Clinical Briefs
By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville
Dr. Kuritzky is an advisor for Endo, Kowa, Pricara, and Takeda.
Our Newest Pharmacologic Class for Treatment of Diabetes: SGLT2 Inhibitors
Source: Polidori D, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: Results of a randomized, placebo-controlled study. 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. Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: Analysis of a randomized control trial comparing surgery with intensive medical treatment. 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. Psoriasis and new-onset diabetes: A Danish nationwide cohort study. 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 of age (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.
