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

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ACP DiabetesMonthly



In the News for the month of February 2014




Highlights

Herbal capsule may lower risk of developing type 2 diabetes in prediabetes patients

Patients with impaired glucose tolerance who were treated with Chinese herbs for a year were significantly less likely to develop diabetes than matched patients who didn't take the herbs, a study found. More...

No 'obesity paradox' for mortality found in diabetics

A new study found no evidence of a mortality benefit for diabetics in being obese or overweight and thus did not support the so-called "obesity paradox." More...

Spousal diabetes associated with personal increase in diabetes risk

Having a spouse with diabetes was associated with a 26% increase in personal diabetes risk, according to a recent study. More...


Test yourself

MKSAP Quiz: type 1 diabetic with hyperglycemia after exercise

This month's quiz asks readers to evaluate a 32-year-old man with type 1 diabetes and significant blood glucose elevations associated with exercise. More...


From ACP InternistWeekly

Intensive BP and cholesterol treatment didn't affect cognitive decline after 40 months

In patients with type 2 diabetes, intensive control of blood pressure and cholesterol did not protect against cognitive decline, a recent study found. More...


From ACP Journal Club

Review: Bariatric surgery increases weight loss and diabetes remission more than nonsurgical treatment

A meta-analysis of 11 randomized, controlled trials found that bariatric surgery improved several health and diabetes outcomes more than nonsurgical treatment. More...

Safety of dipeptidyl peptidase-4 inhibitors analyzed in 2 studies

A meta-analysis of dipeptidyl peptidase-4 inhibitors showed no increase in pancreatic adverse events, while a trial of saxagliptin found no effect on the overall rate of cardiovascular events. More...


FDA update

Saxagliptin under analysis for heart failure risk

The FDA has requested clinical trial data on saxagliptin (Onglyza and Kombiglyze XR) to investigate a possible increase in heart failure in patients taking the drug. More...

Test strips recalled

Twenty lots of Abbott's FreeStyle and FreeStyle Lite blood glucose test strips were recalled. More...


Keeping tabs

Spotlight on new diabetes technologies

Technological advances that could improve diabetes control in the future made the news in the past month. More...


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



Highlights


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Herbal capsule may lower risk of developing type 2 diabetes in prediabetes patients

Patients with impaired glucose tolerance who were treated with Chinese herbs for a year were significantly less likely to develop diabetes than matched patients who didn't take the herbs, a study found.

In a double-blind, multicenter trial, researchers randomized 420 Chinese patients with impaired glucose tolerance (IGT) to receive placebo pills or Tianqui capsules for 12 months. The capsules contain 10 Chinese herbal medicines and are used in China to treat type 2 diabetes. Patients underwent glucose tolerance tests every 3 months to see if normal glucose tolerance was restored or if diabetes had developed. Patients in both groups received a month of lifestyle education, including nutrition counseling, and were asked to maintain their usual patterns of exercise. Results were published in the February Journal of Clinical Endocrinology & Metabolism.

Three hundred eighty-nine patients completed the trial. Eighteen percent of the patients in the Tianqui group (n=36) and 29% in the placebo group (n=56) developed diabetes (P=0.01). Tianqui reduced the risk of diabetes by 32% compared to placebo, according to Cox proportional hazards model analysis. Also, patients in the Tianqui group were more likely to have normal glucose tolerance after 12 months (63% vs. 47%; P=0.001). Patients didn't differ significantly by group in terms of body weight or body mass index changes after a year, and neither group experienced serious adverse events. Fifteen patients in the Tianqui group had mild adverse reactions versus 11 in the placebo group; these included flatulence, nausea, constipation and diarrhea.

The risk reduction associated with Tianqui is less than what has been found with rosiglitazone (62%) and pioglitazone (72%), but similar to that of acarbose (25%) and metformin (31%), the researchers noted. The capsule was safe and well tolerated, they added, suggesting Tianqui has potential for preventing type 2 diabetes, especially in areas where herbal medicines are widely used and culturally accepted.


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No 'obesity paradox' for mortality found in diabetics

A new study found no evidence of a mortality benefit for diabetics in being obese or overweight and thus did not support the so-called "obesity paradox."

Researchers studied participants with diabetes from the Nurses' Health Study (8,970 participants) and the Health Professionals Follow-up Study (2,457 participants) who were free of cardiovascular disease and cancer at the time of their diabetes diagnosis. Body weight shortly before diagnosis and height were used to calculate body mass index (BMI).

Results appeared Jan. 16 in the New England Journal of Medicine.

There were 3,083 deaths from all causes over a mean follow-up of 15.8 years, with a maximum follow-up of 36 years among women and 26 years among men. The mean age at death was 74.68 years for women and 78.7 years for men.

The researchers found a J-shaped relationship between BMI at the time of a diabetes diagnosis and risk of death from all causes, with the lowest risk observed among participants with a BMI from 22.5 to 24.9 kg/m2.

The hazard ratios (HRs) for each BMI group were as follows.

  • 18.5 to 22.4 kg/m2: HR, 1.29; 95% CI, 1.05 to 1.59;
  • 22.5 to 24.9 kg/m2 (reference group): HR, 1.00;
  • 25.0 to 27.4 kg/m2: HR, 1.12; 95% CI, 0.98 to 1.29;
  • 27.5 to 29.9 kg/m2: HR, 1.09; 95% CI, 0.94 to 1.26;
  • 30.0 to 34.9 kg/m2: HR, 1.24; 95% CI, 1.08 to 1.42; and
  • ≥35.0 kg/m2: HR, 1.33; 95% CI, 1.14 to 1.55.

When researchers correlated mortality to smoking status, the relationship was linear among participants who had never smoked (HRs across BMI categories, 1.12, 1.00, 1.16, 1.21, 1.36 and 1.56, respectively) but was nonlinear among participants who had ever smoked (HRs across BMI categories, 1.32, 1.00, 1.09, 1.04, 1.14 and 1.21) (P=0.04 for interaction).

There was a direct linear trend in mortality among participants who were younger than 65 when diagnosed with diabetes, but not among those who were 65 years or older at the time of diagnosis (P<0.001 for interaction).

The researchers noted that, although the findings were largely consistent with the results of previous analyses in the general population, they contradict the results of several studies of BMI and mortality that were specific to diabetes.

The researchers wrote, "There was no evidence of a protective effect of overweight or obesity on mortality. In addition, given the relationship of overweight and obesity to other critical public health end points (e.g., cardiovascular disease and cancer), the maintenance of a healthy body weight should remain the cornerstone of diabetes management, irrespective of smoking status."


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Spousal diabetes associated with personal increase in diabetes risk

Having a spouse with diabetes was associated with a 26% increase in personal diabetes risk, according to a recent study.

Researchers performed a systematic review and meta-analysis to evaluate diabetes concordance in spouses and the effect of socioenvironmental factors on diabetes risk. Cross-sectional, case-control and cohort studies that looked at spousal association and diabetes, prediabetes or both and were published from Jan. 1, 1997, to Feb. 28, 2013, were considered for inclusion. The study was published online by BMC Medicine on Jan. 24.

Six studies were included in the systematic review, and of these, 5 studies involving 75,498 couples were included in the meta-analysis. The mean age of study participants ranged from 52 years to 74 years. One study that used women's self-reports of their own and their spouses' diabetes found the lowest concordance (effect estimate, 1.1; 95% CI, 1.0 to 1.30), and 1 study that systematically assessed glucose tolerance found the highest concordance (effect estimate, 2.11; 95% CI, 1.74 to 5.10). The random-effects pooled estimate was 1.26 (95% CI, 1.08 to 1.45) in patients with a spousal history of diabetes when adjusted for age and other covariates besides BMI; it was 1.18 (95% CI, 0.97 to 1.40) when adjustment for BMI was included. High concordance was also reported in 2 studies that used glucose testing for prediabetes and diabetes (odds ratios, 2.32 with BMI adjustment [95% CI, 1.87 to 3.98] and 1.92 [95% CI, 1.55 to 2.37] without).

The authors noted that 2 studies did not distinguish between type 1 and type 2 diabetes but said this probably did not influence their results since most adults have the latter. In addition, they said, the included studies differed in populations, design, and other characteristics, and spouses of diabetics may have been more likely to recognize and seek treatment for signs and symptoms of diabetes, among other limitations. However, they concluded that according to their results, spousal history of diabetes or prediabetes may increase personal risk of the disease by 26%.

"Recognizing shared couple risk may result in greater support and collaboration within the family to engage in diabetes prevention efforts," the authors wrote. "Physicians and other health care professionals may use this information to encourage couple-based interventions to adopt a balanced dietary intake that is not energy-dense, make healthier food choices, and increase physical activity levels." They also suggested that spousal history be added to existing clinical evaluation and risk assessment tools for diabetes.



Test yourself


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MKSAP Quiz: type 1 diabetic with hyperglycemia after exercise

A 32-year-old man is evaluated for significant blood glucose elevations associated with exercise. The patient has a 22-year history of type 1 diabetes mellitus. He reports that after a recent 6 a.m. 5-mile run, his blood glucose level was 386 mg/dL (21.4 mmol/L); the level was 297 mg/dL (16.5 mmol/L) just before the run and 215 mg/dL (11.9 mmol/L) at bedtime the night before. He took no insulin and ate no food in the morning before his run. During the run, he felt slow and fatigued but was significantly better after drinking water and giving himself insulin. The patient had one episode of diabetic ketoacidosis 15 years ago. Medications are insulin detemir, 16 units/d in the morning, and insulin lispro, 4 to 6 units before each meal, depending on his preprandial blood glucose level and expected carbohydrate intake.

mksap.gif

Physical examination findings, including vital signs, are normal.

Which of the following is the most likely cause of his postexercise hyperglycemia?

A. Excess nocturnal carbohydrate intake
B. Gastroparesis
C. Inadequate insulin replacement
D. Nocturnal hypoglycemia

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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Intensive BP and cholesterol treatment didn't affect cognitive decline after 40 months

In patients with type 2 diabetes, intensive control of blood pressure and cholesterol did not protect against cognitive decline, a recent study found.

This substudy of the ACCORD trial included 2,977 patients with type 2 diabetes, HbA1c of at least 7.5%, and no evidence of cognitive impairment or dementia at baseline. About half of the patients (n=1,439) were randomized to a systolic blood pressure goal of either under 120 mm Hg or under 140 mm Hg. The other group of 1,538 patients had LDL cholesterol levels less than 100 mg/dL (2.6 mmol/L) and were randomized to either a fibrate or placebo. Results were published online Feb. 3 by JAMA Internal Medicine.

Cognition was assessed at baseline, 20 months and 40 months in all patients; a subset of 503 patients also underwent brain magnetic resonance imaging (MRI) at baseline and 40 months. No differences in cognition were found among any of the trial groups. Among the patients who had brain MRIs, total brain volume by 40 months declined more in the intensive blood pressure control group than the standard care group (difference, −4.4 cm3; 95% CI, −7.8 to −1.1; P=0.01).

The study authors concluded that intensive blood pressure and fibrate therapy did not measurably affect cognitive decline in the studied patient population. They noted that the studied patients, with a mean HbA1c of 8.3% and disease duration of 10 years, had relatively longstanding and poorly controlled disease. The findings extend the previous observation of the ACCORD MIND trial that intensive glucose control did not preserve cognitive function in similar patients.

Intensive glucose control did, however, maintain total brain volume more than standard care in that trial, the opposite of this study's finding with blood pressure control. These results suggest that total brain volume cannot be used as a surrogate marker for cognitive outcomes, the researchers said. They also noted that cognitive decline is a slow process and that longer-term data (currently being gathered in an extension of this study) could reveal more subtle differences between the groups. Overall, though, the results "make clear the decreasing returns of intensive medication-based therapy for advanced [type 2 diabetes]," the authors concluded.

According to an invited commentary, the study provides reason for exploring other treatments for preventing the cognitive decline associated with diabetes and a reminder that "enthusiastic control of [blood pressure] later in life should be pursued with caution and based on existing evidence, not extrapolated benefits."



From ACP Journal Club


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Review: Bariatric surgery increases weight loss and diabetes remission more than nonsurgical treatment

A meta-analysis of 11 randomized, controlled trials (including more than 700 patients, some with and some without diabetes, all with a body mass index of 30 kg/m2 or higher) found that bariatric surgery improved weight loss, remission from diabetes, remission from metabolic syndrome, high-density lipoprotein cholesterol levels, waist circumference and HbA1c more than nonsurgical treatment. The groups did not differ in low-density lipoprotein cholesterol levels or blood pressure.

The study was published by BMJ on Oct. 22, 2013. The following commentary by Lawrence J. Cheskin, MD, FACP, and Scott Kahan, MD, MPH, was published in the ACP Journal Club section of the Jan. 21 Annals of Internal Medicine.

While both bariatric surgery and nonsurgical interventions can lead to sustained weight loss, controlled comparisons between the approaches are rare. The review of randomized, controlled trials (RCTs) by Gloy and colleagues provides the highest-quality evidence to date for the relative effectiveness of bariatric surgery. Still, concerns about the relative efficacy, sustainability, and risks of these 2 forms of treatment are warranted.

Bariatric surgery is an intensive intervention, yet no study has included a truly intensive nonsurgical comparison group. Appetite-suppressing drugs (ASD) were not used as part of nonsurgical treatment in any of the included RCTs. Among the newer ASDs, both phentermine/topiramate ER and lorcaserin have shown efficacy for up to 2 years. Evaluating a nonsurgical approach without strategic inclusion of ASDs is like evaluating management of hypertension without using antihypertensive drugs.

Data for long-term outcomes (≥ 5 years) for both surgical and nonsurgical treatments are limited. Even after surgery, slow regain of weight is common, and some patients regain all lost weight. Risks and costs are clearly greater with surgery than with nonsurgical treatment, although neither is risk- or cost-free. Similar to the long-term Look AHEAD trial of nonsurgical weight loss, the meta-analysis by Gloy and colleagues did not show reductions in cardiovascular events or mortality after bariatric surgery.

The approach to seriously obese patients at our specialized center remains first to rule out medical triggers of weight gain and to address such situational triggers as changes in diet, physical activity, and life-altering events. The next step is team-based (dietitian, behavioral psychologist, exercise expert, and physician) treatment combined with low-calorie diets, exercise, and behavior modification. ASDs and bariatric surgery are potential options thereafter.

As with many conditions we encounter, surgery is an option but not necessarily the first approach. Pitting surgery against medical management creates a false dichotomy: Appropriate surgical intervention requires ongoing medical management and support; responsible medical management considers bariatric surgery. Further studies should evaluate how these complementary treatments are best used, integrated, and paid for; financial coverage of obesity treatments is perhaps the greatest limitation to their best use.


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Safety of dipeptidyl peptidase-4 inhibitors analyzed in 2 studies

First, in a meta-analysis by Monami and colleagues, 129 trials of dipeptidyl peptidase-4 inhibitors (DPP4is) showed no difference in serious adverse events related to pancreatitis, pancreatic cancer or the treatments in general between active and control groups. Reviewers concluded that DPP4is do not increase risk of pancreatitis in patients with type 2 diabetes. The study was published online first July 28, 2013, and in the January 2014 Diabetes, Obesity and Metabolism, then reviewed in the ACP Journal Club section of the Jan. 21 Annals of Internal Medicine.

Second, the SAVOR-TIMI trial randomized more than 16,000 patients with type 2 diabetes and either cardiovascular disease or at least 1 vascular risk factor to either saxagliptin or placebo. There was no significant difference between groups in overall cardiovascular events, but saxagliptin was associated with more heart failure hospitalizations and hypoglycemic events. The study was published Oct. 3, 2013, in the New England Journal of Medicine, then reviewed in the ACP Journal Club section of the Jan. 21 Annals of Internal Medicine.

The following ACP Journal Club commentary by Oscar L. Morey-Vargas, MD, and Victor M. Montori, MD, MSc, addressed both studies.

DPP4is modestly reduce HbA1c levels without causing weight gain, but their safety is questionable.

In contrast with the signal from observational studies, neither Monami and colleagues' review nor the SAVOR-TIMI 53 trial found an increased risk for pancreatitis associated with DPP4is. Biased documentation of cases and residual confounding in the observational studies, and careful selection of participants into the trials and potential for incomplete or biased reporting of their results, may explain these differences. Therefore, these studies cannot fully settle the issue. In addition, low event rates and short trial duration in both the review and SAVOR-TIMI 53 trial preclude adequate assessment of the risk for pancreatic cancer. These uncertainties complicate the decision to use DPP4is. Patients and clinicians need to consider the benefits that these agents provide (i.e., modest antihyperglycemic effects) and the availability of alternatives. It seems wise to avoid DPP4is in patients with risk factors for (e.g., alcohol abuse, gallbladder stones) or a history of acute pancreatitis.

SAVOR-TIMI 53 was designed to estimate the extent to which DPP4is, specifically saxagliptin, affect the risk for cardiovascular (CV) events. CV disease is a leading cause of death and morbidity in patients with diabetes, yet the effect of glycemic control or antihyperglycemic agents on the risk for CV complications remains uncertain. It is, therefore, important to evaluate the effect of glucose-lowering medications on patient-important CV outcomes (i.e., CV mortality and serious CV events) and not just surrogate endpoints. Since 2008, the US Food and Drug Administration has required that all new therapies for type 2 diabetes be prospectively evaluated for CV safety before approval. Although widely believed to be a step forward in improving our ability to determine risks and benefits of alternative antihyperglycemic agents, this edict does not require interventions to reduce the risk for diabetes complications, but just to avoid increasing it. SAVOR-TIMI 53 did not find a difference between saxagliptin and placebo for ischemic events. This is disappointing because a previous meta-analysis suggested cardiac benefit with DPP4is. In addition, the unexpected increases in hypoglycemic events and heart failure hospitalizations with saxagliptin in SAVOR-TIMI 53 raise new safety concerns that need investigation. For most patients, these findings suggest delaying the use of DPP4is in favor of other drugs with greater glycemic effect and a longer track record of use.



FDA update


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Saxagliptin under analysis for heart failure risk

The FDA has requested clinical trial data on saxagliptin (Onglyza and Kombiglyze XR) to investigate a possible increase in heart failure in patients taking the drug.

The FDA request was motivated by a manufacturer-sponsored trial of the drug (analyzed by ACP Journal Club) reporting an increased rate of hospitalization for heart failure compared to patients taking a placebo.

The manufacturer is expected to submit the data to the FDA by early March 2014, after which the agency will conduct a thorough analysis and report the findings publicly. The analysis is part of a broader evaluation of all type 2 diabetes drug therapies and cardiovascular risk, and clinicians should continue to follow the prescribing recommendations in the drug labels, the agency advised in a drug safety communication.


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Test strips recalled

Twenty lots of Abbott's FreeStyle and FreeStyle Lite blood glucose test strips were recalled because they may produce erroneously low blood glucose results when used with the FreeStyle or FreeStyle Flash blood glucose meters (manufactured in 2010 or before) as well as the OmniPod insulin management system.



Keeping tabs


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Spotlight on new diabetes technologies

Technological advances that could improve diabetes control in the future made the news in the past month.

Researchers in Chicago conducted a trial using text messaging to improve diabetic patients' self-care. During the 6-month trial, 74 patients received multiple diabetes-related messages per day, including educational messages, prompts to test blood sugar, and questions about their self-care practices. When patients' texted responses indicated a problem, a nurse followed up with a phone call. According to results published in the February Health Affairs, the majority of participants expressed satisfaction with the program, measures of self-care and glucose control improved (average HbA1c dropped 0.7%), and overall health care costs were reduced. The study authors concluded that a business case for the technology had been proven but that the fee-for-service payment system, lack of electronic interoperability, and regulations still posed obstacles to wider implementation.

Google announced on Jan. 16 that it is working to build a smart contact lens that would measure glucose levels in tears, using a tiny wireless chip and miniaturized glucose sensor. In a blog post, the company said it is testing prototypes that can generate a glucose reading once per second. The lens's measurements could potentially warn the wearer of high or low blood glucose with tiny LED lights. Multiple clinical research studies have already been conducted on prototypes, the company said.

Finally, on Feb. 4, the National Institutes of Health announced the launch of partnership with biopharmaceutical companies and nonprofit organizations to develop new diagnostics and drugs for several diseases, including type 2 diabetes. The goals for diabetes include building a knowledge portal that would have DNA sequence, functional genomic and epigenomic information, as well as clinical data on type 2 diabetes and its heart and kidney complications. The portal will include existing data and new data from studies involving 100,000 to 150,000 patients. The partnership will focus on DNA regions that might be critical for the development or progression of type 2 diabetes and search for natural variations in diabetic populations that might allow for targeted drug development, according to a press release.


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MKSAP Answer and Critique



The correct answer is C. Inadequate insulin replacement. This item is available to MKSAP 16 subscribers as item 76 in the Endocrinology section. Information about MKSAP 16 is available online.

This patient's significantly increased blood glucose level after running most likely results from baseline hypoinsulinemia exacerbated by the physiologic changes associated with prolonged exercise, such as stimulation of hepatic glucose release. A patient who has had type 1 diabetes mellitus for more than 20 years, including one episode of diabetic ketoacidosis, will be completely insulin deficient. Although long-acting, the treatment effect of insulin detemir does not always last a full 24 hours. The fact that his blood glucose level was 215 mg/dL (11.9 mmol/L) at bedtime the night before his run and was even higher the next morning before exercise suggests that he had low levels of insulin present in his system during the night and before starting his run. This hypoinsulinemia most likely triggered increased hepatic gluconeogenesis. In the absence of sufficient plasma insulin, the glucose could not be absorbed by the muscles and other tissues, and his blood glucose level continued to increase. Appropriate treatment is to adjust his insulin regimen to ensure adequate insulin replacement before running to minimize the expected physiologic changes associated with exercise.

Excess carbohydrate intake in the evening would likely contribute to his noted elevated bedtime and pre-exercise blood glucose levels but would not independently account for the significant rise in his blood glucose level after exercise.

Although this patient may have some degree of gastroparesis given the duration of his diabetes, this disorder is an unlikely explanation for an increased blood glucose level 12 hours or more since he last ate.

Early morning blood glucose elevations may occur in response to the nocturnal hypoglycemia associated with diabetes therapy. Although this patient had an elevated morning blood glucose level before running, his bedtime measurement also was elevated, and he took no additional insulin beyond his single dose of long-acting insulin the morning before. Therefore, nocturnal hypoglycemia is unlikely to be the cause of this patient's exercise-associated hypoglycemia.

Key Point

  • Hypoinsulinemia causes increased hepatic glucose output and decreased peripheral glucose uptake, which results in a higher blood glucose level and, ultimately, a higher HbA1c value; prolonged exercise, which further stimulates hepatic glucose release, exacerbates this condition.

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Test yourself

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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