Proportion of participants with type 2 diabetes achieving a metabolic composite endpoint with once-weekly semaglutide treatment versus comparators: Post hoc pooled analysis from SUSTAIN 1-5, 7-10 and SUSTAIN China.

AIM: To compare the proportion of participants with type 2 diabetes (T2D) treated with once-weekly (OW) subcutaneous (SC) semaglutide versus comparators who achieved a composite metabolic endpoint. MATERIALS AND METHODS: SUSTAIN 1-5, 7-10 and SUSTAIN China trial data were pooled. Participants with T2D (aged ≥18 years) and glycated haemoglobin ≥7.0% (≥53 mmol/mol) who had been randomized to OW SC semaglutide (0.5 or 1.0 mg) or comparator in addition to background medication. Using patient-level data pooled by treatment, proportions of participants achieving the metabolic composite endpoint, defined as glycated haemoglobin <7% (<53 mmol/mol), blood pressure <140/90 mmHg and non-high-density lipoprotein cholesterol <130 mg/dl (<3.37 mmol/L), were evaluated following baseline adjustments. Endpoints were analysed per trial using a binomial logistic regression model with treatment, region/country and stratification factor as fixed effects and baseline value as covariate. Pooled analysis used logistic regression with treatment and trial as fixed effects and baseline value as covariate. RESULTS: This post hoc analysis included data from 7633 participants across 10 trials. The proportion of participants who achieved the metabolic composite endpoint was significantly higher with OW SC semaglutide 0.5 and 1.0 mg versus comparators (23.7% and 32.0% vs. 11.5%, respectively; p < .0001). Likewise, when the OW SC semaglutide doses were pooled, significantly higher proportions of patients receiving semaglutide achieved the composite metabolic endpoint versus comparators (29.1% vs. 11.4%, respectively; p < .0001). CONCLUSIONS: Treatment with OW SC semaglutide versus comparators was associated with increased proportions of participants with T2D meeting the composite metabolic endpoint.

Safety and efficacy of insulin degludec/liraglutide (IDegLira) added to sulphonylurea alone or to sulphonylurea and metformin in insulin-naïve people with Type 2 diabetes: the DUAL IV trial.

AIM: To investigate the safety and efficacy of insulin degludec/liraglutide (IDegLira), a novel combination product, as add-on therapy for people with Type 2 diabetes uncontrolled on sulphonylurea therapy. METHODS: In this 26-week, double-blind trial, adults with Type 2 diabetes [HbA1c 53-75 mmol/mol (7.0-9.0%)] were randomized to IDegLira (n = 289) or placebo (n = 146) as add-on to pre-trial sulphonylurea ± metformin, titrating to a fasting glycaemic target of 4.0-6.0 mmol/l. Treatment initiation was at 10 dose steps, and maximum dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). RESULTS: The mean HbA1c decreased from 63 mmol/mol (7.9%) to 46 mmol/mol (6.4%) with IDegLira and to 57 mmol/mol (7.4%) with placebo [estimated treatment difference -11 mmol/mol (95% CI -13; -10) or -1.02% (95% CI -1.18; -0.87); P < 0.001]. The HbA1c target of 53 mmol/mol (<7%) was achieved by 79.2% of participants in the IDegLira group vs 28.8% in the placebo group [estimated odds ratio 11.95 (95% CI 7.22; 19.77); P < 0.001]. Mean weight change was +0.5 kg with IDegLira vs -1.0 kg with placebo [estimated treatment difference 1.48 kg (95% CI 0.90; 2.06); P < 0.001]. Confirmed hypoglycaemia occurred in 41.7 and 17.1% of IDegLira- and placebo-treated participants, respectively, with rates of 3.5 vs 1.4 events/patient-years of exposure [estimated rate ratio 3.74 (95% CI 2.28; 6.13); P < 0.001]. IDegLira was generally well tolerated. The rates of serious adverse events were 20.3 and 8.0 per 100 patient-years of exposure with IDegLira and placebo, respectively, without obvious patterns in the type of events. CONCLUSIONS: IDegLira can be used in people uncontrolled with sulphonylurea ± metformin to improve efficacy with a safety profile in line with previous DUAL trials.

Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin.

AIMS: To evaluate the efficacy and safety of titrated canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin and sitagliptin. METHODS: In this randomized, double-blind study, patients with T2DM (N = 218) on metformin ≥1500 mg/day and sitagliptin 100 mg received canagliflozin 100 mg or placebo. After 6 weeks, the canagliflozin dose was increased from 100 to 300 mg (or from placebo to matching placebo) if all of the following criteria were met: baseline estimated glomerular filtration rate ≥70 ml/min/1.73 m(2) ; fasting self-monitored blood glucose ≥5.6 mmol/l (≥100 mg/dl); and no volume depletion-related adverse events (AEs) within 2 weeks before dose increase. Endpoints included change in glycated haemoglobin (HbA1c) at week 26 (primary); proportion of patients achieving HbA1c <7.0%; and changes in fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP). Safety was assessed using AE reports. RESULTS: Overall, 85.4% of patients were titrated to canagliflozin 300 mg or matching placebo (mean ± standard deviation time to titration 6.2 ± 0.8 weeks). At week 26, canagliflozin (pooled 100 and 300 mg) demonstrated superiority in HbA1c reduction versus placebo (-0.91% vs. -0.01%; p < 0.001). Canagliflozin provided significant reductions in FPG, body weight and SBP compared with placebo (p < 0.001). The overall AE incidence was 39.8 and 44.4% for canagliflozin and placebo, respectively. Canagliflozin was associated with an increased incidence of genital mycotic infections. CONCLUSIONS: Titrated canagliflozin significantly improved HbA1c, FPG, body weight and SBP, and was generally well tolerated over 26 weeks in patients with T2DM as add-on to metformin and sitagliptin.

Treatment intensification with an insulin degludec (IDeg)/insulin aspart (IAsp) co-formulation twice daily compared with basal IDeg and prandial IAsp in type 2 diabetes: a randomized, controlled phase III trial.

AIMS: To evaluate the efficacy and safety of two insulin intensification strategies for patients with type 2 diabetes previously treated with basal insulin--insulin degludec (IDeg) and insulin aspart (IAsp)--administered as a co-formulation (IDegAsp) or as a basal-bolus regimen (IDeg and IAsp in separate injections). METHODS: This 26-week, open-label, treat-to-target, phase IIIb, non-inferiority trial randomized patients (1 : 1) to IDegAsp twice daily with main meals (n = 138; IDegAsp group) or IDeg once daily and IAsp 2-4 times daily (n = 136; IDeg+IAsp group). RESULTS: After 26 weeks, the mean glycated haemoglobin (HbA1c) level was 7.0% (53 mmol/mol) for the IDegAsp group and 6.8% (51 mmol/mol) for the IDeg+IAsp group (Δ%HbA1c from baseline -1.31 and -1.50%, respectively). The non-inferiority of IDegAsp versus IDeg+IAsp was not confirmed for mean change in HbA1c [estimated treatment difference (ETD) 0.18, 95% confidence interval (CI) -0.04, 0.41; p = non-significant]. No significant differences were observed in the proportion of patients achieving HbA1c <7.0% (56.5 and 59.6%, respectively). IDegAsp treatment resulted in a significantly lower total daily insulin dose, a smaller change in body weight, numerically lower rates of confirmed hypoglycaemia (self-reported plasma glucose <3.1 mmol/l; rate ratio 0.81; p = non-significant), and nocturnal confirmed hypoglycaemic episodes (rate ratio 0.80; p = non-significant) versus IDeg+IAsp. Patient-reported outcome scores for social functioning were significantly higher for IDegAsp versus IDeg+IAsp (ETD 2.2; 95% CI 0.3, 4.1; p < 0.05). CONCLUSIONS: Both intensification strategies effectively improved glycaemic control. Although non-inferiority was not confirmed, there were no significant differences between the groups that could affect clinical utility.

Benefits of combination of insulin degludec and liraglutide are independent of baseline glycated haemoglobin level and duration of type 2 diabetes.

AIM: To evaluate, using post hoc analyses, whether the novel combination of a basal insulin, insulin degludec, and a glucagon-like peptide-1 receptor agonist, liraglutide (IDegLira), was consistently effective in patients with type 2 diabetes (T2D), regardless of the stage of T2D progression. METHODS: Using data from the DUAL I extension [insulin-naïve patients uncontrolled on oral antidiabetic drugs (OADs), n = 1660, 52 weeks] and DUAL II (patients uncontrolled on basal insulin plus OADs, n = 398, 26 weeks) randomized trials, the efficacy of IDegLira was investigated with regard to measures of disease progression stage including baseline glycated haemoglobin (HbA1c), disease duration and previous insulin dose. RESULTS: Across four categories of baseline HbA1c (≤7.5-9.0%), HbA1c reductions were significantly greater with IDegLira (1.1-2.5%) compared with IDeg or liraglutide alone in DUAL I. In DUAL II, HbA1c reductions were significantly greater with IDegLira (0.9-2.5%) than with IDeg in all but the lowest HbA1c category. In DUAL I, insulin dose and hypoglycaemia rate were lower across all baseline HbA1c categories for IDegLira versus IDeg, while hypoglycaemia was higher with IDegLira than liraglutide, irrespective of baseline HbA1c. In DUAL II, insulin dose and hypoglycaemia rate were similar with IDegLira and IDeg (maximum dose limited to 50 U) independent of baseline HbA1c. The reduction in HbA1c with IDegLira was independent of disease duration and previous insulin dose but varied depending on pre-trial OAD treatment. CONCLUSIONS: IDegLira effectively lowered HbA1c across a range of measures, implying suitability for patients with either early or advanced T2D.

Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo-controlled trial.

AIM: To confirm the superiority, compared with placebo, of adding liraglutide to pre-existing basal insulin analogue ± metformin in adults with inadequately controlled type 2 diabetes [glycated haemoglobin (HbA1c) 7.0-10.0% (53-86 mmol/mol)]. METHODS: In this 26-week, double-blind, parallel-group study, conducted in clinics or hospitals, 451 subjects were randomized 1 : 1 to once-daily liraglutide 1.8 mg (dose escalated from 0.6 and 1.2 mg/day, respectively, for 1 week each; n = 226) or placebo (n = 225) added to their pre-existing basal insulin analogue (≥20 U/day) ± metformin (≥1500 mg/day). After randomization, insulin adjustments above the pre-study dose were not allowed. The primary endpoint was HbA1c change. RESULTS: After 26 weeks, HbA1c decreased more with liraglutide [-1.3% (-14.2 mmol/mol)] than with placebo [-0.1% (-1.2 mmol/mol); p < 0.0001]. More subjects on liraglutide reached HbA1c targets: <7.0% (59% vs 14%; p < 0.0001) and ≤6.5% (43% vs 4%; p < 0.0001) using slightly less insulin (35.8 IU vs 40.1 IU). Greater decreases from baseline (estimated treatment differences vs placebo; p < 0.0001) occurred in fasting plasma glucose (-1.3 mmol/l), seven-point glucose profiles (-1.6 mmol/l), body weight (-3.1 kg) and systolic blood pressure (-5.0 mmHg). Transient gastrointestinal adverse events (nausea: 22.2% vs 3.1%) and minor hypoglycaemia (18.2% vs 12.4%) were more frequent with liraglutide than placebo, and pulse increased (4.5 beats/min) compared with placebo. No severe hypoglycaemia or pancreatitis occurred. CONCLUSIONS: Adding liraglutide to a basal insulin analogue ± metformin significantly improved glycaemic control, body weight and systolic blood pressure compared with placebo. Typical gastrointestinal symptoms and minor hypoglycaemia were more frequent with liraglutide.

One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial.

AIMS: To confirm, in a 26-week extension study, the sustained efficacy and safety of a fixed combination of insulin degludec and liraglutide (IDegLira) compared with either insulin degludec or liraglutide alone, in patients with type 2 diabetes. METHODS: Insulin-naïve adults with type 2 diabetes randomized to once-daily IDegLira, insulin degludec or liraglutide, in addition to metformin ± pioglitazone, continued their allocated treatment in this preplanned 26-week extension of the DUAL I trial. RESULTS: A total of 78.8% of patients (1311/1663) continued into the extension phase. The mean glycated haemoglobin (HbA1c) concentration at 52 weeks was reduced from baseline by 1.84% (20.2 mmol/mol) for the IDegLira group, 1.40% (15.3 mmol/mol) for the insulin degludec group and 1.21% (13.2 mmol/mol) for the liraglutide group. Of the patients on IDegLira, 78% achieved an HbA1c of <7% (53 mmol/mol) versus 63% of the patients on insulin degludec and 57% of those on liraglutide. The mean fasting plasma glucose concentration at the end of the trial was similar for IDegLira (5.7 mmol/l) and insulin degludec (6.0 mmol/l), but higher for liraglutide (7.3 mmol/l). At 52 weeks, the daily insulin dose was 37% lower with IDegLira (39 units) than with insulin degludec (62 units). IDegLira was associated with a significantly greater decrease in body weight (estimated treatment difference, -2.80 kg, p < 0.0001) and a 37% lower rate of hypoglycaemia compared with insulin degludec. Overall, all treatments were well tolerated and no new adverse events or tolerability issues were observed for IDegLira. CONCLUSIONS: These 12-month data, derived from a 26-week extension of the DUAL I trial, confirm the initial 26-week main phase results and the sustainability of the benefits of IDegLira compared with its components in glycaemic efficacy, safety and tolerability.

Health status and hypoglycaemia with insulin degludec versus insulin glargine: a 2-year trial in insulin-naïve patients with type 2 diabetes.

Insulin degludec (IDeg) is a new basal insulin with an ultra-long and stable glucose-lowering effect. We compared once-daily IDeg and insulin glargine (IGlar), both in combination with metformin ± dipeptidyl peptidase-4 inhibitors, in a 52-week, open-label, treat-to-target trial in patients with type 2 diabetes followed by a 52-week extension trial in which subjects [n = 725/1030 (70.4%)] maintained their initial randomised treatment. Health status was assessed at baseline and 105 weeks using the Short Form-36 (SF-36 v2) questionnaire. SF-36 scores were analysed (ITT population) using anova, with adjustments for covariates. At 105 weeks, the overall physical component score was significantly better with IDeg versus IGlar [treatment contrast (TC): 1.1 (0.1; 2.1)95% CI , p < 0.05]. This was largely because of significantly better physical functioning [TC: 1.1 (0.0; 2.3)95% CI , p < 0.05] and bodily pain sub-domain scores [TC: 1.5 (0.2; 2.9)95% CI , p < 0.05]. Improvements in health status with IDeg compared to IGlar were maintained after 2 years.

A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: VICTOZA ADD-ON).

AIM: Two treatment strategies were compared in patients with type 2 diabetes (T2DM) on basal insulin requiring intensification: addition of once-daily (OD) liraglutide (Lira) or OD insulin aspart (IAsp) with largest meal. METHODS: Subjects completing 104 weeks (52-week main trial BEGIN ONCE-LONG + 52-week extension) on insulin degludec (IDeg) OD + metformin with HbA1c ≥ 7.0% (≥53 mmol/mol) were randomized to IDeg+Lira [n = 88, mean HbA1c: 7.7% (61 mmol/mol)] or IDeg+IAsp (n = 89, mean HbA1c: 7.7%) for 26 weeks, continuing metformin. Subjects completing 104 weeks with HbA1c <7.0% continued IDeg + metformin in a third, non-randomized arm (n = 236). RESULTS: IDeg+Lira reduced HbA1c (-0.74%-points) significantly more than IDeg+IAsp (-0.39%-points); estimated treatment difference (ETD) (IDeg+Lira-IDeg+IAsp) -0.32%-points (95% CI -0.53; -0.12); p = 0.0024. More IDeg+Lira (49.4%) than IDeg+IAsp (7.2%) subjects achieved HbA1c <7.0% without confirmed hypoglycaemia [plasma glucose <3.1 mmol/l (<56 mg/dl) or severe hypoglycaemia) and without weight gain; estimated odds ratio (IDeg+Lira/IDeg+IAsp) 13.79 (95% CI 5.24; 36.28); p < 0.0001. IDeg+Lira subjects had significantly less confirmed and nocturnal confirmed hypoglycaemia, and significantly greater weight loss (-2.8 kg) versus IDeg+IAsp (+0.9 kg); ETD (IDeg+Lira-IDeg+IAsp) -3.75 kg (95% CI -4.70; -2.79); p < 0.0001. Other than more gastrointestinal side effects with IDeg+Lira, no safety differences occurred. Durability of IDeg was established in the non-randomized arm, as mean HbA1c remained <7.0% [mean 6.5% (48 mmol/mol) at end-of-trial]. CONCLUSIONS: IDeg+Lira improved long-term glycaemic control, with weight loss and less hypoglycaemia versus adding a single daily dose of IAsp in patients with T2DM inadequately controlled with IDeg + metformin.

Options for prandial glucose management in type 2 diabetes patients using basal insulin: addition of a short-acting GLP-1 analogue versus progression to basal-bolus therapy.

Integrating patient-centered diabetes care and algorithmic medicine poses particular challenges when optimized basal insulin fails to maintain glycaemic control in patients with type 2 diabetes. Multiple entwined physiological, psychosocial and systems barriers to insulin adherence are not easily studied and are not adequately considered in most treatment algorithms. Moreover, the limited number of alternatives to add-on prandial insulin therapy has hindered shared decision-making, a central feature of patient-centered care. This article considers how the addition of a glucagon-like peptide 1 (GLP-1) analogue to basal insulin may provide new opportunities at this stage of treatment, especially for patients concerned about weight gain and risk of hypoglycaemia. A flexible framework for patient-clinician discussions is presented to encourage development of decision-support tools applicable to both specialty and primary care practice.

Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes: a 2-year randomized, treat-to-target trial.

AIMS: The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes. METHODS: This open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9-4.9 mmol/l. RESULTS: At end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI -1 to 3) [0.07% (95% CI -0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects). CONCLUSIONS: In Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine.

Rate and risk predictors for development of self-reported type-2 diabetes mellitus over a 5-year period: the SHIELD study.

AIMS: This investigation determined the proportion of adults newly diagnosed as having type-2 diabetes mellitus (T2DM), and ascertained risk predictors for development of self-reported T2DM. METHODS: The US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) survey was a 5-year longitudinal study of adults with and without diabetes mellitus. Adults completed a baseline health questionnaire in 2004 and ≥1 annual follow-up survey through 2009. Respondents with no self-reported diagnosis of diabetes at baseline were followed to measure rate of and assess risk factors for development of T2DM over 5 years. RESULTS: Among 8582 respondents without diabetes at baseline, 622 (7.2%) reported a diagnosis of T2DM over the subsequent 5 years. Increasing age, family history of T2DM, body mass index ≥30 kg/m(2), abdominal obesity, excessive thirst, asthma, gestational diabetes and 'high blood sugar without diabetes' significantly increased the risk of developing T2DM (p < 0.05 for each). Good to excellent health status and self-reported circulatory problems decreased the risk (p < 0.05 for each). CONCLUSIONS: Among this representative US adult population, the rate of developing T2DM was 7.2% over 5 years. Predictors of T2DM diagnosis identified in this analysis were readily obtainable via self-report.

Is adiposopathy (sick fat) an endocrine disease?

OBJECTIVE: To review current consensus and controversy regarding whether obesity is a 'disease', examine the pathogenic potential of adipose tissue to promote metabolic disease and explore the merits of 'adiposopathy' and 'sick fat' as scientifically and clinically useful terms in defining when excessive body fat may represent a 'disease'. METHODS: A group of clinicians and researchers, all with a background in endocrinology, assembled to evaluate the medical literature, as it pertains to the pathologic and pathogenic potential of adipose tissue, with an emphasis on metabolic diseases that are often promoted by excessive body weight. RESULTS: The data support pathogenic adipose tissue as a disease. Challenges exist to convince many clinicians, patients, healthcare entities and the public that excessive body fat is often no less a 'disease' than the pathophysiological consequences related to anatomical abnormalities of other body tissues. 'Adiposopathy' has the potential to scientifically define adipose tissue anatomic and physiologic abnormalities, and their adverse consequences to patient health. Adiposopathy acknowledges that when positive caloric balance leads to adipocyte hypertrophy and visceral adiposity, then this may lead to pathogenic adipose tissue metabolic and immune responses that promote metabolic disease. From a patient perspective, explaining how excessive caloric intake might cause fat to become 'sick' also helps provide a rationale for patients to avoid weight gain. Adiposopathy also better justifies recommendations of weight loss as an effective therapeutic modality to improve metabolic disease in overweight and obese patients. CONCLUSION: Adiposopathy (sick fat) is an endocrine disease.

Self-reported prevalence and awareness of metabolic syndrome: findings from SHIELD.

PURPOSE: This study assessed awareness of metabolic syndrome and evaluated health knowledge, attitudes and behaviours of respondents at risk. METHODS: Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD), a longitudinal US population-based survey initiated in 2004, included respondents, > or = 18 years of age, reporting a diagnosis of metabolic syndrome. Prevalence of metabolic syndrome was compared in SHIELD and National Health and Nutrition Examination Survey (NHANES) 1999-2002 survey. The proportion of SHIELD respondents who had heard of and/or understood metabolic syndrome was estimated. Respondents at high risk for metabolic syndrome were stratified into attitude-behaviour categories of 'Already Doing It', 'I Know I Should' and 'Don't Bother Me' and differences in attitudes and behaviours were evaluated with chi-square tests. RESULTS: Prevalence of reported metabolic syndrome was 0.6% in SHIELD screening questionnaire respondents (n = 211,097) vs. 25.9% in NHANES (n = 10,780). Less than 15% of SHIELD baseline questionnaire respondents (n = 22,001) had heard of or understood metabolic syndrome. Attitudes toward health status were more favourable in the 'Doing' group (27% reported fair/poor health) compared with those in the 'Should' (38%) and 'Don't' (54%) groups (p < 0.0001). The 'Don't' group was most likely to prefer medications to lifestyle change (13% vs. 2-4%) compared with 'Should' and 'Doing' groups (p < 0.0001). More 'Doing' respondents (79%) than 'Should' (59%) and 'Don't' (48%) respondents reported exercising regularly (p < 0.0001). CONCLUSIONS: The lack of knowledge about metabolic syndrome reported in SHIELD indicates limited penetration of this concept into public awareness. With behaviour categories, respondents who report healthy attitudes are more likely to embrace lifestyle changes, while respondents who do not care may be more difficult to treat.

Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size.

This study was designed to determine whether exogenous hCG alone can complete spermiogenesis in men with isolated hypogonadotropic hypogonadism (IHH). hCG was administered to 22 men with IHH until maximal testicular growth was achieved. Their mean testicular volume increased from 5.5 +/- 1.1 (+/- SE) mL (pretreatment) to 10.8 +/- 1.6 mL (maximum) during treatment (P less than 10(-6)). The maximum mean testicular volume was highly positively correlated with initial volume (r = 0.84; P less than 10(-6)). All men attained normal serum testosterone levels, and 7 of 22 men achieved supraphysiological serum estradiol levels. During hCG treatment, 14 of the 22 men had sperm appear in their semen. Six of 11 men with complete gonadotropin deficiency, defined as an initial mean testicular volume less than 4 mL, became sperm positive during hCG treatment. In contrast, 9 of 11 men with partial gonadotropin deficiency (initial mean testicular volume of 4 mL or more) produced sperm during treatment (P less than 0.001). Sperm concentration was highly positively correlated with both pretreatment (r = 0.65; P less than 0.01) and final testicular volume (r = 0.73; P less than 0.0001). Of 13 men attempting to impregnate their partners, 7 were successful in initiating conception; a total of 8 pregnancies ensued. The sperm concentration at the time of conception was less than 10 million/mL in all but 1 man. Our study demonstrates that hCG, in the absence of exogenous FSH, can complete spermiogenesis in men with partial gonadotropin deficiency. The response to hCG in men with IHH is predicted by the initial testicular volume.

Insulin resistance in Cushing's disease. Evaluation by studies of insulin binding to erythrocytes.

Studies of 125I -insulin binding to erythrocytes (RBC) from 5 patients with Cushing's disease were performed in an attempt to evaluate the insulin resistance in this disease. Five obese, nondiabetic patients and six normal subjects served as controls. Insulin resistance was present in both the obese, nondiabetic subjects and in the patients with Cushing's disease. Patients with Cushing's disease showed insulin resistance out of proportion to obesity, and of greater severity than in the obese subjects. As in previous studies, the insulin resistance of the obese subjects could be at least partially ascribed to a reduced number of receptors. In contrast, in our patients with Cushing's disease, no physiologically significant changes in the parameters of insulin-receptor interaction could be demonstrated. This suggests that the RBC insulin receptor is not involved in this type of insulin resistance.