By Devyani Kothari, MD
Faculty Peer Reviewed
In news this week, Obama’s healthcare reform is under scrutiny by the Supreme Court, the NCAA’s March Madness comes to a close with the championship game tonight, and Mitt Romey and Rick Santorum are still battling it out in the GOP primaries.
In Primecuts this week, I will present new research on two prevalent and chronic health conditions: type II diabetes mellitus and hypercholesterolemia.
In the first paper, published in The New England Journal of Medicine, entitled “Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes,” Schauer et al. present the results of a randomized, nonblinded, single-center trial (at the Cleveland Clinic) evaluating the efficacy of intensive medical therapy alone versus medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy in 150 obese patients (BMI 27 to 43) with uncontrolled type 2 diabetes (a total of three groups.
The primary end point was the proportion of patients with a glycated hemoglobin level of 6.0% or less twelve months after treatment. The proportion of patients with the primary end point was 12% in the medical-therapy group versus 42% in the gastric bypass group (P=0.002) and 37% in the sleeve-gastrectomy group (P=0.008). There were no significant differences in the primary end point between the two surgical groups (P=0.59). Secondary end points included levels of fasting plasma glucose, fasting insulin, lipids and high-sensitivity C-reactive protein; the homeostasis model assessment of insulin resistance (HOMA-IR) index; weight loss; blood pressure; adverse events; coexisting illnesses; and changes in medications. Of note, weight loss was greater in the gastric-bypass group and sleeve-gastrectomy group than in the medical-therapy group. The use of drugs to lower glucose, lipid, and blood-pressure levels decreased significantly after both surgical procedures but increased in patients receiving medical therapy only. The HOMA-IR index improved significantly after bariatric surgery. In terms of adverse events, four patients underwent reoperation but there were no deaths or life-threatening complications. The main limitation of this study was the short duration of follow-up—how long will the glycemic control last? The question remains to be answered.
How will the results of this paper affect the current management of patients with type II diabetes? First, if your patient is obese (BMI greater than 30), you may want to raise the possibility of bariatric surgery as a treatment option. Second, the study population in this paper had relatively advanced disease, including many patients with major diabetes-related coexisting illnesses or evidence of end-organ damage. In this patient population, significant improvement in type II diabetes can occur after bariatric surgery versus modest improvement with medical therapy alone. Therefore, if your patient is obese AND has advanced disease, bariatric surgery may be a good treatment option. It is also important to keep in mind that obesity is a risk factor for many diseases, not just type II diabetes, so it is crucial to emphasize weight loss with your patient, whether that is achieved with diet and exercise or bariatric surgery.
In the second paper, entitled “Bariatric Surgery versus Conventional Medical Therapy for Type 2 Diabetes,” also published in The New England Journal of Medicine, Mingrone et al. present the results of a single-center (Catholic University of Rome, Italy), nonblinded, randomized controlled trial of 60 patients with a BMI of 35 or more who were assigned to receive conventional medical therapy or undergo either gastric bypass or biliopancreatic diversion (a type of bariatric surgery not done in the previous paper). The two surgical groups discontinued pharmacologic treatment (oral hypoglycemic agents and insulin) within 15 days after the operation (a difference from the previous study).
The primary end point in this study was the rate of diabetes remission at 2 years (versus 1 year in the previous paper) defined as a fasting glucose level of <100 mg per deciliter and a glycated hemoglobin level of <6.5% (versus 6 % in the previous paper) in the absence of pharmacologic therapy. At 2 years, diabetes remission had occurred in no patients in the medical-therapy group versus 75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group (P<0.001 for both comparisons). Secondary endpoints were changes in baseline in levels of fasting plasma glucose and glycated hemoglobin, the average glycated hemoglobin level, body weight, waist circumference, arterial blood pressure, and levels of plasma cholesterol, HDL cholesterol, and triglycerides at 2 years. Of note, there were no operative deaths but two patients underwent reoperation, one in the biliopancreatic diversion group and one in the gastric bypass group. Also, there seems to be no correlation between the degree of postoperative weight loss and glycemic control, a finding that is consistent with previous studies. The surgeries may exert effects on diabetes that are independent of weight loss. The main limitation of this study was the small sample size and again length of follow-up (although 2 years instead of 1 in the previous study); it still does not address the question of long-term outcomes.
This paper affects management of type II diabetes in a similar fashion to the previous study. One difference includes the type of bariatric surgery performed: biliopancreatic diversion leads to substantial malabsorption of fat and consequently greater weight loss (versus gastric bypass) and higher percentage of diabetes remission. However, biliopancreatic diversion can lead to more nutritional complications, such as hypoalbumenia and deficiencies in vitamin D and calcium.
The third study relating to type II diabetes, published in the British Medical Journal is entitled “White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review” by Hu et al. This is a meta-analysis of prospective cohort studies to summarize evidence on the association between white rice consumption and risk of type 2 diabetes as well as to quantify the potential dose-response relationship.
From the literature search, the group identified 4 articles that included 7 distinct cohort analyses in Asian (Chinese and Japanese) and Western populations (the United States and Australia). Two studies were done in Asian populations and the other two studies in Western populations. A total of 13,284 incident cases of type II diabetes were included among 352,384 participants with follow-up periods ranging from 4 to 22 years. Asians had much higher white rice consumption levels than did Western populations (average intake levels were three to four servings/day versus one to two servings/week). One serving was defined as 158 g of cooked rice. The pooled relative risk (RR) was 1.55 (95% confidence interval 1.20 to 2.01) comparing the highest with the lowest category of white rice intake in Asians, whereas the corresponding RR was 1.12 (0.94-to 1.33) in Western populations (P=0.038). In the total population, the dose-response meta-analysis indicated that for each serving per day increment of white rice intake, the RR of type II diabetes was 1.11 (1.08 to 1.14) (P<0.001). In other words, each serving per day of white rice consumption was associated with an 11% increase in risk of diabetes in the overall population. Therefore, the authors concluded that higher consumption of white rice is associated with a significantly increased risk of type 2 diabetes, especially in Asian (Chinese and Japanese) populations. The weaknesses of this meta-analysis include the limited number of studies (4), confounding biases (because the individual studies were observational) and biases resulting from self-reporting (all studies used food frequency questionnaires). The strengths include the large sample size and long duration of follow-up in the included studies.
How will this study affect patient management? Patients with type II diabetes must understand and receive proper nutritional counseling on the glycemic index of various foods. For example, although different types of white rice have different glycemic index values, the mean glycemic index value for white rice is 64, brown rice 55, whole wheat 41 and barley 25. It is also important to understand what the patient’s diet actually consists of by asking them to keep a food diary or food log and to take time to sort through ethnic differences. Suggesting substitution of brown rice with white rice is easy, but compliance and cultural norms may get in the way. White rice is the primary contributor to glycemic load for many Asian populations that consume rice as a staple food.
Next, on a related note, let’s turn to new research in the treatment of hypercholesterolemia. In the paper “Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol) published in The New England Journal of Medicine, Stein et al reported three phase 1 studies of a monoclonal antibody to PCSK9 designated as REGN727. REGN727 is a human monoclonal antibody that is highly specific for human PCSK9, a serine protease that is synthesized in the liver and binds to hepatic LDL receptors and targets them for degradation. This process reduces the capacity of the liver to bind and remove LDL cholesterol and results in increased LDL cholesterol levels. REGN727 blocks PCSK9, thus decreasing LDL cholesterol levels.
In healthy volunteers, two randomized, single ascending-dose studies of REGN727 administered either intravenously (40 subjects) or subcutaneously (32 subjects), as compared with placebo, were performed. These studies were followed by a randomized, placebo-controlled, multiple-dose trial in adults with heterozygous familial hypercholesterolemia who were receiving atorvastatin (21 subjects) and those with nonfamilial hypercholesterolemia who were receiving atorvastatin (30 subjects) (baseline LDL cholesterol, >100 mg per deciliter) or a modified diet alone (10 subjects) (baseline LDL cholesterol, >130 mg per deciliter). REGN727 doses of 50, 100, or 150 mg were administered subcutaneously on days 1, 29 and 43. The primary outcome for all studies was the occurrence of adverse events. Two subjects in the single-dose studies had serious adverse events but they did not discontinue participation early. In the multiple-dose study, no subject had a serious adverse event, and all subjects completed all visits. There were a few injection-site reactions which were mild and the most common side-effect was headache. The principal secondary outcome was the effect of REGN727 on the lipid profile. REGN727 significantly lowered LDL cholesterol levels in all the studies. In the multiple-dose study, REGN727 doses of 50, 100, 150 mg reduced LDL cholesterol levels in the combined atorvastatin-treated populations to 77.5 mg, 61.3 mf and 53.8 mg as compared with placebo (P<0.001 for all comparisons). In conclusion, REGN727 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia in three phase 1 studies.
On a side note, REGN727 seemed to work faster than statins (it lowered LDL cholesterol within 2 weeks while statins typically take longer). Furthermore, in these studies, the effects of REGN727 and atorvastatin in lowering LDL cholesterol appeared to be additive, not synergistic, since mean percent reductions were similar when REGN727 was administered alone or in subjects already receiving atorvastatin.Of note, this study was sponsored by the pharmaceutical companies that are developing the new drug (Regeneron Pharmaceuticals and Sanofi).
Although it is exciting to read about a new drug to treat high cholesterol by a different mechanism than the statins, this paper will not affect current medical management, and we will likely be hearing more about REGN727 in the near future.
Dr. Devyani Kothari, is a copy editor for Clinical Correlations
Peer reviewed by Cara Litvin, MD, Editor At Large, Clinical Correlations
Image courtesy of Wikimedia Commons
References:
1. Schauer, P et al. Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes. N Engl J Med 2012. Published on March 26, 2012, at NEJM.org http://www.nejm.org/doi/full/10.1056/NEJMoa1200225
2. Mingrone, G et al. Bariatric Surgery versus Conventional Medical Therapy for Type 2 Diabetes. N Engl J Med 2012. Published on March 26, 2012, at NEJM.org http://www.nejm.org/doi/full/10.1056/NEJMoa1200111
3. Hu et al. White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review. BMJ 2012; 344:e1454. http://www.bmj.com/content/344/bmj.e1454
4. Stein, E et al. Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol. N Engl J Med 2012; 366: 1108-18. http://www.nejm.org/doi/full/10.1056/NEJMoa1105803