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There was a significant increase in drug-related adverse events with combination therapy vs. Men with planned cataract surgery should avoid the initiation of alpha-blockers until their cataract surgery is completed. The original report linked this condition with the preoperative use of tamsulosin; iris dilator smooth muscle inhibition has been suggested as a potential mechanism. Reference lists of the retrieved papers were reviewed for additional original reports. A review of these data supports the following conclusions: Copyright ©2010 American Urological Association Education and Research, Inc. Therefore, the Panel believed that these new findings were supportive of their original conclusions. The serum half life of finasteride ranges from six to eight hours whereas that of dutasteride is five weeks. This pharmacokinetic difference may have implications in terms of treatment compliance as well as persistence of side effects. Comparisons are difficult if not impossible due to the fact that inclusion and exclusion criteria do not match for any trials of finasteride or dutasteride. In different studies, various thresholds have been proposed for the definition of prostate enlargement (25, 30 or 40 mL). The majority of studies with finasteride were published before the 2003 Guideline and since then the compound has lost patent protection. Only a small number of subset or post hoc analyses and open-label extension studies have been reported since the 2003 Guideline. Whether these differences are clinically important is unknown; there are no published trials directly comparing the two agents. Indirect comparisons of efficacy outcomes are limited in that only patients with baseline prostate volumes > 30 Copyright ©2010 American Urological Association Education and Research, Inc. Combination Therapy with Alpha-adrenergic Antagonists See Guideline Statement and text in section on alpha-adrenergic antagonists. A similar level of evidence concerning dutasteride was not reviewed; it is the expert opinion of the Panel that dutasteride likely functions in a similar fashion. Anticholinergics should be used with caution in patients with a post-void residual greater than 250 to 300 mL. This class of medication reduces the effects mediated by acetylcholine on its receptors in bladder neurons through competitive inhibition. Five muscarinic subclasses (M1 through M5) of cholinergic receptors have been described in the human bladder muscle, the majority comprises subtypes M2 and M3. While M2 receptors predominate, M3 receptors are primarily responsible for bladder contraction. The occurrence of constipation, diarrhea, and somnolence were also similar in frequency to placebo. Of particular appeal are dietary supplements, which include extracts of the saw palmetto plant (Serenoa repens) and stinging nettle (Urtica dioica), among several others. Since the publication of the last version of this Guideline, higher-quality evidence has begun to appear and assessments of the efficacy of the dietary supplements are beginning to evolve. Since the development of the 2003 Guideline, little new information on effectiveness and safety has been published. There are only three prospective, randomized trials (one trial reports outcomes at two time points). The remainder are cohort studies from which the reporting of outcomes varies considerably. In addition, the bulk of the literature suggests a high longterm retreatment rate. This leads to conflicting results, as may be seen in studies of shorter versus longer follow-up. There is no compelling evidence from comparator trials to conclude that one device is superior to another. Most studies analyze only those patients who remained in the study at the time of analysis; these patients would tend to represent the best "responders". In many studies, less than half of the initial group of men treated was analyzed at the end of the study period. Outpatient capability, lack of sexual side effects and avoidance of actual surgery are attractive to patient and clinician alike.

This results in frequent hypoglycemic symptoms at non-hypoglycemic blood sugar levels and means that large doses of insulin may be required to reduce fasting hyperglycemia to normal levels [20,21]. In some cases where the fetus has inherited the mutation, intensive insulin treatment has resulted in a low birth weight child [21]. This is to be expected as a small baby is seen when the fetus inherits a mutation from the father and is born to a normoglycemic mother [18,22]. Treatment decisions in glucokinase gestational diabetes should therefore be related to fetal growth as shown by scans rather than being made solely on maternal glycemia [21]. If the abdominal circumference is greater than the 75th centile insulin may be used but early delivery is the most successful strategy. The weight is increased by the presence of a maternal mutation and decreased by the presence of a fetal mutation. Their identification is important because they have a different clinical course, both within and outside pregnancy, than other subjects with gestational diabetes. The birth weight of the newborn infant will depend on the mutation status of both the mother and the fetus (Figure 15. Where only the mother carries the mutation, maternal hyperglycemia may result in increased fetal insulin secretion and growth causing the fetus to be large for gestational age [18]. If the fetus inherits the mutation from the father, however, birth weight is reduced by approximately 500 g as a result of reduced fetal insulin secretion and insulin-mediated fetal growth [18]. An absence of family history should not exclude the diagnosis as asymptomatic hyperglycemia in a parent may not have been detected. Management Patients with hyperglycemia resulting from glucokinase mutations are often treated with insulin during pregnancy in an attempt to correct the fasting hyperglycemia. Fetal genotype, however, is a far greater determinant of fetal birth weight than treatment of the mother and insulin treatment appears to have little effect on fetal growth [19]. Transcription factor mutations alter insulin secretion in the mature -cell as well as altering -cell development, proliferation and cell death. Reduced -cell proliferation and preserved or increased apoptosis could explain the progressive deterioration in -cell function seen in these patients [25­28]. Clinical features Heterozygous transcription factor mutations cause autosomal dominant diabetes presenting in adolescence or early adulthood resulting from progressive failure of insulin secretion. Diabetes Patients are usually born with normal glucose tolerance and then show progressive -cell dysfunction until they develop diabetes, 249 Part 4 Other Types of Diabetes Table 15. These features appear to relate to increased insulin secretion in utero and in early infancy which evolves into reduced insulin secretion and diabetes in later life [37]. Evidence of non-insulin dependence increases the likelihood of a positive result; this would include no ketosis in the absence of insulin treatment, good glycemic control on low doses of insulin, or detectable C peptide with plasma glucose >8 mmol/L 3­5 years after diagnosis (outside the honeymoon period) [39]. Patients show deteriorating glycemia with age and require pharmacologic treatment. In the oral glucose tolerance test, in contrast to patients with glucokinase mutations, the fasting glucose is often normal initially but there is marked elevation of glycemia at 2 hours and consequently a large 2-hour increment (>5. Microvascular complications are frequent particularly when hyperglycemia is inadequately treated [34]. These patients have a normal renal glucose threshold and frequently have a personal and/or family history of high birth weights and/or neonatal hypoglycemia. Mutation carriers without diabetes may develop glycosuria after a glucose challenge even if glycemia remains within normal limits [36]. Transfer to sulfonylurea treatment is successful in the majority of patients although insulin therapy may be required as diabetes progresses [44]. The starting dose should therefore be low ­ we use a starting dose of 40 mg/ day gliclazide or 2. If there is hypoglycemia with low doses of standard agents, a short-acting agent such as nateglinide may be appropriate [45]. Neonatal diabetes results from mutations of key genes involved in -cell development or function. Our current practice is to continue sulfonylureas if glycemic control is good before pregnancy but otherwise institute treatment with insulin. Consideration should be given to switching to glibenclamide in the prepregnancy period as this sulfonylurea has the most evidence for safety in pregnancy [46,47]. Sulfonylurea responsive Macroglossia and umbilical hernia Both parents have heterozygous glucokinase associated hyperglycemia Hypergalactosemia, hepatic failure Congenital hypothyroidism, glaucoma, liver fibrosis and cystic kidney disease Pancreatic and cerebellar agenesis Pancreatic agenesis Exocrine pancreas insufficiency and renal cysts Spondyloepiphyseal dysplasia, renal failure, recurrent hepatitis and mental retardation Immune dysregulation, intractable diarrhoea, eczematous skin rash and elevated IgE None 50% of permanent neonatal diabetes, 25% of transient neonatal diabetes 70% of transient neonatal diabetes Rare Rare Rare Rare Rare Rare Rare Rare 12% of permanent neonatal diabetes 85% spontaneous. Channel closure triggers depolarization of the -cell membrane which leads to insulin secretion.

In the only study of sexual function after surgery, a significant increase in sexual desire and overall satisfaction was observed. Longer-term Complications Mortality was infrequently reported in these studies and perioperative death rates were low (1%) and generally related to cardiovascular disease. Sotelo reported a mean operative time of 156 minutes (range 85 to 380) and a mean blood loss of 516 mL (range 100 to 2500 mL). Large prostate glands were examined in several studies: >100 g,213, 215 40 to 200 g211 and 70 to 220 g. A significant percentage of subjects were in urinary retention at baseline in several studies, although this information was infrequently reported at baseline. Follow-up interval ranged from six weeks236 to three years,246 with only two studies providing data for longer than 12 months. Efficacy and Effectiveness Outcomes Similar to the analysis of the surgical therapies in the 2003 analysis, the symptom score and peak-flow data were available for most laser treatments and QoL scores were available for most treatments. Men without impaired detrusor Copyright ©2010 American Urological Association Education and Research, Inc. While there are no direct comparisons between the various laser technologies, the improvements in symptom scores appear to be comparable to other surgical therapies and durable to five years. Data from a single investigator suggest that the QoL assessment in the interval between one year and six years follow-up is still improved but variable, as reported scores ranged between -2. Single group cohort studies using holmium ablation of the prostate report that the improvements in QoL scores noted at three months postoperatively were sustained at seven years although no statistics were provided. In the single cohort study that included 54 patients improvement was found in the QoL score at one-year however, due to limited data, conclusions about this modality cannot be drawn. All surgical therapies provided similar outcomes over time with regard to peak flow. The studies involving thulium laser therapy did not report the outcomes for the post-void urinary residuals. Changes following laser therapy may impact the outer diameter of the prostate as well as the inner lumen of the urethra. Thus total prostate volume measured after ablative therapies may not accurately reflect the amount of prostate tissue removed or the changes in the prostate. Studies concerning holmium lasers do not address changes in prostate volume following therapy but do refer to weight of resected tissue. The literature does not contain information concerning the impact of the various laser therapies on the detrusor pressures at maximum flow. Randomized controlled studies of the holmium laser compared to open prostatectomy found a total withdrawal rate of 38. The concerns for mortality rates associated with laser therapies are referred to the section addressing mortality for all surgical therapies. Intraoperative, immediate, postoperative, and short-term complications involve a broad spectrum of events and reporting rates may be based on subjective thresholds. The ability to directly compare laser therapies with respect to the operative time is constrained by the fact that each laser modality seems to select from patient populations with different baseline characteristics and seldom selects the same comparison therapy as a control. The sole study for the thulium laser is a single-cohort study reporting an operative time of 52 minutes in men with a mean pretreatment prostate volume of 32 mL. The published data in the interval from the 2003 analysis of the literature does not provide sufficient information to assess a change in risk. Minimally invasive and surgical procedures induce irritative voiding symptoms immediately after and for some time subsequent to the procedure. Periprocedure and postprocedure adverse events associated with voiding symptoms include frequency, urgency, and urge incontinence and are categorized as postprocedure irritative adverse events. Such events are reported more often following heat-based therapies than following tissue-ablative surgical procedures. Because they impact QoL, irritative events are important and warrant documentation. Unfortunately, all patients will have some symptoms during the healing process immediately following the procedure. Because there is no standard for reporting this outcome, some studies reported these early symptoms while others did not. Further, because it is not possible to stratify these complaints according to severity, it is not possible to compare the degree of bother of these symptoms across therapies. Unfortunately, some studies report "protocol-required" or "investigator option" episodes of postprocedure catheterization while others report only catheterization performed for inability to urinate.

There has been concern that the powerful inhibitory effect could represent a problem in patients with gastroparesis, but so far there have been no reported cases. Clinical studies have shown that the effects on food intake are maintained for several years and lead to a sustained or progressive weight loss. It has therefore been suggested that a different receptor mediates at least some of the cardiovascular effects, although not all studies support this [61]. The intact peptide has an apparent intravenous half-life of 1­2 minutes and a plasma clearance amounting to 2­3 times the cardiac plasma output [16]. In addition, insulin sensitivity, determined by a hyperinsulinemic euglycemic clamp, almost doubled, and insulin secretion capacity (measured using a 30 mmol/L glucose clamp + arginine) greatly improved. There was no significant difference between results obtained after treatment for 1 or 6 weeks, but there was a tendency towards further improvement of plasma glucose as well as insulin secretion. Exenatide is not recommended for patients with severe kidney failure (creatinine clearance <30 mL/minute), because it is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. Exenatide, administered twice daily within 60 minutes of morning and evening meals, lowers glucose for 5­7 hours and predominately affects post-prandial glycemic excursion, with only modest effects on lunch hyperglycemia and on fasting blood glucose [89­90]. The main side effect, nausea, is dose-dependent after subcutaneous injection, but may show some tachyphylaxis [88]. Therefore, it is recommended to start therapy with 5 g twice daily for 1 month and subsequently to increase to 10 g twice daily. Increased insulin secretion, inhibition of glucagon secretion and delayed gastric emptying are the main mechanisms by which exenatide improves glucose metabolism (Figure 30. Some oral antidiabetics are associated with weight gain (sulfonylureas, glinides and glitazones), hypoglycemia (sulfonylureas and glinides), lactate acidosis (metformin), intestinal side effects (metformin and glucosidase inhibitors) or peripheral edema and fractures (glitazones) [86]. Improvements were observed in some cardiovascular risk factors and hepatic biomarkers [71]. As in most of the other studies, the drop-out rate in the exenatide group was twice that in the placebo group (29% vs 14%) [97]. In an open-label trial, insulin glargine once daily or exenatide twice daily were added for patients inadequately controlled by metformin and sulfonylurea [98]. Frequencies of hypoglycemia did not differ between treatments, but nocturnal hypoglycemia was less frequent with exenatide. Approximately 19% and 10% of the patients withdrew from the study in the exenatide and glargine groups, respectively [98]. In a 52-week trial, exenatide was compared with twice daily biphasic 482 Non-Insulin Parenteral Therapies Chapter 30 insulin aspart (baseline mean HbA1c 8. Systolic (-5 mmHg) and diastolic (-2 mm Hg) blood pressures were significantly reduced with exenatide, but remained unchanged with insulin. Rapid acting and premix insulin doses were reduced by 28% and 60%, respectively, while the dose of basal insulin was unchanged. Other studies have shown that exenatide improved first-phase insulin responses to intravenous glucose and decreased the proinsulin: insulin ratio, indicating a beneficial effect of exenatide treatment on -cell function [94,102]. Nevertheless, no human data indicate that exenatide can protect or restore the -cell mass. Thus, the -cell function did not change from before start of treatment when tested after 1 year treatment with exenatide followed by 1 month wash-out of exenatide [103]. After initiation of treatment, steady-state concentrations are obtained after 3­4 days [108]. Adverse effects with exenatide Exenatide has generally been well tolerated and rarely causes treatment discontinuation because of side effects, but in the phase 3 studies drop-out rates in the exenatide groups were twice those in the placebo-treated groups [93­95]. Hypoglycemia is not a problem when exenatide is used in monotherapy or in combination with metformin [94], but mild hypoglycemia was observed in 15­36% of subjects receiving sulfonylurea in combination with exenatide [93,95]. Mild to moderate nausea has been reported in up to 57% of patients treated with exenatide compared to about 7­23% on placebo in combination with oral antidiabetic drugs [93­95]. Nausea generally occurs during the first days of treatment and, in most patients, decreases with time. Other adverse effects reported include diarrhoea, dizziness and constipation [106]. About 40­50% of treated subjects develop antibodies to exenatide [93­95]; the importance of these is unknown, but they do not seem to influence efficacy on glucose control, except in some subjects with very high titers.