Sulfonylurea as second-line therapy appeared to lower cost in a population-based model

Sulfonylurea as second-line therapy for glycemic control in type 2 diabetes appeared to yield similar outcomes and quality-adjusted life-years but led to lower costs and longer time to insulin dependence compared with a dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, and insulin, according to a recent study. More...

Elderly patients most likely to land in ED, get admitted for insulin-related hypoglycemia

Elderly patients are more likely than younger patients to land in the ED and be hospitalized for insulin-related hypoglycemia and errors, a new study found. More...


Test yourself

MKSAP quiz: Nocturnal hypoglycemia in type 1 diabetes

This month's quiz asks readers to evaluate a 21-year-old man with type 1 diabetes being seen in the office for a follow-up to a recent hospitalization. More...


From ACP InternistWeekly

Standard blood glucose targets are lower than HbA1c goals require

A recent study determined the pre- and postprandial blood glucose levels that should be targeted to reach a specific HbA1c goal in patients with type 1 or type 2 diabetes. More...


From ACP Journal Club

Review: In type 1 or type 2 diabetes, group medical visits improve HbA1c levels compared with usual care

A meta-analysis of 13 randomized, controlled trials of adults with type 1 or type 2 diabetes found that group medical visits improved HbA1c levels but not the other factors studied, which included blood pressure, body mass index, weight, cholesterol, triglycerides, and quality of life. More...


FDA update

New drug approved, meters recalled

Dapaglifozin (Farxiga), a new medication to treat type 2 diabetes, was recently approved by the FDA for use along with diet and exercise. More...


Keeping tabs

Spotlight on stroke risk

The effect of hyperglycemia on stroke risk was examined by several studies published in the past month. More...

Editorial note: ACP DiabetesMonthly will not be published next month due to Internal Medicine 2014, which will be held April 10-12.


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



Highlights


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FDA finds no link between incretin-based drugs, pancreatic complications

Data do not support a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, concluded a review by U.S. and European regulatory agencies.

Researchers from the FDA and the European Medicines Agency (EMA) outlined how they conducted comprehensive evaluations in response to postmarketing reports of pancreatitis and pancreatic cancer in patients using incretin-based drugs. Their conclusions appeared in a Feb. 27 Perspective in the New England Journal of Medicine.

The FDA reevaluated more than 250 toxicology studies completed as part of all marketing applications for incretin-based drugs. The studies, conducted in nearly 18,000 healthy animals, found no overt pancreatic toxic effects or pancreatitis. The EMA conducted a similar review and found no drug-induced pancreatic tumors in rats and mice that had been treated for up to 2 years with incretin-based drugs, even at doses that greatly exceed the level of human clinical exposure.

To gather data that might more closely match the drugs' uses in humans, the FDA required drugmakers to conduct 3-month pancreatic toxicity studies in a rodent model of diabetes. Three studies submitted to the FDA found no treatment-related adverse effects on the pancreas.

Clinical safety databases reviewed by the FDA included data from more than 200 trials, involving about 41,000 participants, more than 28,000 of whom were exposed to an incretin-based drug. In these trials, 15,000 patients received a drug for 24 weeks or more, and 8,500 received a drug for 52 weeks or more. EMA conducted a similar review. Small imbalances in the incidence of pancreatitis were reported in premarketing trials, but a pooled analysis of data from 14,611 patients with type 2 diabetes in 25 clinical trials of sitagliptin showed no compelling evidence of an increased risk of pancreatitis or pancreatic cancer.

The agencies also looked at 2 cardiovascular outcome trials: the Saxagliptin Assessment of Vascular Outcomes Recorded (SAVOR) trial and the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. There were similar rates of acute pancreatitis in the treatment and placebo groups in both trials. There were also similar rates of pancreatic cancer in the drug and placebo groups in the SAVOR trial, with no incidence of pancreatic cancer in either group in the EXAMINE trial.

The FDA and the EMA agreed that the data do not currently support a causal association between incretin-based drugs and pancreatitis or pancreatic cancer. "Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal," the Perspective concluded.


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Sulfonylurea as second-line therapy appeared to lower cost in a population-based model

Sulfonylurea as second-line therapy for glycemic control in type 2 diabetes appeared to yield similar outcomes and quality-adjusted life-years (QALYs) but led to lower costs and longer time to insulin dependence compared with a dipeptidyl peptidase-4 (DPP-4) inhibitor, glucagon-like peptide-1 (GLP-1) receptor agonist, and insulin, according to a recent study.

Researchers used a population-based glycemic control Markov model to simulate natural variation in HbA1c progression. A U.S. data set of type 2 diabetes patients who were privately insured was used for calibration. Treatment intensification of metformin monotherapy with a sulfonylurea, a DPP-4 inhibitor, a GLP-1 receptor agonist, and insulin was compared, with the goals of addressing the benefits and harms of each regimen. In those treated with a sulfonylurea, a DPP-4 inhibitor, or a GLP-1 receptor agonist, the second-line drug was started if and when the goal HbA1c was exceeded; insulin was started as a third-line agent in place of the second-line agent if and when the goal HbA1c was exceeded again. In those treated with insulin as second-line therapy, the drug was started as soon as the goal HbA1c was exceeded. None of the regimens were changed after initiation of insulin.

The study's outcome measures were life-years, QALYs, mean time to insulin dependence, and expected medication cost per QALY from diagnosis to first diabetes-related complication or death. Results were published online Feb. 26 by Diabetes Care.

In the model, life-years and QALYs were similar for all regimens at all glycemic control goals. However, second-line therapy with a sulfonylurea led to significantly lower costs per QALY. Compared with sulfonylurea in the base-case analysis, a DPP-4 inhibitor, a GLP-1 agonist, and insulin as second-line agents were associated with mean additional medication costs in women and men of $141 and $160 per QALY, $191 and $216 per QALY, and $150 and $170 per QALY, respectively. The mean time from diabetes diagnosis to insulin initiation in men and women was 2.76 years and 2.59 years in those whose second-line agent was a sulfonylurea, 2.33 years and 2.13 years in those whose second-line agent was a DPP-4 inhibitor, 2.40 years and 2.21 years in those whose second-line agent was a GLP-1 agonist, and 1.72 years and 1.59 years in those whose second-line agent was insulin, respectively. For all regimens, a HbA1c goal of 7% resulted in higher QALYs than a goal of 8%.

The authors cautioned that their results are from a model and do not necessarily reflect what would occur in clinical practice. In addition, they used data from privately insured patients and the study model assumed that HbA1c values varied not continuously but among discrete states and at discrete time intervals. However, the authors concluded that a sulfonylurea as second-line therapy for type 2 diabetes was comparable to other second-line therapies in glycemic control and QALYs but appeared to cost less at all HbA1c goals ranging from 6.5% to 8%. "Our model can serve as an adjunctive decision aid to facilitate treatment selection for people newly diagnosed with type 2 diabetes in a way that trades off health and economic implications for patients," the authors wrote. "It can also be used by health care providers and payers to determine whether a particular treatment option is consistent with the goal of high-value care."


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Elderly patients most likely to land in ED, get admitted for insulin-related hypoglycemia

Elderly patients are more likely than younger patients to land in the ED and be hospitalized for insulin-related hypoglycemia and errors, a new study found.

Researchers used data on insulin-related hypoglycemia and errors (IHE) from the 63 U.S. hospitals that participated in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project. They also estimated the number of patients with diabetes who used insulin or oral medication from the National Health Interview Survey. Outcomes included annual numbers and annual rates of ED visits and hospitalizations for IHEs among insulin-treated patients with diabetes from January 2007 through December 2011. Results were published online March 10 by JAMA Internal Medicine.

An estimated 97,648 annual ED visits occurred for IHEs, 29% of which resulted in hospitalization. Patients who were at least 80 years old and treated with insulin were 2.5 times as likely to visit the ED (rate ratio [RR], 2.5; 95% CI, 1.5 to 4.3) and almost 5 times as likely to be hospitalized (RR, 4.9; 95% CI, 2.6 to 9.1) for IHEs as patients aged 45 to 64 years. The estimated median age of those who came to the ED for IHEs was 60 years for patients treated with insulin alone and 67 years for those treated with insulin and at least 1 oral antidiabetic medication. Indeed, across all age groups, patients who took only insulin were more likely than those taking insulin with oral glucose-lowering medications to have an ED visit.

In about 61% of the ED visits, severe neurologic sequelae were documented, such as hypoglycemia-associated shock, loss of consciousness or seizure. In 53% of ED visits, blood glucose levels of 50 mg/dL (2.8 mmol/L) or below were documented. Twenty-nine percent of ED visits for IHEs required admission, transfer to another facility, or observation. The most commonly reported precipitating factors for ED visits for IHEs were reduced food intake and having taken the wrong insulin product—often, having confused long- and short-acting products.

The risks of hypoglycemic sequelae in patients aged 80 years and older ought to be considered in decisions about prescribing and intensifying insulin, the authors wrote. An editorialist noted that, while occasional episodes are bound to occur, this study indicates insulin-related hypoglycemia is "far too common." To reduce insulin-related hypoglycemia, the editorialist recommended specifically targeting an HbA1c of 6.5% to 7% (as opposed to under 7%), developing glycemic-overtreatment quality indicators, and avoiding insulin in most adults older than 80 years.



Test yourself


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MKSAP quiz: Nocturnal hypoglycemia in type 1 diabetes

A 21-year-old man comes to the office for a follow-up evaluation. He has a 12-year history of type 1 diabetes mellitus and a recent HbA1c value of 8.2%. Two days ago, he was brought to the emergency department after having a seizure at 3 a.m. in his dormitory. Earlier that day, he ate a hearty dinner, played basketball with friends for 3 hours, and then had three beers at a local microbrewery. His glucose monitor showed a blood glucose level of 163 mg/dL (9.0 mmol/L) before he went to bed at 11 p.m. His initial plasma glucose level in the emergency department was 28 mg/dL (1.6 mmol/L). He was given intravenous glucose and recovered fully. His only medications are insulin detemir before breakfast and dinner and insulin aspart before all meals.

Physical examination shows a fit, muscular young man. Vital signs are normal; BMI is 19. All other physical examination findings are normal.

Laboratory studies show an HbA1c value of 8.2%.

Which of the following is the most appropriate advice related to evening exercise to give this patient?

A. Avoid evening exercise
B. If alcohol is consumed, drink only light beer
C. Eat complex carbohydrates at bedtime
D. Omit the evening dose of insulin detemir and insulin aspart

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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Standard blood glucose targets are lower than HbA1c goals require

A recent study determined the pre- and postprandial blood glucose levels that should be targeted to reach a specific HbA1c goal in patients with type 1 or type 2 diabetes.

Researchers used data from participants in the hemoglobin A1c-Derived Average Glucose (ADAG) study, a multicenter observational study that included continuous glucose monitoring and self-monitoring blood glucose (SMBG) readings. Of the 470 patients included in this analysis, 237 had type 1 diabetes and 147 had type 2 diabetes. Their average fasting, premeal, postmeal and bedtime blood glucose readings were compared to their HbA1c levels.

Results were published online Feb. 10 by Diabetes Care.

The researchers found that an HbA1c of 5.5% to 6.49% was associated with an average fasting glucose of 122 mg/dL (95% CI, 117 to 127 mg/dL), an HbA1c of 6.5% to 6.99% was associated with 142 mg/dL fasting (95% CI, 135 to 150 mg/dL), an HbA1c of 7.5% to 7.99% was associated with 167 mg/dL (95% CI, 157 to 177 mg/dL), and an HbA1c of 8.0% to 8.5% was associated with 178 mg/dL (95% CI, 164 to 192 mg/dL). Postmeal average glucose was 139 mg/dL for patients with an HbA1c of 6.5% to 6.99% and 152 mg/dL for those with an HbA1c of 7.0% to 7.49%. Bedtime glucose was 153 mg/dL and 177 mg/dL in those HbA1c categories, respectively. Type 1 and type 2 diabetes patients were analyzed separately, but because their results were fairly similar, they were combined in the final analysis. (To convert glucose values to approximate equivalents in mmol/L, divide the mg/dL value by 18.)

The results show that "currently published SMBG targets are not consistent with the empirical data," the authors concluded. They noted that most SMBG targets are based on expert opinion or extrapolations from average daily glucose levels. Current recommendations typically target a fasting glucose of under 100 to 115 mg/dL, the authors noted, but this study shows that patients with an HbA1c of 5.5% to 6.49% have a fasting glucose of 122 mg/dL. For postprandial glucose, this study provides more specific numbers than the usual target of less than 180 mg/dL, they said.

Glucose monitoring schedules and goals are complex issues that should be decided based on individual factors, but these data may help patients and clinicians choose appropriate SMBG goals to achieve their selected HbA1c targets, the study authors said. They encouraged professional societies, clinicians and patients to consider these data in their future decision-making.



From ACP Journal Club


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Review: In type 1 or type 2 diabetes, group medical visits improve HbA1c levels compared with usual care

A meta-analysis of 13 randomized, controlled trials of adults with type 1 or type 2 diabetes found that group medical visits improved HbA1c levels but not the other factors studied, which included blood pressure, body mass index, weight, cholesterol, triglycerides, and quality of life.

The study was published in CMAJ on Sept. 17, 2013. The following commentary by Marianne Sumego, MD, and David L. Bronson, MD, MACP, was published in the ACP Journal Club section of the Feb. 18 Annals of Internal Medicine.

The growing burden of chronic disease management, insufficient numbers of clinicians, suboptimal outcomes, and the need to provide increased patient access are generating a second look at shared medical appointments (SMAs). Early adopters have cited improved access, increased productivity, and education as benefits of the SMA care model. SMAs are set apart from usual care by the addition of a facilitator to address factors influencing patient care, such as understanding the disease, compliance, and lifestyle changes. SMAs are medical visits and differ from group therapy visits where the focus is providing therapy.

The conclusion of Housden and colleagues that SMAs improve HbA1c levels is both intuitive and substantiated by the studies included in their review. However, the nonstandardized nature of SMAs between studies needs to be considered when outcome data are being evaluated. Variations in targeted patient populations, resources added to SMAs, and length of appointments can make evaluating the benefits challenging. In addition, predetermined visit goals would change the focus and potentially the outcomes affected by SMAs. Interestingly, the duration of treatment, but not the frequency of SMA visits, may be associated with greater reduction of HbA1c levels.

Larger studies over a longer duration are needed to detect important changes in long-term micro- and macrovascular outcomes. In addition, studies are needed to identify the best SMA structure and characteristics of patients most likely to benefit.

The complexity of managing such diseases as diabetes and multiple health care needs and the projected decrease in available physicians requires us to consider innovative, high-quality management approaches. Learning more about how SMAs affect patient care and which patients may benefit most will guide the future role of SMAs. The less tangible benefits of peer support, understanding, and patient engagement may be more difficult to quantify but are critical to patient care.



FDA update


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New drug approved, meters recalled

Dapaglifozin (Farxiga), a new medication to treat type 2 diabetes, was recently approved by the FDA for use along with diet and exercise.

The drug is a sodium-glucose co-transporter 2 inhibitor. Safety and effectiveness were evaluated in 16 clinical trials of more than 9,400 patients, which showed improvement in HbA1c. It has been studied as a stand-alone therapy and in combination with other therapies, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin. It should not be used to treat type 1 diabetes or patients with diabetic ketoacidosis, moderate or severe renal impairment, or end-stage renal disease. The most common side effects are genital mycotic infections and urinary tract infections. An increased number of bladder cancers were diagnosed in patients on the drug, so it is not recommended for patients with active bladder cancer. It can cause dehydration, leading to hypotension that can result in dizziness and/or fainting and a decline in renal function.

The FDA also announced a recall of some TRUEbalance and TRUEtrack blood glucose meters by Nipro Diagnostics, Inc. because they may have an incorrect factory-set unit of measure that displays the glucose result in mmol/L rather than mg/dL.



Keeping tabs


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Spotlight on stroke risk

The effect of hyperglycemia on stroke risk was examined by several studies published in the past month.

Diabetes increases the risk of stroke more for women than for men, according to a systematic review and meta-analysis published online by The Lancet March 7. The analysis of 64 studies, including more than 12,000 strokes, found diabetic women's relative risk (RR) of stroke was 2.28 (95% CI, 1.93 to 2.69), compared with diabetic men's RR of 1.83 (95% CI, 1.60 to 2.08). Thus, women had a 27% greater RR for stroke, even after controlling for baseline differences in major cardiovascular risk factors. The authors speculated that women may have greater deterioration in their cardiovascular function before development of overt diabetes and that a sex-specific intervention in prediabetic women could have substantial effect on vascular events.

Another group of researchers conducted a prospective study of stroke risk in patients already diagnosed with type 2 diabetes. Their study, published by Diabetologia Feb. 24, included 20,000 patients with about 3,000 incident strokes and compared HbA1c levels with stroke risk. In women, they found a graded association between increasing glycemia and stroke risk: For example, compared to women with an HbA1c of 6.0% to 6.9%, those with an HbA1c of 10% or higher had adjusted hazard ratio for stroke of 1.42 (95% CI, 1.23 to 1.65). The trend was particularly significant in women older than 55. No such trend was found in men. These findings contrast with the same researchers' earlier work in which they had found a graded positive association between HbA1c and heart disease in both women and men.

The relationship between cerebral white matter disease (WMD) identified on an MRI and HbA1c was explored in a study of 512 patients with a first acute ischemic stroke, published in Stroke on Feb. 25. White matter disease is the name given to hyperintense changes seen on T2 imaging on MRI scans. The pathophysiology (or significance) of WMD is not entirely clear but previous work suggests it may relate to chronic ischemia and associates it with age and hypertension. The authors performed MRIs on all the stroke patients, and almost 90% patients were found to have WMD. Using multiple regression analysis, the authors found more WMD after stroke to be associated with increasing age, arterial hypertension, and HbA1c. The analysis suggested that even prediabetic glucose levels might increase the risk of WMD and the authors called for additional studies to investigate.


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MKSAP Answer and Critique



The correct answer is C. Eat complex carbohydrates at bedtime. This item is available to MKSAP 16 subscribers as item 79 in the Endocrinology section. Information about MKSAP 16 is available online.

This patient should eat complex carbohydrates (at least 45 grams) at bedtime on evenings of vigorous exercise. He developed severe hypoglycemia several hours after playing basketball for 3 hours, drinking, and not eating before bedtime. Vigorous exercise depletes the muscles' glycogen stores. Although his blood glucose level was 163 mg/dL (9.0 mmol/L) just before he went to bed, his muscles continued to extract glucose from the blood for several hours to replenish their glycogen stores. The alcohol in his system inhibited the liver's ability to release glucose into the blood, and thus his plasma glucose level decreased severely while he was asleep. A substantial snack containing complex carbohydrates before bedtime would have been absorbed over several hours and thereby prevented hypoglycemia.

It is neither reasonable nor necessary to advise a fit young man with diabetes to avoid exercising in the evening.

Even light beer contains enough alcohol to inhibit hepatic glucose output. If he is willing to make the change, he should be advised to drink no alcohol on evenings of vigorous exercise.

Although omitting the insulin aspart dose might be reasonable, stopping both forms of insulin would be a poor choice. Doing so would cause his plasma glucose level to increase because of hypoinsulinemia. His plasma glucose level most likely would be extremely high by bedtime and even higher the following morning.

Key Point

  • In a patient with diabetes mellitus, vigorous exercise should be followed by consumption of complex carbohydrates to avoid hypoglycemia, especially when the exercise occurs in the evening.

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