Weight changes in type 2 diabetes and the impact of gender.

AIMS: Many studies suggest that weight gain occurs during treatment of type 2 diabetes, irrespective of the treatment type. The aim of this study was to address the questions (i) whether weight gain is inevitable in patients treated for type 2 diabetes, and (ii) whether treatment escalation is prompted by a rise in glycaemic control [haemoglobin A 1c (HbA 1c)] or weight gain. METHODS: A diabetes database was used to identify all patients with type 2 diabetes attending our clinic between 1 January 1990 and 31 December 2000. To facilitate further analysis, independent anonymized database resources were established. Data collected included height, weight, gender, HbA(1c), age and diabetes treatment at each visit. RESULTS: One thousand and eighty-four patients were included; after 6 months of treatment, patients' average weight had reduced by 1.0 kg (s.d. 4.6) (p < 0.001). Sixty per cent of the patients had either a decrease or no change in weight, while 40% demonstrated a weight gain. Women demonstrated more weight loss than men. After a mean follow-up of 50 months (s.d. 25.7), 439 patients (40%) who received treatment with diet alone, diet followed by metformin or metformin alone demonstrated a maintained weight reduction in addition to improved glycaemic control. A rise in HbA(1c) rather than weight gain prompted treatment change. CONCLUSIONS: This study provides evidence that weight gain is not a necessary consequence of the treatment of type 2 diabetes. Women were more successful than men in losing weight, and diet, with or without the addition of metformin, was the treatment type most usually associated with weight loss.

The occurrence of hypothyroidism following radioactive iodine treatment of toxic nodular goiter is related to the TSH level.

BACKGROUND: Strategies to increase frequency of euthyroidism following radioactive (RAI) treatment of hyperthyroidism are required. AIMS: To examine the role of TSH in development of hypothyroidism post RAI treatment in patients with Graves' disease (N = 98) or toxic nodular goiter, TNG (N = 88). DESIGN: This retrospective study examined thyroid status over a mean of 3.7 years post-RAI. RESULTS: Although RAI dose was significantly higher in TNG group, hypothyroidism occurred more frequently in Graves' disease (71.4 and 22.7%) P < 0.001. The TSH levels at the time of RAI treatment were lower in TNG patients who remained euthyroid, (0.4+/-0.1 vs. 1.2+/-0.5 mU/l, P < 0.0022). CONCLUSIONS: A higher frequency of euthyroidism occurs in patients with TNG than with Graves' disease following RAI, particularly when suppressed TSH levels were suppressed at time of RAI-treatment.

Diagnosis, misdiagnosis and management of hyperprolactinemia.

Hyperprolactinemia is a commonly encountered disorder that suppresses both male and female gonadal function. The etiology includes pituitary tumors, hypothalamic or pituitary stalk lesions, drugs and hypothyroidism. In women, the hyperprolactinemic syndrome is characterized by menstrual disorders with or without galactorrhea, while men present with hypogonadism and related symptoms. Occasionally, a pituitary macroadenoma may be associated with pressure symptoms and/or hypopituitarism. Clinically, the most important cause of hyperprolactinemia is a prolactin-secreting pituitary adenoma. The majority of patients with prolactinomas are successfully managed medically with dopamine agonists such as cabergoline or bromocriptine. Misdiagnosis of hyperprolactinemia owing to immunoassay interference by a biologically minimally active form of prolactin termed macroprolactin is common in laboratory medicine . Alhough the etiology of macroprolactinemia is unclear, the condition is commonly associated with the presence of circulating antiprolactin antibodies. In the absence of specific testing, macroprolactin represents a diagnostic pitfall resulting in misdiagnosis and mismanagement of patients. This review examines the investigation and treatment of hyperprolactinemia in the broadened context of screening for macroprolactin and the consequences of failure to identify its presence.

The cost of treating type 2 diabetes (CODEIRE).

Diabetes mellitus is the most common chronic metabolic disease and a major source of morbidity and mortality. Type 2 diabetes (T2D) is by far the most prevalent form of diabetes accounting for around 90% of cases worldwide. In recent years it has become apparent that a diabetes epidemic is unfolding as a result of increasing obesity, sedentary lifestyles and an ageing population. The enormity of the diabetes epidemic raises concern about the total cost to healthcare systems. This study was undertaken to investigate the direct healthcare costs of managing T2D in Ireland. Data was captured on 701 diabetes patients attending four diabetes centres. A bottom-up, prevalence-based design was used, which collected data on hospital resource use and clinical outcome measures over a 12-month period (1999/2000). The study was observational in nature, focusing on usual care of patients with T2D. Although the true prevalence of T2D in Ireland is unknown, conservative estimates are 3.9% for diagnosed diabetes and 6% for both diagnosed and undiagnosed diabetes. Using these figures the annual total direct cost was estimated at 377.2 million euro for diagnosed diabetes and 580.2 million euro for both diagnosed and undiagnosed diabetes. This corresponds to 4.1% and 6.4% of total healthcare expenditure respectively. Hospitalisations were the main driver of costs, accounting for almost half of overall costs, while ambulatory and drug costs accounted for 27% and 25% respectively. Hospitalisation costs were high because 60% of patients had developed complications. The most common microvascular and macrovascular complications were neuropathy and angina respectively. The annual cost of care for patients with microvascular and macrovascular complications were 1.8 and 2.9 times the cost of treating those without clinical evidence of complications respectively. The figure for patients with both types of complications was 3.8. This study shows that T2D is a very costly disease, largely due to the cost of and the management of complications. Many diabetes related complications are preventable, therefore it would appear a cost-effective approach for government to invest in the prevention of T2D and diabetes related complications.

The impact on clinical practice of routine screening for macroprolactin.

BACKGROUND: Macroprolactin has reduced bioactivity in vivo and accumulates in the sera of some subjects, resulting in pseudo-hyperprolactinemia and consequent misdiagnosis. METHODS: We have audited our experience of routine screening for macroprolactin using polyethylene glycol (PEG) precipitation over a 5-yr period in a single center. RESULTS: Application of a reference range for monomeric prolactin (the residual prolactin present in macroprolactin-depleted serum) for normal individuals revealed that 453 of 2089 hyperprolactinemic samples (22%) identified by Delfia immunoassay were explained entirely by macroprolactin. The percentage of hyperprolactinemic samples explained by macroprolactinemia was similar across all levels of total prolactin (18, 21, 19, and 17% of samples from 700-1000, 1000-2000, 2000-3000, and greater than 3000 mU/liter, respectively). Application of an absolute prolactin threshold after polyethylene glycol treatment of sera, rather than the traditional method, i.e. less than 40% recovery, minimizes the opportunity for misclassification of patients in whom macroprolactin accounted for more than 60% of prolactin and the residual bioactive prolactin was present in excess. Macroprolactinemic patients could not be differentiated from true hyperprolactinemic patients on the basis of clinical features alone. Although oligomenorrhea/amenorrhea and galactorrhea were more common in patients with true hyperprolactinemia (P < 0.05), they were also frequently present in macroprolactinemic patients. Plasma levels of estradiol and LH and the LH/FSH ratio were significantly greater in macroprolactinemic compared with true hyperprolactinemic subjects (P < 0.05). Reduced use of imaging and dopamine agonist treatment resulted in a net cost savings, offsetting the additional cost associated with the introduction of screening. CONCLUSION: Routine screening of all hyperprolactinemic sera for macroprolactin is recommended.

Hyperprolactinaemia: analysis of presentation, diagnosis and treatment in the endocrine service of a general hospital.

The charts of 184 patients with clinically significant hyperprolactinaemia who presented to a teaching hospital between 1978-1995 were reviewed, 158 (86%) females and 26 (14%) males. Hyperprolactinaemia was due to a microadenoma or was idiopathic in 36.4%, drug induced in 16%, associated with a macroadenoma in 12%, due to epilepsy in 7%, with other causes each contributing 5% or less. The presenting symptoms were amenorrhoea in 64%, galactorrhoea in 40.5%, infertility in 15%, visual field defect in 9%, with impotence in 30% and, gynaecomastia in 8% of men. One hundred and one patients were treated with bromocriptine (80%), surgery (35.4%) and radiotherapy (10.7%). Twenty-five percent of patients developed side-effects of bromocriptine for which cabergoline, a new long-lasting dopaminergic agonist, was successfully substituted. Presenting features responded to drug treatment in 70-80% of patients.

Protective action recommendations based upon plant conditions.

Analyses conducted by the Nuclear Regulatory Commission (NRC) indicate that timely and effective protective action would be necessary to protect the public in a major nuclear power plant accident. Given the large amount of time required to implement an evacuation around most reactor sites, protective action recommendations (PARs) must be based upon specific plant indicators regarding the status of the core and systems that protect the core. This article describes the assumptions made, and the analyses conducted, by the NRC in developing its procedures for PARs based upon plant conditions.

Relapse of hirsutism following long-term successful treatment with oestrogen-progestogen combination.

OBJECTIVE: While several forms of treatment have been reported to be successful in relieving hirsutism over periods of 6-12 months, there is little if any information on the long-term outcome of hirsutism following the withdrawal of successful treatment. The combination of ethinyl oestradiol, 35 micrograms, and cyproterone acetate, 2 mg (EE-CA) for 21 days followed by 7 days without treatment is widely used in a cyclical manner in the treatment of hirsutism. The present study was undertaken to evaluate the outcome of withdrawal of long-term successful treatment of hirsutism with EE-CA. DESIGN, PATIENTS AND MEASUREMENT: In this retrospective study the clinical records of 57 patients with idiopathic hirsutism or polycystic ovary syndrome who had been treated with EE-CA were reviewed. The degree of hirsutism had been assessed by the Ferriman and Gallwey scoring system (FG). The testosterone/sex hormone binding globulin ratio (T/SHBG), was derived prior to and following the introduction of treatment with EE-CA. RESULTS: Fifty-two of the 57 patients achieved a satisfactory clinical response. In the group of patients who were satisfied with the outcome of treatment, FG decreased from 12.9 +/- 3.6 to 5.5 +/- 2.5 and T/SHBG ratio decreased from 11.3 +/- 9.5 to 1 +/- 0.8 (reference range: 1-5.2). The duration of treatment prior to its withdrawal in this group was 28.2 +/- 13.7 months. The five patients who were not satisfied with the response abandoned treatment after 16 +/- 2.8 months; the pretreatment FG was 16.2 +/- 8.3, while the T/SHBG decreased from 6.1 +/- 3.1 to 1.1 +/- 0.6 in these patients. Subsequent follow-up data, after withdrawal of treatment, were available on 34 of these 52 patients. Twenty-eight of the 34 patients exhibited relapse of hirsutism after 6.15 +/- 2.8 months. Six patients did not relapse during a follow-up period of 18.8 +/- 7. 8 months. The six patients who did not relapse were treated for a significantly longer period than the group who relapsed, 40 +/- 6.9 and 26.1 +/- 8.3 months, respectively, P < 0.01. However, the groups did not differ significantly when examined for pretreatment FG, 11.5 +/- 3.8 and 13.2 +/- 3.6 and pretreatment T/SHBG 8.9 +/- 5 and 13.4 +/- 11.9. CONCLUSION: These data indicate that ethinyl oestradiol and cyproterone acetate achieved a satisfactory clinical outcome in the treatment of hirsutism in 90% of patients. However, on withdrawal of treatment after a mean duration of over 2 years, relapse occurred in 80% of these patients after a mean of 6 months. If it is assumed that the successfully treated patients lost to follow-up all maintained long-term remission, the relapse rate is still an unsatisfactory 65% at 6 months. These are disappointing results which indicate for the first time that successful outcome requires that treatment be maintained for several years. Patients embarking upon treatment for hirsutism should be advised that maintenance of reduced hair growth requires long-term treatment, probably for at least 3-4 years.

Premixed insulin preparations and glycaemic control in type 1 diabetes mellitus.

The role of premixed insulin preparations in Type 1 DM remains unresolved. The degree of glycaemic control achieved with the use of premixed insulin preparations in an unselected group of subjects with Type 1 DM has not previously been reported. We abstracted and reviewed data on 600 subjects with Type 1 diabetes mellitus in our computer data base. 134 (23%) were taking two injections of premixed insulin daily. In these subjects glycaemic control as assessed by the most recent HbA1c measurement was 7.6 +/- 0.1% vs 7.4 +/- 0.1% in those subjects on separate insulins, p = N.S. In those subjects aged < 35 years, 62/220 (28%) used premixed insulin. HbA1c was higher in those on premixed insulin 7.8 +/- 0.2% and 7.2 +/- 0.1%, p < 0.05. This difference in HbA1c was seen only in those subjects with diabetes duration of 3 to 8 years (n = 78) where HbA1c was higher in those subjects on premixed insulin, 8.4 +/- 0.5% versus 6.9 +/- 0.2%, p < 0.01. In subjects aged > 35 years, 74/318 (23%) used premixed insulin. HbA1c did not differ between those using premixed insulin and those using separate insulin preparations, 7.5 +/- 0.2% and 7.5 +/- 0.1% respectively. We conclude that use of premixed insulin preparations achieved a similar level of glycaemic control as use of individual insulin preparations with the exception of patients aged less than 35 years who were 3 to 8 years following diagnosis. The relatively good glycaemic control achieved may make these preparations a useful alternative to multiple injection therapy for many patients with Type 1 DM.

Gender difference in the response of growth hormone (GH)-deficient adults to GH therapy.

While individual hypopituitary patients undoubtedly benefit from growth hormone (GH) therapy, there is considerable variability in the response to treatment. Given the expense, possible lack of benefit, and potential risks associated with long-term therapy, we sought to identify characteristics potentially associated with a favorable response to GH replacement. Twelve GH-deficient adults (seven men and five women aged 35.4+/-2.5 years, mean +/- SEM) participated in a 12-month open study of GH replacement (0.125 IU/kg/wk for 4 weeks and 0.25 IU/kg/wk thereafter) designed to examine the impact of GH on body composition, lipid profile, and psychological well-being. Using bioelectrical impedance analysis (BIA), there was a reduction in body fat (BF) and an increase in lean body mass (LBM) and total body water (TBW) (P < .05) following 12 months of GH treatment. In addition, there was a significant improvement in psychological well-being as indicated by a decrease in the Nottingham Health Profile (NHP) score (P < .05) and a decrease in both total cholesterol (P = .005) and low-density lipoprotein (LDL) cholesterol (P < .03). GH therapy was associated with an increase in fasting plasma glucose (P = .008) and hemoglobin A1c (HbA1c (P = .06). When analyzed by gender, the beneficial effect of GH was greater in men versus women for the increment in insulin-like growth factor-1 ([IGF-1] 375+/-59 v 148+/-73 microg/L, mean +/- SEM), increase in LBM (6.8+/-2.5 v -0.06+/-1.6 kg), reduction in BF (5.6+/-1.6 v 1.0+/-1.9 kg), and increase in TBW (5.0+/-1.6 v 0.14+/-1.29 L) (P < .05). HbA1c increased significantly in women (P < .05). The beneficial effect of GH tended to be greatest in those with the most significant abnormality in baseline values (P < .05). The duration of hypopituitarism showed an indirect correlation with the change in total cholesterol (P < .005). Baseline IGF-1 levels correlated directly with changes in TBW (P < .05). These data indicate that men with GH deficiency appear more responsive to GH therapy than women with respect to the increase in IGF-1 levels and improvement in body composition. In general, patients with the most significant abnormality in baseline values, the highest IGF-1 levels, and the shortest duration of hypopituitarism respond best. With long-term GH therapy, careful monitoring of glucose tolerance is indicated.

Non-ACTH POMC fragments stimulate aldosterone production by human adrenal cells in vitro.

The possibility that non-ACTH proopiomelanocortin-derived fragments may stimulate aldosterone production has previously been studied using nonhuman cells with inconsistent results. We have examined the response of aldosterone to beta-endorphin (beta-End) and joining peptide (JP) and compared these with the response to ACTH using eight cell suspensions prepared from human adrenal glands. ACTH, 10(-6), 10(-8), and 10(-10) M, consistently stimulated aldosterone accumulation above that occurring in unstimulated cells (150 +/- 83, 120 +/- 62, and 77 +/- 32 fmol/10(4) cells above basal, respectively; mean +/- SE; p < 0.05). beta-End significantly stimulated aldosterone production at 10(-6) and 10(-8) M (114 +/- 84 and 50 +/- 24 fmol/10(4) cells above basal; p < 0.05); 10(-10) M beta-End did not provide significant stimulation. Furthermore, JP stimulated aldosterone biosynthesis (41 +/- 16 fmol/10(4) cells above basal; p < 0.05), only at the highest concentration used, 10(-6) M. The addition of 10(-8) M ACTH plus 10(-6) and 10(-10) M beta-End to human adrenal cells yielded values significantly greater than those achieved with either agent alone (267 +/- 152 and 183 +/- 89 fmol/10(4) cells above basal; p < 0.05). These data indicate for the first time that beta-End and JP have the capacity to stimulate aldosterone production in human adrenal cells in vitro. The physiological and potential clinical significance of these observations has yet to be elucidated.

Decline in insulin-like growth factor I levels after clomiphene citrate does not correct hyperandrogenemia in polycystic ovary syndrome.

It is widely accepted that the action of clomiphene citrate (CC) is mediated through its antiestrogenic properties on the hypothalamic-pituitary axis. Although insulin-like growth factor I (IGF-I) enhances the thecal cell response to LH, and estrogen treatment is associated with a reduction in IGF-I levels, CC is known to decrease circulatory IGF-I levels in polycystic ovary syndrome (PCOS) patients. The impact of lowering IGF-I levels on androgen levels in PCOS is unknown. This study was designed to examine the impact of CC treatment on the interrelationships of IGF-I, androgens, and estrogens in normal subjects and patients with PCOS. IGF-I, gonadotropin, androgen, estrogen, and sex hormone-binding globulin levels were measured in 8 PCOS patients and 10 normal subjects before and after treatment with the antiestrogen CC. Studies were performed in the early follicular phase, days 4-6 of the menstrual cycle in normal subjects. In normal subjects, CC treatment led to a significant increase in estradiol (84 +/- 10 to 234 +/- 62 pmol/L, untreated and CC treated; P < 0.05) and estrone (125 +/- 14 to 257 +/- 29 pmol/L; P < 0.05) levels with a significant lowering of IGF-I levels (297 +/- 25 to 230 +/- 17 micrograms/L; P < 0.05). Similarly, in PCOS patients a significant increase in estradiol (110 +/- 11 to 245 +/- 58 pmol/L; P < 0.05) and estrone (301 +/- 32 to 401 +/- 90 pmol/L; P < 0.05) levels and a significant lowering of IGF-I levels (330 +/- 43 to 214 +/- 27 micrograms/L; P < 0.05) were observed after CC treatment. However, no significant correlation was observed between changes in IGF-I and changes in estradiol in either group. Compared to pretreatment levels, no significant changes in the following parameters were observed after 5 days of CC treatment in either study group: testosterone, testosterone/sex hormone-binding globulin ratio, and androstenedione. The relationship among CC treatment, gonadotropin, estrogen, and IGF-I levels is complex. Changes in blood IGF-I levels are not associated with changes in androgen levels, although paracrine and or autocrine effects cannot be excluded.

Intra-adrenal factors are not involved in the differential control of cortisol and adrenal androgens in human adrenals.

The differential control of adrenal androgens and cortisol may be due to intra-adrenal factors, which may be age- or sex-related, or due to extra-adrenal factors, such as circulating hormones. The purpose of this study was to identify any intrinsic differences that may exist in steroidogenic production occurring within adrenals obtained from males and females, and any maturational differences that may evolve with age. Using human adrenals from 48 transplant donors (32 males, 16 females; ages 5-60 years), the influences of age and sex on basal production of and ACTH-stimulated cortisol, androstenedione and dehydroepiandrosterone (DHEA) were examined in freshly prepared adrenal cell suspensions. Basal and ACTH-stimulated cortisol, androstenedione and DHEA production were similar in adrenals from males and females and did not correlate significantly with age when the whole group was examined. When steroidogenesis in male and female adrenals was examined separately against age, a significant correlation was observed only for basal and ACTH-stimulated androstenedione in adrenals from males in the younger age group, 5-30 years (basal: r=0.84, P=0.0001; ACTH-stimulated: r=0.52, P=0.007). Examination of the relationships between the steroids disclosed that the basal and ACTH-stimulated cortisol/androgen ratios did not correlate significantly with age, but the androstenedione/DHEA ratio showed a significant direct relationship with age in males only (basal: r=0.53, P=0.006; ACTH-stimulated: r=0.5, P=0.01). These data suggest that the influences of sex and age are minor in the modulation of adrenal steroidogenesis and support the concept that extra-adrenal factors dominate in the differential modulation of adrenal androgens and cortisol. The relationship between the androstenedione/ DHEA ratio and increasing age in men is consistent with the recently reported stimulatory effect of testosterone on adrenal steroidogenesis by induction of the conversion of DHEA to androstenedione.

A critical review of the origin and control of adrenal androgens.

The reticularis and fasciculata zones of the adrenal cortex are the predominant sources of dehydroepiandrosterone (DHEA) and DHEA-sulphate and contribute directly or indirectly 60-75% of androstenedione and testosterone in women. The specific control of adrenal androgens remains unclear. While ACTH stimulates adrenal androgen secretion, the dissociation of cortisol and androgens occurring during adrenarche and under pathological conditions suggests other factors are involved. Recent studies using human adrenal cells in vitro have demonstrated that the ratio of androgen to cortisol produced is substantially independent of the age and gender of the adrenal, indicating that extra-adrenal factors are of greater importance. beta-Endorphin and joining peptide have been shown to stimulate androgen production in human adrenal cells and to influence ACTH-stimulated steroidogenesis in a manner that promotes adrenal androgen production. The activity of these pro-opiomelanocortin-derived peptides may explain the physiological and pathological dissociations of androgens and cortisol.

Virilization in a postmenopausal woman as a result of hilus cell hyperplasia associated with a simple ovarian cyst.

A 68-year-old woman who had virilization was found to have an androgen-secreting simple ovarian cyst at laparotomy. Histologic examination demonstrated hilus cell hyperplasia in the ovarian hilus and cyst wall. In the differential diagnosis of postmenopausal virilization, hilus cell hyperplasia, although rare, should be considered.

Effects of nifedipine treatment on the renin-angiotensin-aldosterone axis.

Nifedipine is a commonly used agent in treating hypertension and angina because of its vasodilator properties. An inhibitory role of nifedipine on aldosterone (Aldo) biosynthesis has been documented in in vitro studies. This study was designed to examine the impact of a sustained release nifedipine formulation on Aldo biosynthesis and its clinical consequences. Early and late effects of nifedipine on Aldo, PRA, and Aldo/PRA ratio levels were studied in a single blind, placebo-controlled, 10-day pilot study. Ten normotensive subjects and 10 patients with hypertension were studied. Blood samples for the measurement of Aldo and PRA were obtained at 2-h intervals for 10 h on a control day and on days 1 and 8 of nifedipine treatment for the determination of baseline, early, and late values. Placebo was administered at 0800 h on the first and second days of the study, whereas nifedipine (60 mg/day) was given for the following 8 days. The Aldo/ PRA ratio was used as a sensitive indirect index of the responsiveness of Aldo secretion to adrenal stimulation with angiotensin. Compared to those on the control day, a significant rise in the integrated PRA levels occurred on the first day of nifedipine treatment, with a further rise observed on the eighth day of the treatment in the normotensive subjects (1.1 +/- 0.6, 1.7 +/- 1.2, and 2.5 +/- 1.8 ng/mL.h on the control day and the first and eighth days of treatment, respectively; P < 0.05) and by the eighth day in the hypertensive subjects (2.2 +/- 2.8 and 4.0 +/- 4.1 ng/mL.h; P < 0.05). A significant rise in integrated Aldo levels occurred in the normotensive subjects on the eighth day of nifedipine treatment (control day, 319 +/- 187; eighth day of nifedipine, 363 +/- 167 pmol/L; P < 0.05) and in the hypertensive subjects (426 +/- 219 and 535 +/- 284 pmol/L; P < 0.05). This was associated with a significant lowering of the Aldo/PRA ratio on the first day of the treatment, with further lowering on the eighth day in the normotensive (435 +/- 454, 269 +/- 209, and 182 +/- 107; P < 0.05) and by the eighth day in the hypertensive subjects (716 +/- 833 and 305 +/- 315; P < 0.05). When individual time points were examined in the normotensive subjects, Aldo/PRA levels were significantly lower on day 8 of nifedipine treatment at 1000, 1200, and 1400 h than corresponding values on the control day. The fall in the Aldo/PRA ratio during nifedipine treatment indicates that the previously reported in vitro inhibition of Aldo biosynthesis in adrenal cells is reproduced in vivo. In the absence of nifedipine, it is likely that Aldo levels would be higher for any given level of PRA. It is probable that the Aldo inhibition and the vasodilatatory effect of nifedipine combine to bring about the lowering of blood pressure. Drugs that inhibit renin-angiotensin axis activity are likely to be particularly effective when additional lowering of blood pressure is required.