Clinical Briefs in Primary Care
Evidence-based updates in primary care medicine By Louis Kuritzky, MD
Supplement to Clinical Cardiology Alert, Clinical Oncology Alert, Critical Care Alert, Hospital Medicine Alert, Infectious Disease Alert, Neurology Alert, OB/GYN Clinical Alert, Primary Care Reports.
Our Newest Pharmacologic Class for Treatment of Diabetes: SGLT2 Inhibitors
Source: Polidori D, et al. Diabetes Care 2013;36:2154-2161.
The role of the kidney in glucose regulation has been underappreciated. Although perhaps counterintuitive, after persistent exposure to elevated glucose levels in the glomerular filtrate presented to the proximal renal tubule, the kidney adapts by reabsorbing increased amounts of glucose, thereby increasing blood sugar. The sodium glucose cotransporter (SGLT2) receptor is the primary pathway for renal tubular glucose reabsorption; blockade of this receptor results in enhanced urinary glucose excretion. Currently, the only FDA-approved agent for blockade of the SGLT2 receptor is canaglifozin.
In addition to potent SGLT2 receptor blockade, it has been suspected that canaglifozin might affect intestinal absorption of glucose by its modest inhibition of intestinal SGLT1. Polidori et al tested the impact of canagliflozin SGLT1 inhibition by examining the rate of gastrointestinal glucose absorption in healthy volunteers following a 600-kcal mixed-meal tolerance test.
Canagliflozin produced a very modest reduction in glucose absorption over a 6-hour interval (about 6%). The effects were accentuated in the early postprandial intervals, indicating a slowed absorption of glucose that was not attributable to delayed gastric emptying. Blunting of early postprandial glucose absorption should have a favorable effect on postprandial glucose excursions in diabetics.
Although enhanced urinary glucose excretion is the primary mechanism of plasma glucose lowering by SGLT2 inhibitors, modest gastrointestinal SGLT1 inhibition also appears to impact postprandial glucose excursion.
Bariatric Surgery vs Intensive Medical Therapy for Diabetes
Source: Kashyap SR, et al. Diabetes Care 2013;36:2175-2182.
The benefits of bariatric surgery (BAS) are increasingly recognized for obese patients with type 2 diabetes mellitus (T2DM). Indeed, the mechanisms by which diversionary surgery (e.g., gastric bypass) produces such prompt and dramatic remission in diabetic patients are still being elucidated. Long-term observational data on BAS for persons with severe obesity (body mass index [BMI] > 40) confirm durable weight reduction, improved control of diabetes, and even suggest reduced mortality.
Few trials have directly compared the efficacy of BAS with intensive medical treatment (IMT). Kashyap et al randomized T2DM subjects (n = 60) with moderate obesity (mean BMI = 36) to one of two BAS interventions (gastric sleeve or gastric bypass) or IMT in the Surgical Therapy And Medications Potentially Eradicate Diabetes (STAMPEDE) trial. Currently reported data include outcomes at 24 months.
In essentially every category assessed, BAS patients had superior outcomes to IMT. No BAS-related deaths occurred. At 2 years, degree of A1c control, LDL, HDL, total cholesterol, triglycerides, and CRP were all more improved in the BAS patients than in the IMT patients.
When comparing outcomes in the two BAS groups, even though weight loss was similar between gastric sleeve and bypass surgery, the latter achieved greater improvements in truncal fat reduction, leptin, insulin sensitivity, beta cell function, and incretin responses. BAS is more effective for multiple metabolic markers than IMT over the long term in T2DM patients.
Psoriasis and Risk for New Onset Diabetes
Source: Khalid U, et al. Diabetes Care 2013;36:2402-2407.
Inflammatory disorders like rheumatoid arthritis (RA) and psoriasis (PSOR) have recently been confirmed to be risk factors for adverse cardiovascular (CV) events, although the precise pathways through which such risk occurs remain controversial. Some have even gone so far as to say that RA should be considered an independent CV risk factor of equal potency to the already registered risk factors like hypertension, history of premature cardiovascular death, etc. Since PSOR and RA share common inflammatory pathways, it’s perhaps not surprising that both are associated with CV adversity.
To date, the relationship between PSOR and diabetes mellitus (DM) has been controversial. Since DM is a major contributor to CV events, if PSOR and DM are related, that would account for some of the increased CV risk.
Khalid et al report on an analysis of the PSOR-DM relationship discerned through a 12-year follow-up of Danish persons ≥ 10 years (n = 4,614,807). They studied the incidence of new-onset DM in PSOR subjects vs controls. A graded linear association between PSOR and new onset DM was found. Compared to the reference population, the incidence of DM in persons with mild PSOR was almost doubled, and in severe PSOR, nearly tripled.
Osteoporosis: Are Two Drugs Better Than One?
Source: Tsai JN, et al. Lancet 2013;382: 50-56.
Most women today who are receiving pharmacotherapy for treatment of osteoporosis receive oral bisphosphonates (e.g., alendronate, risedronate). Other effective treatments, like teriparatide (TERI) and denosumab (DENO) are usually reserved for more severe cases, in some part because they require parenteral administration.
Even though osteoporosis treatments have shown risk reduction for fracture and improved bone mineral density (BMD), restoration of full bone integrity remains a challenge. As one of the few anabolic tools (as opposed to anticatabolic tools like bisphosphonates), some investigators have tried to augment the favorable activity of TERI by combination with bisphosphonates, but the results have been disappointing. Whether the addition of DENO to TERI might be beneficial was the subject of investigation by Tsai et al. Postmenopausal women with osteoporosis (n = 100) were randomized to DENO, TERI, or both for 6 months. The primary outcome of the study was improvement in BMD.
Combination TERI+DENO appeared to be synergistic, with improvements in BMD greater than either agent alone and arithmetically greater than the anticipated benefit of combined monotherapies. For example, BMD increases at the hip were 4.2% for TERI+DENO, 0.8% for TERI, and 2.1% for DENO. These data support the consideration of TERI+DENO in highest-risk patients, those unable to take other treatments, or patients who fail to respond to other regimens.
Long-Term Impact of Weight Management on Blood Pressure
Source: Tyson CC, et al. J Clin Hypertens 2013;15:458-464.
The weight loss maintenance (wlm) trial randomized adults (n = 741) with hypertension (HTN) and/or dyslipidemia — but without evidence of cardiovascular disease — to one of several weight loss management programs. Although the initial outcome reports from WLM addressed the relative efficacies of different weight loss strategies over time, this report stratified study participants into those who lost, maintained, or gained weight over the 5-year study period. Tyson et al compared blood pressure effects between the three categories of weight impact, irrespective of which particular method of weight loss had been applied.
At study end, the weight-stable group had gained 0.6 kg, as compared with a 9.1 kg increase in the weight-gain group, and a 7.1 kg decrease in the weight-loss group. The weight-stable and the weightgain groups were noted to have similar increases in systolic blood pressure (SBP) over 5 years (SBP increase mean 4.2 mmHg), whereas the weight-loss group SBP was not statistically significantly changed.
In contrast to some other trials that report a "legacy effect" (prolonged beneficial impact of early intervention, even after the intervention has ceased), initial weight loss in WLM was not associated with favorable SBP effects if weight was regained. On the other hand, sustained modest weight reduction (< 10% of baseline BMI) had a sustained effect to maintain SBP. Although simply maintaining weight over the long term might appear to be a laudable goal, it is apparently insufficient to favorably affect SBP.
The WEAVE Study: Does Special Training in Domestic Violence Improve Outcomes?
Source: Hegarty K, et al. Lancet 2013; 382:249-258.
Intimate partner violence (ipv) is a public health problem that knows no boundaries of age, country of residence or origin, economic status, or education. Primary care clinicians, particularly family physicians, are often the first point of clinical contact for victims of IPV, but may lack confidence in their ability to identify and/or address IPV. Hegarty et al report on a trial from Australia in which women who screened positive for concerns about fear of their partner (n = 272) received care from family physicians who were randomized to receive special training in IPV or no intervention. The intervention group physicians participated in the Healthy Relationships Training program, which is intended to provide the ability to respond effectively to women who have experienced IPV and give brief counseling. The primary outcomes of the trial were changes in quality of life (as per the WHO QOL-BREF), safety planning and behavior, and mental health (as per the SF-12) at 1 year.
At 1 year, there was no difference in the primary endpoint between the intervention group and controls. A favorable impact on depression (a secondary endpoint) was seen. However, since the primary endpoint was not achieved, the potential for benefits on depression must remain considered as hypothesis generating.