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Compliance with treatment is crucial to the optimal management of any chronic disease. Non-compliance with antihyperglycemic treatment is clearly a significant issue for patients with type 2 diabetes mellitus as it decreases the efficacy of the treatment and increases the risk of developing microvascular and macrovascular complications, therefore increasing the human and economic costs of this disease. The effect of low compliance on metabolic control has been shown to represent an increase of up to 1.4% in glycosylated hemoglobin. Achieving optimal compliance is therefore a therapeutic objective of prime importance. Many factors have been cited as contributing to poor compliance. Some of these, such as age, severe complications and disabilities, and social, educational, and financial difficulties, affect compliance with treatment in quite a significant manner, but are not modifiable by the healthcare provider. Other factors, such as the number of tablets per dose and polymedication, are modifiable but do not appear to be of major importance, whereas the frequency of administration is both an important and a modifiable factor affecting compliance with treatment. One strategy for optimization of compliance involves treatment of type 2 diabetes using oral antihyperglycemic agents with once-daily formulations. Recent data indicate that reducing the daily administration frequency of oral antihyperglycemic agents improves compliance with treatment and consequently metabolic control. Therefore, optimization of treatment through a reduction in the frequency of antihyperglycemic administration could be a valuable weapon in the battle to improve health outcomes and reduce the burden of type 2 diabetes.

Protracted critically ill patients have a seriously deranged metabolism, characterized by severe hyperglycemia, a disturbed serum lipid profile, and protein hypercatabolism. The severity of stress-induced hyperglycemia and insulin resistance in critically ill patients reflect the risk of death. A large, prospective, randomized, controlled study showed that maintaining normoglycemia with intensive insulin therapy reduces morbidity and mortality of surgical intensive care patients. These results were recently confirmed by two studies: one randomized controlled study of surgical intensive care patients and a prospective observational study of a heterogeneous patient population admitted to a mixed medical/surgical intensive care unit. The clinical benefits of intensive insulin therapy appear to be related both to prevention of glucose toxicity and to other direct insulin actions that are independent of glycemic control. Prevention of the toxic effects of high circulating glucose levels protected the ultrastructure and function of hepatocyte mitochondria. Benefits of the non-glycemic effects of insulin included partial correction of the deranged serum lipid profile and possibly counteraction of the catabolic state. In addition to its metabolic effects, intensive insulin therapy also prevented excessive inflammation and improved immune function.

Ethinylestradiol 30μg/drospirenone 3mg (Yasmin®1, petibelle®) [EE/DRSP] is a combined contraceptive pill (CC) for the prevention of pregnancy in women of reproductive age. Drospirenone is a novel progestogen with antimineralocorticoid, progestogenic and antiandrogenic activity. The theoretical (0–0.07) and corrected (0.41–0.71) Pearl indices and pregnancy ratios (0.3–0.84) in young, healthy women aged 18–35 years (or 18–30 years if smokers) given 13–26 cycles of EE/DRSP in large multicenter trials indicate that this CC is highly effective in preventing pregnancy. EE/DRSP is equally as effective as ethinylestradiol 30μg/desogestrel 150μg (EE/DSG; corrected Pearl index 0.28–0.41) in preventing pregnancy. EE/DRSP is generally well tolerated. The frequency and type of adverse event reported in clinical trials are typical of those observed with other CCs, and comparable to those in women receiving EE/DSG. The incidence of intermenstrual bleeding (spotting, breakthrough bleeding or both) during treatment with EE/DRSP in young, healthy women decreased rapidly after the first cycle to 9 to 18% in the second cycle and 6% after 26 cycles, indicating good cycle control. The incidence of intermenstrual bleeding was similar in recipients of EE/DSG (9 and 14% in cycle 2 and 10% in cycle 26). Body weight was maintained ±2kg in most young women who received EE/DRSP for up to 26 cycles. Neither EE/DRSP nor EE/DSG showed clinically significant effects on blood pressure. EE/DRSP improved premenstrual and menstrual symptoms (negative affect, water retention, increased appetite) compared with baseline in a noncomparative trial. A similar improvement in skin condition (acne, seborrhea) was observed in women receiving EE/DRSP or ethinylestradiol 35μg/cyproterone acetate 2mg in a randomized, double-blind trial. Conclusions: Data from several 1- to 2-year studies show that EE/DRSP is an effective oral contraceptive, with Pearl index values similar to those of established low-dose CCs. This combination is well tolerated, demonstrating good cycle control and a beneficial effect on skin condition and well-being (including some premenstrual and menstrual symptoms). EE/DRSP has demonstrated similar efficacy and tolerability to EE/DSG, but long-term clinical experience is required to establish the position of EE/DRSP among other available CCs and to clarify any potential tolerability advantages. Nevertheless, because the management of tolerability is complicated by the idiosyncratic nature of the response of women to CCs containing different progestogens, EE/DRSP appears to be a useful treatment option for women desiring oral contraception. Receptor binding: The in vitro receptor binding affinity and pharmacologic profile of drospirenone are similar to those of progesterone; both have progestogenic, antiandrogenic and antimineralocorticoid activity. Estrogenic activity: Estrogen acts synergistically with drospirenone in suppressing cyclic pituitary follicle stimulating hormone and luteinizing hormone (LH); in addition, estrogen maintains the endometrium and helps to prevent breakthrough bleeding. The ethinylestradiol-induced increases in levels of sex-hormone binding globulin (SHBG; 3- to 4-fold) and corticosteroid-binding globulin (CBG; 2- to 2.5-fold) were not affected when women were given 13 cycles of ethinylestradiol 30μg/drospirenone 3mg (Yasmin®, petibelle®1) [EE/DRSP]; in this study a treatment cycle consisted of a once-daily dose of the drug for 21 days followed by 7 drug-free days. Drospirenone had no effect on the estrogen-stimulated increase in plasma renin substrate levels over three cycles of ethinylestradiol 30μg/drospirenone 2 or 3mg. Progestogenic activity: Drospirenone inhibits follicular stimulation and ovulation by suppressing LH. It also helps to prevent fertilization by slowing sperm transport through changes to the cervix and cervical mucus and affects implantation through atrophy of the endometrium during treatment. Drospirenone inhibits ovulation in a dose-dependent manner; results from a number of randomized studies in healthy, menstruating women indicate that the optimal oral dosage is 3mg. In these studies, treatment with EE/DRSP completely suppressed ovarian activity (follicular ripening or ovulation) in most women. Furthermore, none of the women receiving the 3mg dosage ovulated, unlike women receiving ethinylestradiol 30μg/drospirenone 2mg (three women receiving this dosage ovulated in a 3-cycle study). Ethinylestradiol/drospirenone inhibited cervical function and reduced spinnbarkeit and crystallization of cervical mucus irrespective of the dose of drospirenone; the effect on spinnbarkeit was partially reversed in a follow-up cycle. Long-term treatment (13 cycles) with EE/DRSP had a marked antiproliferative effect on the endometria of healthy, menstruating women. Antimineralocorticoid activity: Like endogenous progesterone, drospirenone has an antimineralocorticoid effect on the renin-angiotensin-aldosterone system. In several small studies in healthy women, drospirenone treatment caused natriuresis when given as a single agent or in combination with ethinylestradiol. Unlike cyproterone acetate, desogestrel or levonorgestrel (which have no antimineralocorticoid activity), drospirenone affected the physiologic natriuresis observed in the normal menstrual cycle by significantly increasing urinary aldosterone and sodium excretion (p < 0.01 for both parameters), plasma renin activity (p < 0.05) and plasma aldosterone levels (p < 0.01) in the follicular phase. A small increase in serum potassium levels was noted when estradiol 1mg/drospirenone 3mg was coadministered with enalapril maleate in hypertensive women; however, this increase was not statistically or clinically significant, and clinical hyperkalemia was not observed. Antiandrogenic activity: Drospirenone, cyproterone acetate and dienogest are the only progestogens demonstrating antiandrogenic activity at therapeutic dosages. Like ethinylestradiol 35μg/cyproterone acetate 2mg (a progestogen with antiandrogenic activity), EE/DRSP reduced ovarian androgen production and seborrhea in women with mild-to-moderate acne participating in a randomized, double-blind trial. Ethinylestradiol: Ethinylestradiol is absorbed within 2 hours of oral administration of EE/DRSP (absorption is slowed by food). Steady-state Cmax and AUC values are achieved during the second half of a treatment cycle. The absolute bioavailability is approximately 40%, and the apparent volume of distribution is 4 to 5 L/kg. Ethinylestradiol is rapidly metabolized, primarily by conjugation and aromatic hydroxylation via the hepatic cytochrome P450 (CYP) 3A4 isoenzyme, and is excreted in urine and feces. Drospirenone: Drospirenone is absorbed within 2 hours of oral administration of EE/DRSP, and maximum serum concentrations (Cmax) and areas under curves of drug concentration versus time (AUC) increase in a dose-related fashion after single doses. The absolute bioavailability is 76%. Absorption is slowed by food. Steady-state Cmax values were achieved by day 7 to 10 of the first treatment cycle when young women weregiven EE/DRSP. Steady-state AUC values demonstrated a slight accumulation (12 vs 17%) during the first six treatment cycles. Serum drospirenone concentrations were increased in women with moderate renal impairment; EE/DRSP is contraindicated in women with renal insufficiency. Although drospirenone is extensively bound to serum albumin (95 to 97%), it does not bind to SHBG or CBG and the apparent volume of distribution is 4 L/kg. Prior to elimination (which is both fecal and renal), drospirenone is extensively metabolized in the liver; the two main metabolites found in the plasma (the acid form of drospirenone and 4,5-dihydrodrospirenone-3-sul-phate) are pharmacologically inactive. Although the CYP isoenzyme CYP2C19 is inhibited in vitro by drospirenone, the clearance of concomitant omeprazole was not affected. Elimination is moderately slow and biphasic; the terminal disposition half-life after single or multiple doses is approximately 30 hours. Oral EE/DRSP effectively prevented pregnancy, with theoretical Pearl indices of 0 to 0.07 (corrected Pearl indices were 0.41 to 0.71) and pregnancy rates of 0.3 to 0.7% in three large multicenter 13- or 26-cycle trials in 326 to 1657 women (3192 to 18 418 cycles). In two randomized, nonblind trials, the contraceptive efficacy of EE/DRSP was similar to that observed with ethinylestradiol 30μg/desogestrel 150μg (EE/DSG). Theoretical (0 to 0.28) and corrected (0.28 to 0.41) Pearl indices and pregnancy rates (0.2 to 0.7% of women) in women receiving EE/DSG (n = 412 and 445; 4685 to 9422 cycles) were similar to those of EE/DRSP recipients. EE/DRSP is generally well tolerated and the type and frequency of adverse event reported in clinical trials are typical of those reported with other combined contraceptive pills (CCs). The frequency of adverse events possibly, probably or definitely related to treatment with EE/DRSP (39 and 43%) was not significantly different to that with EE/DSG (32 and 42%). The most frequent adverse events reported in clinical trials (≤26 cycles) by women in both treatment groups were headache (6 to 14%) and breast pain (5 to 12%); other adverse events included nausea, abdominal pain, migraine, depression and acne (all <5%). No significant differences were observed between the two treatment groups. Approximately 10% of women in each treatment group withdrew prematurely from two randomized, comparative, nonblind 13- or 26-cycle studies because of adverse events. No clinically significant changes in hematology, urinalysis, chemistry profiles or systolic or diastolic blood pressure recordings were observed in clinical trials. Cycle control: Cycle control in women receiving EE/DRSP appears to be good, with a low incidence of intermenstrual bleeding (spotting, breakthrough bleeding or both) after the first cycle that is maintained for up to 26 cycles. Intermenstrual bleeding is greatest in the first cycle (25 to 66% of women), decreasing to 9 to 18% by cycle 2, 5 to 8% by cycle 13 and 6% in cycle 26. Spotting alone occurred in 20 to 44% of women in cycle 1, decreasing to 4 to 6% in cycle 13 and 5% in cycle 26. Approximately 50% of women receiving EE/DRSP reported no intermenstrual bleeding. The incidence of intermenstrual bleeding in women receiving EE/DRSP or EE/DSG appears to be similar. The percentages of women receiving EE/DSG who experienced breakthrough bleeding and/or spotting in cycles 1 and 2, 13 and 26 were similar to those in women receiving EE/DRSP. The majority of cycles in one study (91 %) in both treatment groups (8572 and 8351 cycles) were free of intermenstrual bleeding. Similar percentages of cycles in each treatment group were associated with spotting, breakthrough bleeding or both. Amenorrhea is uncommon, occurring in 3.2, 0.8 and 1.6% of cycles in women receiving EE/DRSP for 13 or 26 cycles and in 0.8% of cycles in those receiving EE/DSG in clinical trials. Other effects: EE/DRSP has a lesser effect on mean bodyweight gain compared with EE/DSG. However, similar numbers in both treatment groups maintained their bodyweight ±2kg in clinical trials (<26 cycles). Acne, seborrhea and hirsutism improved to a similar extent during treatment with EE/DRSP, EE/DSG or ethinyl-estradiol 35μg/cyproterone acetate 2mg over 9 to 13 cycles. Treatment with EE/DRSP significantly improves perceptions about negative affect, water retention and increased appetite during the menstrual cycle (p < 0.001). Oral EE/DRSP is indicated for use as a contraceptive in women of reproductive age. A treatment cycle consists of a once-daily tablet of ethinylestradiol 30μg/drospirenone 3mg for 21 consecutive days, followed in the US by an inert tablet for 7 days, and in the UK by 7 tablet-free days; for maximum contraceptive efficacy the interval between tablets should not exceed 24 hours. In the US, EE/DRSP is contraindicated in women with conditions that predispose to hyperkalemia, including renal or adrenal insufficiency or hepatic dysfunction. Drospirenone has potent antimineralocorticoid activity; according to the US and European manufacturer’s prescribing information, EE/DRSP has the potential to cause hyperkalemia when administered to women receiving daily, long-term treatment for chronic conditions or diseases with drugs that may increase serum potassium levels, including ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists, potassium supplements and nonsteroidal anti-inflammatory drugs. Consequently, monitoring of serum potassium levels is required during the first treatment cycle. In Europe, CCs (including EE/DRSP) are contraindicated in patients with existing or previous serious liver disease, severe renal insufficiency or acute renal failure. CCs, including EE/DRSP, are contraindicated in the US in women over 35 years of age who smoke 15 or more cigarettes a day; furthermore, in the US and Europe, the manufacturer’s prescribing information strongly recommends that women who use this form of contraception should not smoke cigarettes. In addition, US and European prescribing information recommends that women with an increased risk of thrombophlebitis, thromboembolic disorders, cerebral vascular or coronary artery disease (including the presence or prior history of the condition or disorders increasing the risk) should not use CCs, nor should those with known or suspected estrogen-dependent neoplasia or pregnancy, undiagnosed abnormal genital bleeding, liver disease or liver tumors. Women with medical conditions associated with a lower increase in risk (including treated hyperlipidemia, diabetes mellitus and hypertension) who elect to take CCs require close monitoring.

Objective: To compare the cycle control, efficacy, and safety of a new low-dose combined oral contraceptive containing ethinylestradiol 20μg and drospirenone 3mg with an established formulation containing ethinylestradiol 20μg and desogestrel 150μg. Methods: This was a randomized, open-label, parallel-group, multicenter study of healthy women (aged 18–35 years) over seven treatment cycles. Both combined oral contraceptives were administered once daily for 21 consecutive days followed by a 7-day hormone-free interval. Results: A total of 445 women were randomized to treatment; of these, 441 (ethinylestradiol 20μg/drospirenone 3mg, n = 220; ethinylestradiol 20μg/desogestrel 150μg, n = 221) went on to receive study medication. There was a trend towards reduced intracyclic bleeding with continued treatment in both treatment groups, consistent with clinical experience. Intracyclic bleeding was highest during the first treatment cycle in both treatment groups, but was generally much lower in subsequent cycles. More than 90% of women in each of the groups experienced withdrawal bleeding during the study. The duration of withdrawal bleeding remained fairly constant throughout the study. The maximum intensity was mainly bleeding, rather than spotting. Overall, cycle control, efficacy, and safety profiles were comparable between both groups. Adverse events were generally of mild-to-moderate intensity and were those typical of hormonal contraceptive use. Conclusion: In conclusion, both ethinylestradiol 20μg/drospirenone 3mg and ethinylestradiol 20μg/desogestrel 150μg are effective and well tolerated contraceptives that provide good cycle control.

Imperfect use of contraceptive methods notably increases the likelihood of pregnancy. One means of improving user adherence with hormonal contraception is to minimize the dosing schedule. Two forms of hormonal contraceptive have currently achieved this goal: the transdermal patch and the vaginal ring. The first and only transdermal contraceptive patch to receive worldwide regulatory approval (ethinylestradiol/norelgestromin) is a convenient approach to contraception that has a similar efficacy to oral contraceptives (OCs), but with the benefit of once-weekly administration. In addition, transdermal delivery of contraceptive hormones eliminates variability in gastrointestinal absorption, avoids hepatic first-pass metabolism, and prevents the peaks and troughs in serum concentrations that are seen with OCs. Norelgestromin, the progestin contained in the patch, is the active metabolite of norgestimate and is structurally related to 19-nortestosterone. Norgestimate and norelgestromin mimic the physiologic effects of progesterone at the progesterone receptor; however, norelgestromin has negligible direct or indirect androgenic activity, suggesting that it may be suitable for women with disorders related to androgen excess (such as hirsutism, acne, and lipid disorders). Contraceptive effectiveness is usually a function of the efficacy of a contraceptive in combination with compliance with its dosing regimen. The efficacy of the contraceptive patch has been clearly demonstrated in three phase III trials, two of which were randomized comparisons with an OC. The likelihood of pregnancy was similar between these contraceptive methods; however, compliance with the patch was notably better, particularly in younger women. The safety and tolerability profile of the patch was similar to that of the OC. A cost-effectiveness analysis has suggested that the contraceptive patch is more cost effective than the OC, due to decreased costs related to unwanted pregnancy.

Because dehydroepiandrosterone (DHEA) levels decline dramatically with aging and low DHEA levels correlate with age-related diseases, it has been suggested that old age may represent a condition of DHEA deficiency. Accordingly, there have been some studies of the effects of restoring the DHEA levels of older individuals back to the normal range in the young. Emerging evidence from these studies shows that prasterone (DHEA replacement) may significantly enhance bone mineral density (BMD). In fact, the improvements of BMD in response to prasterone are accompanied not only by suppression of bone resorption but more importantly, stimulation of bone formation. Thus, prasterone appears to have additional anabolic effects on the skeleton, which represents an advantage over current pharmacologic agents that only inhibit bone loss. The osteogenic effects in elderly people are consistent with DHEA serving primarily as a precursor to active androgens and estrogens in local tissues such as bone. DHEA replacement may also increase levels of insulin-like growth factor-1, which may contribute to its anabolic effects. Although prasterone may be an effective therapy for improving BMD in both sexes, there appears to be gender differences in responses with more osteogenic effects in older women compared with older men. More studies, particularly randomized, placebo-controlled trials which include fractures as an outcome, are needed to fully define the potential utility of DHEA replacement as an anabolic intervention for age-related osteoporosis. These studies would also be important to gain information on risks associated with long-term DHEA replacement therapy. Further investigations are particularly warranted because prasterone is available over-the-counter in many countries and many older individuals are taking this hormone, without medical supervision, for its purported anti-aging properties.

A number of aldose reductase inhibitors (ARIs) have been developed over the past few decades with the expectation of therapeutic effects for diabetic complications. Neuropathy is the complication that has been most intensively studied as a potential target for ARIs. Most ARIs have shown satisfactory effects in animal models. However, the clinical potential of ARIs in diabetic patients has been controversial due to the lack of conclusive evidence. The safety of this category of drugs is also uncertain. This article summarizes the results of clinical trials of ARIs for patients with diabetic neuropathy that have been performed to date. The efficacy and toxicity of each ARI will be briefly assessed by the clinical data. The theoretical background along with major issues in the evaluation of drug efficacy will also be discussed. Overall the observed efficacy varied among the compounds. A few ARIs showed favorable effects in multiple endpoints in the majority of trials, while the results from many ARIs seemed ambivalent. One drug barely exhibited positive effects on any endpoint. This discrepancy may be attributable at least in part to the different degree of inhibition of the polyol pathway in nerve tissues, which is determined not only by the pharmacokinetic properties of the drug but also by its penetration into nerve tissues. In addition to the uncertain potential of each ARI, the issues of design and analytical methods used for clinical trials may underlie the ambivalent outcomes. The power of analysis and the duration of trials were apparently inadequate in a large number of the studies. Various indices selected as endpoints are not necessarily sensitive or reproducible. Studies of longer duration, large-scale trials, better methods to assess neuropathy, and the selection of patients with a homogenous background would provide more conclusive evidence. The risk of serious adverse reactions, for example, hypersensitivity reactions and hepatic damage, has led to some ARIs being withdrawn from the market or from further development. These adverse effects, however, do not appear to result from the inhibition of aldose reductase activity per se but from specific reactions to each compound. In conclusion, sufficient inhibition of the nerve aldose reductase activity seems likely to prevent or ameliorate diabetic neuropathy, and further development of more potent and safe ARIs is necessary before extensive clinical application.

Hormonal therapy forms part of the treatment of every intersex condition. For some conditions, such as salt-wasting congenital adrenal hyperplasia, hormonal replacement therapy is life saving because hormones necessary for survival (cortisol and aldosterone) are replaced. In contrast, other hormones such as androgens or mineralocorticoids are secreted in excessive amounts in congenital adrenal hyperplasia due to an enzyme imbalance, and the role of hormonal therapy is to suppress the unwanted hormone excess by exerting negative feedback. For patients with one of the many causes of hypogonadism, sex hormone replacement therapy may be prescribed to stimulate sexual development: growth of a hypoplastic penis in a young boy, pubertal changes (male or female), psychosexual development, and adult sexual behavior. It has equally important and highly beneficial effects on bone mineral density. Hormonal therapy is also used to treat the unborn child. For the last 20 years, prenatal dexamethasone treatment administered to the pregnant woman has been used to prevent the development of ambiguous genitalia in females with 21-hydroxylase deficiency. Outcome studies show this treatment to be well tolerated and, in general, efficacious. Intersex conditions are, however, difficult to treat because they may intrinsically perturb complex aspects of the person’s gender identity, gender-role behavior, sexual orientation, sexual functioning, and psychologic adjustment. Furthermore, decisions made about the sex of an infant by doctors and parents do not always turn out to be correct; the person may grow up feeling uncertain about his or her gender identity, or worse still, harbor a sense of outrage about their life and treatment experiences. Such a person will have definite views about hormonal therapy when the time comes and skilful counseling will be needed. A vigorous debate about ethical aspects of current medical practices relating to intersex conditions has been waged for the last 7 years between certain patient advocacy organizations and the medical profession, and is expected to continue for some time. The quality of the debate will be improved by evidence. The results of a number of long-term follow-up studies have been published, and more are expected. The published studies show mixed, but mainly encouraging, results.

While diabetes mellitus is recognized clinically as a complication of alcohol dependence, in the last 15 years several large prospective studies have demonstrated a significant reduction in risk of incident type 2 diabetes in moderate drinkers. In this article, we review prospective studies on the association between alcohol consumption and incidence of diabetes. Few prospective studies have demonstrated an unequivocal positive association between alcohol use and incidence of diabetes. A number of large prospective studies have now demonstrated an inverse association: typically a 40% risk reduction after controlling for other major risk factors. Studies based on cohorts of health professionals have not demonstrated an increased risk of diabetes with heavier consumption, but these cohorts contain few heavy drinkers. Some cohorts drawn from the general population have shown a J- or U-shaped association between level of alcohol consumption and incidence of diabetes. Frequent moderate drinking has been reported to be associated with lower risk than infrequent drinking. There have been contradictory reports on the importance of the type of alcoholic beverage and whether the effect of alcohol differs according to the bodyweight of the drinker. We conclude that like many other chronic diseases, there is a delicate balance between the harmful and beneficial effects of alcohol on the incidence of diabetes. In moderate amounts, drinking is associated with a reduced risk of diabetes, whereas in higher amounts with an increased risk.