Clinical Briefs
By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville
Dr. Kuritzky is a retained consultant for Boehringer Ingelheim, Daiichi Sankyo, Forest Pharmaceuticals, Janssen, Lilly, Novo Nordisk, Pfizer, and Sanofi.
Finasteride for Prevention of Prostate Cancer: 18 Years of Follow-up
Source: Thompson IM, et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med 2013;369:603-610.
The prostate cancer prevention trial (PCPT) was a randomized, double- blind, placebo-controlled trial (n = 18,880) performed to evaluate the efficacy of the 5-alpha-reductase inhibitor finasteride (FIN) for prevention of prostate cancer. At the end of 7 years, the good news was a 25% reduction in total prostate cancer; the bad news was that there was a 27% increase in higher-grade prostate cancers, intimating that although the total amount of prostate cancer was reduced, overall outcomes could possibly be worsened by the increase in more aggressive cancers. Mitigating explanations for the increased risk of higher-grade tumors included alpha-reductase inhibitor-induced shrinkage of healthy prostate tissue (thereby increasing the likelihood of biopsy-positive results) and alteration of tissue architecture induced by FIN; insufficiently reassured by these explanations, most primary care clinicians have opted not to use FIN for prostate cancer prevention.
The outcomes of this population in very long-term follow-up can better answer the question of whether the risk-benefit balance was indeed unfavorably tipped by high-grade prostate cancers. Reviewing the outcomes of patients originally enrolled in PCPT, the survival rates at 18 years were essentially identical among men who had been randomized to FIN or placebo. Although FIN treatment did not appear to reduce mortality, the increased incidence of higher-grade Gleason scores among FIN-treated patients did not appear to increase mortality either. In the absence of mortality improvement, unless men are seeking alpha-reductase treatment for symptomatic benign prostatic hyperplasia, FIN treatment for prevention of prostate cancer would appear unwarranted, albeit otherwise safe.
Addressing Diabetic Neuropathy
Source: Tesfaye S, et al. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care 2013;36:2456-2465.
Type 2 diabetes (t2dm) remains the No. 1 cause of atraumatic limb loss in the United States. Neuropathy is a primary culprit in the process beginning with undetected foot injury that progresses to deep-seated infection and, ultimately, limb loss. Hence, it is hoped that early identification and management of diabetic peripheral neuropathy (DPN) might improve outcomes. Unfortunately, of the microvascular consequences of T2DM, neuropathy appears to be the most recalcitrant to glucose control: Glucose control appears to forestall progression of neuropathy, but not improve nerve function or reverse neuropathy.
In clinical practice, it is recommended that the diagnosis of DPN should be based on typical symptoms and physical examination (e.g., lower extremity deep tendon reflex changes). On the other hand, clinical trials usually employ sophisticated techniques such as nerve conduction testing. Comparison of tuning fork testing vs monofilament testing found the former to be the most sensitive test for identification of neuropathy. The postulated pathophysiology of DPN is uncertain and may be multifactorial, but there is some support for dysfunction of the neural microvasculature.
FDA-approved agents for DPN pain are duloxetine and pregabalin, although venlafaxine, gabapentin, carbamazepine, and alpha-lipoic acid have also demonstrated some efficacy. A recently published algorithm created by the Toronto International Neuropathy Consensus Group suggests that when traditional agents are not effective, opioid analgesia may be considered.
When Metformin and Sulfonylurea Are Not Enough: Canagliflozin or Sitagliptin?
Source: Schernthaner G, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: A 52-week randomized trial. Diabetes Care 2013; 36:2508-2515.
Many type 2 diabetes (t2dm) patients are unable to achieve or maintain their A1c goals even when appropriately treated with oral agents. Currently, the combination of metformin with a sulfonylurea (MET/SFU) is a very commonplace initial combination. Because T2DM is a progressive disorder, and because some agents lose efficacy over time, most patients must recognize that augmentation of treatment is usually required. But which next step is best when MET/SFU is insufficient?
Canaglifozin (CAN) is the first approved member of a new class of agents for T2DM, known as the SGLT2 inhibitors, which work by blocking renal reabsorption of excess glucose, leading to increased urinary glucose excretion. Sitagliptin (SIT) is one of three approved DPP-4 inhibitors that work by increasing blocking glucagon and stimulating insulin production when glucose is elevated.
In a 1-year trial comparing the addition of CAN or SIT to MET/SUF (n = 755), A1c reduction with CAN was substantially greater (-1.03 vs -0.66) and both agents were well tolerated. SGLT2 inhibitors are potentially useful when A1c goals are not attained or maintained with MET/SUF.
