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

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ACP DiabetesMonthly



In the News for the month of August 2012




Highlights

Adults at normal weight when diagnosed with diabetes have higher mortality

Participants who had a normal body mass index when initially diagnosed with diabetes had higher mortality rates compared with those who were overweight or obese, a study found. More...

Linagliptin appears safe, effective for long-term use, study indicates

Long-term use of linagliptin appears to be safe and effective, according to a study funded by the drug's manufacturer. More...

Hyperfiltration may affect renal function, nephropathy in type 2 diabetes

Hyperfiltration may lead to renal function loss and onset or progression of nephropathy in some patients with type 2 diabetes, a new study has found. More...


Test yourself

MKSAP Quiz: Poorly controlled type 2 diabetes

This month's quiz asks readers to evaluate a 72-year-old man during an office visit for type 2 diabetes. More...


From ACP InternistWeekly

No reason for higher HbA1c threshold to diagnose diabetes in blacks

Retinopathy occurs at lower hemoglobin A1c (HbA1c) levels in blacks than in whites, so there is no reason to recommend a higher HbA1c threshold for diagnosing diabetes in blacks, a study concluded. More...


From ACP Journal Club

Gastric bypass or biliopancreatic diversion increases remission from type 2 diabetes in obese adults

A randomized controlled trial (RCT) of 60 severely obese adults with type 2 diabetes found that gastric bypass or biliopancreatic diversion increased diabetes remission more than medical therapy. More...

DPP-4 inhibitors are less effective than metformin for reducing hemoglobin A1c

A meta-analysis of randomized controlled trials comparing dipeptidyl peptidase-4 (DPP-4) inhibitors to metformin and other drugs found that DPP-4 monotherapy is less effective. More...


Tool of the month

What to say to patients with pre-diabetes

This month's tool offers tips on talking to patients about pre-diabetes. More...


Keeping tabs

Spotlight on risk factors for developing diabetes

Several factors that increase or decrease one's risk of developing diabetes were identified by research released this month. More...


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



Highlights


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Adults at normal weight when diagnosed with diabetes have higher mortality

Participants who had a normal body mass index when initially diagnosed with diabetes had higher mortality rates compared with those who were overweight or obese, a study found.

The study consisted of a pooled analysis of five longitudinal studies involving 2,625 participants with new diabetes who totaled 27,125 person-years of follow-up. Participants (all age 40 or over) were classified as normal weight if their body mass index was 18.5 to 24.99 kg/m2 or overweight/obese if it was 25 kg/m2 or greater. Results appeared in the Aug. 8 Journal of the American Medical Association.

The proportion of adults who were normal weight at the time of diabetes diagnosis ranged from 9% to 21% among the studies (overall average 12%). During follow-up, 449 participants died, 178 from cardiovascular causes and 253 from noncardiovascular causes. The other 18 deaths were not classified.

The rates of total, cardiovascular, and noncardiovascular mortality were higher in normal-weight participants (284.8, 99.8, and 198.1 per 10,000 person-years, respectively) than in overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively).

After adjustment for demographic characteristics and blood pressure, lipid levels, waist circumference, and smoking status, hazard ratios for normal-weight participants for total, cardiovascular, and noncardiovascular mortality were 2.08 (95% CI, 1.52 to 2.85), 1.52 (95% CI, 0.89 to 2.58), and 2.32 (95% CI, 1.55 to 3.48), respectively, compared to overweight/obese participants.

The researchers wrote that "previous research suggests that normal-weight persons with diabetes have a different genetic profile than overweight or obese persons with diabetes. If those same genetic variants that predispose to diabetes are associated with other illnesses, these individuals may be 'genetically loaded' toward experiencing higher mortality."

An editorial commented that medical societies are currently revising their prevention guidelines to reflect the impact of weight loss on diabetes, which may not help those with metabolically obese normal weight (MONW). "This could be a wake-up call for timely prevention and management to reduce adverse outcomes in all patients with type 2 diabetes, particularly in those MONW at diagnosis, who may have a false sense of protection because they are not overweight or obese," wrote the editorialist. The editorial concluded by advocating for investigating the benefits of increasing physical activity and fitness to improve the prognosis of diabetics.


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Linagliptin appears safe, effective for long-term use, study indicates

Long-term use of linagliptin appears to be safe and effective, according to a study funded by the drug's manufacturer.

Researchers performed a 78-week open-label extension study plus one week of follow-up in patients with type 2 diabetes who had participated in one of four 24-week randomized, double-blind, placebo-controlled parent trials. Patients were drawn from 231 sites in 32 countries. Regimens studied in the parent trials included once-daily oral linagliptin alone or in combination with metformin, metformin plus a sulfonylurea, or pioglitazone. The 1,532 patients who received one of these regimens during a parent trial continued to receive it for up to 102 weeks, while the 589 patients who had received placebo during the parent trials were switched to linagliptin.

The goal of the study was to examine the safety, efficacy and tolerability of linagliptin alone or in combination with other oral glucose-lowering agents over the long term. The safety and tolerability outcomes included incidence and intensity of adverse events, withdrawal because of adverse events, and physical exam and other test results, as well as hypoglycemic events. Secondary efficacy outcomes included change in hemoglobin A1c (HbA1c), HbA1c below 7.0% at week 78, and an HbA1c reduction of at least 0.5% by week 78. Change over time in fasting plasma glucose, body weight and use of rescue therapy were also assessed. The study, which was funded by Boehringer Ingelheim, appeared in the August International Journal of Clinical Practice.

The study cohort had a mean age of 57.5 years; approximately three-quarters were younger than age 65, and slightly more than half were men. Patients who had been assigned to an active treatment group in their parent study retained their previously achieved reductions in HbA1c during the 78-week extension, with a change of −0.8% from baseline to week 102. Eighty-one percent of patients reported at least one adverse event during the 78-week extension, with the highest incidence in the metformin plus sulfonylurea group. Drug-related adverse events occurred in 14.3% of patients, and 13.9% of patients developed hypoglycemia (13.6% of those who had previously received active treatment and 14.6% of those who had switched to linagliptin from placebo). Body weight showed no clinically relevant changes over the study period.

The authors acknowledged that the open-label nature of the 78-week extension period and lack of blinded comparison limit interpretation of their safety data. However, they concluded that linagliptin provided sustained, long-term glycemic control, either alone or combined with other oral therapy for type 2 diabetes, without notable changes in its safety profile.


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Hyperfiltration may affect renal function, nephropathy in type 2 diabetes

Hyperfiltration may lead to renal function loss and onset or progression of nephropathy in some patients with type 2 diabetes, a new study has found.

European researchers performed a longitudinal cohort study to examine hyperfiltration (defined as a glomerular filtration rate [GFR] ≥120 mL/min/1.73 m2) and its relation to GFR decreases and nephropathy in patients with type 2 diabetes and normo- or microalbuminuria. Six hundred patients from two randomized trials examining the effect of angiotensin-converting enzyme inhibitors on nephropathy in hypertensive patients with type 2 diabetes and normo- or microalbuminuria (albuminuria <200 µg/min) were included. Predefined study end points were rate of GFR decline over time and time to persistent micro- or macroalbuminuria (≥20 µg/min and <200 µg/min or ≥200 µg/min, respectively). The study results were published online July 6 by Diabetes Care.

Patients were followed for a median of 4.0 years (range, 1.7 to 8.1 years). Ninety study patients (15%) had hyperfiltration at baseline. Of the 47 with persistent hyperfiltration, 11 (23.4%) developed micro- or macroalbuminuria compared with 53 of 502 patients (10.6%) who had ameliorated hyperfiltration (defined as a GFR reduction of 10%) at six months or who never developed hyperfiltration (hazard ratio, 2.16; 95% CI, 1.13 to 4.14). Over the study period, GFR decreased by 3.37 mL/min/1.73 m2 per year. Change in GFR from baseline to six months was the best predictor of subsequent slope; a large change during this period indicated a higher likelihood of a slower slope later. Patients with persistent hyperfiltration tended to have faster GFR decline than those with ameliorated hyperfiltration or those who never developed hyperfiltration (4.19 vs. 3.23 mL/min/1.73 m2; P=0.09). Hyperfiltration amelioration did not appear to be related to baseline characteristics or angiotensin-converting enzyme inhibitor treatment but was significantly associated with improved blood pressure and improved metabolic control, amelioration of glucose disposal rate and slower long-term decline of GFR during follow-up.

The authors acknowledged that the post hoc observational nature of the study limited their findings and that their results are hypothesis-generating. However, they concluded that persistent hyperfiltration may be an independent risk factor for faster renal loss and nephropathy in patients with type 2 diabetes and hypertension who have normo- or microalbuminuria, and that ameliorating hyperfiltration may be renoprotective in such patients. "Prospective ad hoc studies are needed to unravel the mechanisms underlying persistent hyperfiltration despite optimized metabolic and [blood pressure] control and to assess whether and to what extent glomerular hyperfiltration can be a specific treatment target for novel interventions aimed to limit renal function loss in this population," they wrote.



Test yourself


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MKSAP Quiz: Poorly controlled type 2 diabetes

A 72-year-old man comes to the office for a follow-up evaluation. He has had type 2 diabetes mellitus for 13 years. Over the past 5 years, his hemoglobin A1c value has slowly risen to 9.8%, and his fasting blood glucose levels at home have frequently exceeded 180 mg/dL (10.0 mmol/L). He has been adherent to recommended lifestyle changes. The patient is currently on metformin, 1,000 mg twice daily, and extended-release glipizide, 20 mg/d. He has hypertension treated with candesartan and hydrochlorothiazide and hyperlipidemia treated with atorvastatin.

mksap.jpg

Results of physical examination are normal.

Which of the following is the best next step in therapy?

A) Add exenatide
B) Add insulin glargine
C) Add pioglitazone
D) Add sitagliptin
E) Double his dosage of glipizide

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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No reason for higher HbA1c threshold to diagnose diabetes in blacks

Retinopathy occurs at lower hemoglobin A1c (HbA1c) levels in blacks than in whites, so there is no reason to recommend a higher HbA1c threshold for diagnosing diabetes in blacks, a study concluded.

Recent studies have indicated that at the same blood glucose levels, black patients have higher HbA1c levels than white patients. This distinction has led some experts to propose setting a higher HbA1c threshold for diagnosing diabetes in black patients

To compare the relationships between HbA1c level and the prevalence of retinopathy in non-Hispanic black and white adults, researchers conducted a cross-sectional study from data in the National Health and Nutrition Examination Survey (NHANES) from 2005 through 2008. The study included 2,804 whites and 1,008 blacks age 40 years or older who were examined for the prevalence of retinopathy. Results appeared in the Aug. 7 Annals of Internal Medicine.

annals.jpg

The weighted crude prevalence (±SE) of retinopathy was 6.3% ± 0.5% for whites and 13.1% ± 1.1% for blacks. In whites, the adjusted prevalence of retinopathy was significantly higher beginning at HbA1c levels of 6%-6.4%, compared with HbA1c levels less than 5.5% (the reference category).

Among black adults, those with HbA1c levels of 5.5% to 5.9% had significantly higher risk for prevalent retinopathy than those with HbA1c levels less than 5.5%, according to the study. The adjusted risk difference for retinopathy for blacks with HbA1c levels of 5.5% to 5.9% was similar to that of whites with HbA1c levels of 6% to 6.4%.

Researchers noted that if the diagnostic threshold of HbA1c were lowered from the current adopted level of 6.5% to 6%, an estimated additional 1.8 million black and 7.6 million white U.S. adults aged 40 years or older would be diagnosed with diabetes, of whom 0.2 million blacks and 0.8 million whites would be anticipated to have diabetic retinopathy at the time of examination. For both blacks and whites, this translates to diagnosing nine additional cases of diabetes to detect one additional case of prevalent diabetic retinopathy.

If the diagnostic threshold for diabetes were lowered from 6.5% to 5.5%, an additional 5.7 million blacks and 39.0 million whites would be diagnosed with diabetes, among which there would be 0.5 million cases of retinopathy among blacks and 2.2 million cases among whites. This new diagnostic threshold would result in diagnosing 11 additional cases of diabetes among blacks and 18 additional cases among whites to detect one additional case of diabetic retinopathy.

The authors wrote, "The results of our study suggest that the risk for diabetic retinopathy is higher for blacks at any given HbA1c level between 5.0% and 7.0%...Therefore, our findings argue against increasing the HbA1c diagnostic threshold for blacks."



From ACP Journal Club


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Gastric bypass or biliopancreatic diversion increases remission from type 2 diabetes in obese adults

A randomized controlled trial (RCT) of 60 severely obese adults with type 2 diabetes found that gastric bypass or biliopancreatic diversion increased diabetes remission more than medical therapy.

The study was published in New England Journal of Medicine on April 26. The following commentary by Suma Pokala, MD, FACP, was published in the ACP Journal Club section of the July 17 Annals of Internal Medicine.

Bariatric surgery has been in vogue for > 15 years and has been shown to decrease BMI and improve glycemic control or even resolve type 2 diabetes.

In the RCT by Mingrone and colleagues, diabetes remission and glycemic control were more common in the surgical groups than in the medical therapy group. Preoperative body mass index and weight loss did not predict improvement in hyperglycemia. Trial results, however, were too imprecise to rule out differences in weight loss, metabolic parameters, or diabetes remission between biliopancreatic diversion and gastric bypass at 2 years.

Mingrone and colleagues measured surrogate markers for clinical outcomes. Two years seems sufficient to detect effects on glycemic control and diabetes remission. Given the progressive nature of type 2 diabetes, longer follow-up could help characterize with greater precision the extent to which these benefits are sustained over time. Further ascertainment of the nature and frequency of surgical complications associated with different procedures, surgical experience and volume levels, and patient characteristics would be helpful in decision making. Longer, larger multicenter studies measuring such patient-important outcomes as mortality, morbidity, end-organ damage, functional capacity, and quality of life are needed. The findings of Mingrone and colleagues add to the body of evidence favoring bariatric surgery but, alone, should not result in a rush to do more surgeries.


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DPP-4 inhibitors are less effective than metformin for reducing hemoglobin A1c

A meta-analysis of randomized controlled trials comparing dipeptidyl peptidase-4 (DPP-4) inhibitors to metformin and other drugs found that DPP-4 monotherapy is less effective than metformin monotherapy for reducing hemoglobin A1c (HbA1c) levels, and that DPP-4 inhibitors plus metformin are less effective than metformin plus a sulfonylurea or a GLP-1 agonist.

The study was published in BMJ on March 12. The following commentary by Saurav Chatterjee, MD, was published in the ACP Journal Club section of the July 17 Annals of Internal Medicine.

Karagiannis and colleagues evaluated the safety and efficacy of DPP-4 inhibitors by assessing HbA1c levels, changes in body weight, and adverse events, most notably hypoglycemia.

The findings support the validity of guidelines that relegate use of DPP-4 inhibitors to patients at high risk for hypoglycemia or who are intolerant to other medications. The safety results were diluted by inconsistent definitions of hypoglycemia in the included trials. There was significant heterogeneity in the results, and only 3 trials had a low risk for bias for the primary outcome. Generalizability of the pooled outcomes therefore remains inconclusive.

Karagiannis and colleagues did not evaluate such hard clinical endpoints as cardiovascular events. Previous meta-analyses have not identified increased risks for cardiovascular outcomes with use of DPP-4 inhibitors, and a large-scale trial is under way to assess the effect of DPP-4 inhibitors on cardiovascular events.



Tool of the month


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What to say to patients with pre-diabetes

Patients who have a high risk of developing diabetes should be educated about the effectiveness of regular physical activity and modest weight loss in slowing the progression to diabetes. Here are some educational issues to discuss with patients diagnosed with pre-diabetes:

  • Never tell patients that they have "a little bit of diabetes" or "borderline diabetes." Patients need to know that they have pre-diabetes, which already has an increased risk of mortality, but that they can do specific things to prevent progression to diabetes.
  • Discuss the importance of smoking cessation as a strategy for helping to prevent cardiovascular complications.
  • Stress that incremental changes are more long-lasting and effective than sudden, drastic changes in eating and exercise behaviors.
  • Ask patients to choose a behavioral goal at the end of your discussion; for example: "Will you do anything between now and our next visit to help lower your risk for diabetes?"
  • Refer for education and/or medical nutrition therapy. Some, but not all, insurance plans and managed care organizations offer reimbursement for education and medical nutrition counseling for the prevention of diabetes. Preparing by first clarifying reimbursement with the diabetes educator or common insurance plans in your area will facilitate referral.

From the ACP Diabetes Care Guide.



Keeping tabs


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Spotlight on risk factors for developing diabetes

Several factors that increase or decrease one's risk of developing diabetes were identified by research released this month.

Higher consumption of cheese or other fermented dairy products (such as yogurt) was associated with lower risk of developing diabetes, according to a large prospective study of Europeans, published in the American Journal of Clinical Nutrition. Another study, from Diabetes Care, found that taking capsules of curcumin (an ingredient in turmeric) decreased progression from pre-diabetes to diabetes compared to placebo.

In other food-related research, an analysis of the Women's Health Initiative found that women who were a healthy weight and highly active had less than one-third the diabetes risk of obese and inactive women. The study, published in Diabetes Care, also noted that much of the racial and ethnic differences in diabetes incidence could be attributed to these lifestyle factors. Confirming the importance of physical activity, an analysis of the Health Professionals Follow-up Study, published in Archives of Internal Medicine, found that weight training or aerobic exercise (or better yet, both) reduced men's risk of developing diabetes.

Two studies of women identified other factors potentially associated with diabetes development. A case-control analysis of the Nurses' Health Study, published in the Canadian Medical Association Journal, revealed that women with higher plasma bicarbonate levels were less likely to develop diabetes. Higher urinary phthalate concentrations, on the other hand, were associated with increased risk of diabetes, according to NHANES data published in Environmental Health Perspectives.


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MKSAP Answer and Critique



The correct answer is B) Add insulin glargine. This item is available to MKSAP 15 subscribers as item 8 in the Endocrinology section. Part A of MKSAP 16 was released on July 31. Part B, including the Endocrinology section, will be released at the end of the year. More information is available online.

Insulin glargine should be added to this patient's regimen. Type 2 diabetes mellitus is associated with progressive beta cell dysfunction, resulting in deterioration of endogenous insulin secretory capacity over time. This leads to secondary failure rates of previously successful oral pharmacologic therapy and, ultimately, the need for insulin therapy in most patients with diabetes.

This patient has poor glycemic control, despite combination therapy with metformin and extended-release glipizide (a sulfonylurea), and thus requires insulin. The standard method of initiating insulin therapy is to begin with a single daily injection of a basal insulin, such as insulin glargine, insulin detemir, or neutral protamine Hagedorn (NPH) insulin; this approach minimizes the risk of hypoglycemia. Starting doses in the 0.2 to 0.3 U/kg range will be well tolerated in most patients, with future titration based on the results of home glucose monitoring. Dose changes are typically made in increments of 2 to 4 units every few days or weekly until the fasting glucose level is consistently in the range of 70 to 130 mg/dL (3.9 to 7.2 mmol/L). The addition of insulin glargine or insulin detemir to this patient's regimen should result in a substantial reduction in his hemoglobin A1c value. Randomized studies of stepped therapy in type 2 diabetes showed that most patients were able to achieve target hemoglobin A1c goals of 7% using a combination of oral antihyperglycemic agents and basal insulin therapy. If such a reduction is not achieved and postprandial hyperglycemia occurs, the addition of a mealtime rapid-acting insulin analogue or the substitution of a premixed insulin should be recommended.

Adding the injectable agent exenatide or another oral agent to this patient's medication regimen is unlikely to reduce his hemoglobin A1c value sufficiently. When added to a combination oral regimen, exenatide has been shown to reduce hemoglobin A1c values by only 1% and the oral agents pioglitazone and sitagliptin by 1% or less.

In most studies of patients with diabetes, increasing the sulfonylurea dosage beyond the half maximal dosage has resulted in little to no improvement in glycemic control. Therefore, doubling this patient's dosage of glipizide is unlikely to be effective.

Key Point

  • In patients who have persistent fasting hyperglycemia despite combination oral agents, the addition of insulin, typically a basal formulation, will improve glycemic control.

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Test yourself

A 19-year-old man is evaluated for a sore throat, daily fever, frontal headache, myalgia, and arthralgia of 5 days' duration. He also has severe discomfort in the lower spine and a rash on his trunk and extremities. He returned from a 7-day trip to the Caribbean 8 days ago. The remainder of the history is noncontributory. Following a physical exam and lab studies, what is the most likely diagnosis?

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