Changes in HbA1c and weight, and treatment persistence, over the 18 months following initiation of second-line therapy in patients with type 2 diabetes: results from the United Kingdom Clinical Practice Research Datalink.

BACKGROUND: Intensification of metformin monotherapy with additional glucose-lowering drugs is often required in patients with type 2 diabetes (T2D). This study evaluated changes in HbA1c and weight, as well as treatment persistence, associated with different second-line therapies used in UK clinical practice. METHODS: The UK Clinical Practice Research Datalink was used to identify patients with T2D who initiated second-line therapy after metformin monotherapy between 1 August 2013 and 14 June 2016. Treatment persistence and changes in HbA1c and weight were assessed at 6-month intervals up to 18 months. RESULTS: In total, 9097 patients (mean age 61.2 years, 57.2% men, mean [standard deviation] HbA1c 9.0% [1.8]/ 75 mmol/mol [19.7]) were included in the analysis, with a median 2.3 years between initiating metformin monotherapy and initiating second-line therapy. Patients were stratified according to second-line therapy: metformin in combination with sulfonylurea (SU; n = 4655 [51.2%]), a dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor; n = 2899 [31.9%]), or a sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor; n = 441 [4.9%]) or other therapies (all other second-line treatments; n = 1102 [12.1%]). At 18 months, the cumulative proportion of patients changing treatment was lowest for those who received metformin plus an SGLT-2 inhibitor (42.3%), followed by patients on metformin plus SU or metformin plus a DPP-4 inhibitor (46.8%). HbA1c reductions were seen with all second-line therapies, with an overall mean (standard error) reduction of -1.23% (0.05)/-13.4 mmol/mol (0.5). Changes were directly, but not linearly, related to baseline HbA1c and were greater in those with higher HbA1c at baseline. Weight loss from baseline was greatest in patients treated with metformin plus either an SGLT-2 inhibitor (-4.2 kg) or a DPP-4 inhibitor (-1.5 kg). The highest proportion of patients who achieved the composite outcome of HbA1c reduction ≥ 0.5%, body weight loss ≥ 2.0 kg and treatment persistence for 18 months was observed in those receiving metformin plus an SGLT-2 inhibitor (36.5%). CONCLUSIONS: In this population-based cohort, all second-line therapies added to metformin monotherapy improved glycaemic control, but the lowest treatment change/discontinuation rate and most sustained weight loss was seen with patients receiving metformin plus an SGLT-2 inhibitor.

Insulin degludec in Japanese patients with type 1 diabetes mellitus: A randomized controlled trial.

INTRODUCTION: Insulin degludec is an ultra-long-acting insulin with a flat time-action profile and duration of action >42 h. Data from several studies have shown insulin degludec to have a favorable therapeutic profile in type 1 and type 2 diabetes. MATERIALS AND METHODS: This was a 6-week, parallel-group, randomized controlled trial carried out in 65 Japanese patients with type 1 diabetes, previously treated with mealtime insulin aspart and either insulin glargine or neutral protamine Hagedorn insulin. Patients were randomized to receive either insulin degludec or insulin detemir, each once daily and at the same unit dose as pretrial basal insulin. During the trial, basal insulin was titrated according to a prespecified algorithm in order to achieve a fasting plasma glucose target of 80-109 mg/dL. RESULTS: No severe hypoglycemia occurred; there was no significant difference in confirmed hypoglycemia rates with insulin degludec and insulin detemir (rate ratio degludec/detemir 0.78; 95% confidence interval 0.45-1.34). The rate of nocturnal confirmed hypoglycemia was 69% lower with insulin degludec than with insulin detemir (rate ratio 0.31; 95% confidence interval 0.13-0.78). Final fasting plasma glucose levels were similar (insulin degludec 147 mg/dL, insulin detemir 136 mg/dL), despite differing baseline fasting plasma glucose levels. CONCLUSIONS: In conclusion, no concerns relating to hypoglycemia or general safety were observed when initiating insulin degludec in Japanese patients with type 1 diabetes at the same unit dose as previous basal insulin. This trial was registered with ClinicalTrials.gov (no. NCT00841087).

Insulin degludec compared with insulin glargine in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, Pan-Asian, treat-to-target trial.

INTRODUCTION: Insulin degludec (IDeg) is an ultra-long-acting basal insulin with a consistent action profile of >42 h. This trial compared the efficacy and safety of IDeg with insulin glargine (IGlar) in insulin-naïve Asian patients with type 2 diabetes. MATERIALS AND METHODS: In this multinational, 26-week, open-label, treat-to-target trial, 435 participants (202 females, 233 males; mean age 58.6 years; mean body mass index 25 kg/m(2); mean glycated hemoglobin [HbA1c] 8.5%) were randomized (2:1) to IDeg or IGlar, each administered once daily with ≥1 oral antidiabetic drug(s) (OAD). RESULTS: After 26 weeks, HbA1c had decreased by 1.24 and 1.35% in the IDeg and IGlar groups, respectively (treatment difference [IDeg - IGlar] 0.11%, 95% confidence interval [CI] -0.03 to 0.24), confirming non-inferiority. Rates of overall confirmed hypoglycemia were similar for IDeg and IGlar during the full trial period (3.0 vs 3.7 episodes/patient-year of exposure [PYE]; rate ratio [RR] 0.82, 95% CI 0.60 to 1.11, P = 0.20), but significantly lower (by 37%) for IDeg during the maintenance period (from week 16 onward; RR 0.63, 95% CI 0.42 to 0.94, P = 0.02). No significant difference in the rate of nocturnal confirmed hypoglycemia was found between IDeg and IGlar in the full trial period (0.8 vs 1.2 episodes/PYE; RR 0.62, 95% CI 0.38 to 1.04, P = 0.07) or maintenance period (RR 0.52, 95% CI 0.27 to 1.00, P = 0.05). Adverse event rates were similar between treatments. CONCLUSIONS: Initiating insulin therapy with IDeg in Asian patients with type 2 diabetes, inadequately controlled with OADs, provides similar improvements in long-term glycemic control to IGlar, but at a significantly lower rate of overall confirmed hypoglycemia once stable glycemic control and insulin dosing are achieved. This trial was registered with www.clinicaltrials.gov (no. NCT01059799).

The once-daily human glucagon-like peptide-1 analog, liraglutide, improves ß-cell function in Japanese patients with type 2 diabetes.

UNLABELLED: Aims/Introduction: ß-cell function was evaluated by homeostasis model assessment of ß-cell function (HOMA-B) index, proinsulin:insulin and proinsulin:C-peptide ratios in adult, Japanese type 2 diabetes patients receiving liraglutide. MATERIALS AND METHODS: Data from two randomized, controlled clinical trials (A and B) including 664 Japanese type 2 diabetes patients (mean values: glycated hemoglobin [HbA1c] 8.61-9.32%; body mass index [BMI] 24.4-25.3 kg/m(2)) were analyzed. In two 24-week trials, patients received liraglutide 0.9 mg (n = 268) or glibenclamide 2.5 mg (n = 132; trial A), or liraglutide 0.6, 0.9 mg (n = 176) or placebo (n = 88) added to previous sulfonylurea therapy (trial B). RESULTS: Liraglutide was associated with improved glycemic control vs sulfonylurea monotherapy or placebo. In liraglutide-treated groups in trials A and B, area under the curve (AUC) insulin 0-3 h was improved (P < 0.001 for all) and the AUCinsulin 0-3 h:AUCglucose 0-3 h ratio was increased (estimated treatment difference [liraglutide-comparator] 0.058 [0.036, 0.079]). HOMA-B significantly increased with liraglutide relative to comparator in trial B (P < 0.05), but not in trial A. The reduction in fasting proinsulin:insulin ratio was 50% greater than in comparator groups. CONCLUSIONS: In Japanese type 2 diabetes patients, liraglutide was associated with effective glycemic control, restoration of prandial insulin response and indications of improved ß-cell function. This trial was registered with Clinicaltrials.gov (trial A: no. NCT00393718/JapicCTI-060328 and trial B: no. NCT00395746/JapicCTI-060324). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00193.x, 2012).

Reduced weight gain with insulin detemir compared to NPH insulin is not explained by a reduction in hypoglycemia.

BACKGROUND: Weight gain often occurs when insulin therapy is initiated. The long-acting insulin analog insulin detemir has been shown to be effective and well tolerated when used in basal-bolus regimens or as an add-on to oral antidiabetic drugs (OADs) and causes less weight gain than other insulins. The aim of this exploratory analysis was to investigate any correlations between weight change and occurrence of hypoglycemia with NPH insulin and insulin detemir. METHODS: The analysis was based on a 26-week, randomized, multicenter, open-label, parallel-group trial in which glycemic control, hypoglycemia, and weight change were compared between insulin detemir and NPH insulin. A total of 476 insulin-naive patients with type 2 diabetes treated with one or two OADs added insulin detemir (n=237) or NPH insulin (n=239) morning and evening to their current oral treatment. Weight gain data from this study were analyzed as a function of hypoglycemia frequency. RESULTS: Both groups achieved excellent glycosylated hemoglobin control (insulin detemir, 6.6%; NPH insulin, 6.5% [difference not significant]). Weight gain with insulin detemir was less than half that of NPH insulin (1.2 vs. 2.8 kg, respectively [P<0.001]), and the overall risk of hypoglycemia was 47% lower with insulin detemir (P<0.001). No significant relationship between hypoglycemia and weight gain was seen with insulin detemir (P=0.2), while a statistically significant correlation was found for NPH insulin (P=0.003). CONCLUSIONS: Hypoglycemia is predictive of weight gain with NPH insulin, but the same relationship is not seen with insulin detemir. It is therefore likely that the weight-sparing effect of insulin detemir involves other mechanisms.

The effect of exercise on the absorption of inhaled human insulin in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Exercise is known to affect absorption of other inhaled substances, but so far there are no reports on the effect of exercise on the absorption of inhaled insulin in humans. WHAT THIS PAPER ADDS: This report is the first to investigate the effect of exercise on the absorption of inhaled insulin. In this study in healthy volunteers we found that exercise early after dosing increased absorption (15-20%) of inhaled insulin over the first 2 h after start of exercise, with an approximately 30% increase in maximal insulin concentration, and unchanged overall absorption. AIMS: To investigate the effect of moderate exercise on the absorption of inhaled insulin. METHODS: A single-centre, randomized, open-label, three-period cross-over trial was carried out in 12 nonsmoking healthy subjects. A dose of 3.5 mg inhaled human insulin was administered via a nebulizer and followed in random order by either 1) no exercise (NOEX), 2) 30 min exercise starting immediately after dosing (EX0), or 3) 30 min exercise starting 30 min after dosing (EX30). The study was carried out as a 10 h euglycaemic glucose clamp (90 mg dl(-1) (5.0 mmol l(-1))). RESULTS: The absorption of insulin over the first 2 h after start of exercise was 16% increased for EX0 (ratio (95%CI) 1.16 (1.04, 1.30), P = 0.01) and 20% increased for EX30 (1.20 (1.05, 1.36), P < 0.01), both compared with NOEX; the overall insulin absorption during 6 h and 10 h after dosing was not influenced by exercise. The maximum insulin concentration (C(max)) increased by 32% for EX0 and 35% for EX30 (both P < 0.01) compared with NOEX, while the time to C(max) was 31 min faster for EX0 (P < 0.01), but not significantly different after EX30, compared with NOEX. CONCLUSIONS: A significant and clinically relevant increase of insulin absorption over the first 2 h after the beginning of exercise was observed. Until data from studies using the specific insulin inhalers exists, patients using inhaled insulin should be made aware of a potential increased absorption and higher concentration of insulin in connection with exercise.

Lower risk of hypoglycemia with insulin detemir than with neutral protamine hagedorn insulin in older persons with type 2 diabetes: a pooled analysis of phase III trials.

OBJECTIVES: To compare the safety and efficacy of insulin detemir with that of neutral protamine Hagedorn (NPH) insulin in older (aged >/=65) and younger (aged 18-64) persons with type 2 diabetes mellitus (DM). DESIGN: Pooled, post hoc analysis of data from three open-label, randomized studies. SETTING: Three multinational Phase III trials. PARTICIPANTS: Four hundred sixteen older and 880 younger persons with DM, treated for 22 to 26 weeks with basal insulin plus mealtime insulin or oral agents. MEASUREMENTS: Hemoglobin A(1c) (HbA(1c)), fasting plasma glucose, glucose variability, hypoglycemic episodes. RESULTS: Mean treatment difference for HbA(1c) (insulin detemir-NPH insulin) indicated that insulin detemir was not inferior to NPH insulin for both age groups (0.035%, 95% confidence interval (CI)=-0.114-0.183 and 0.100%, 95% CI=-0.017-0.217, for older and younger persons, respectively). Relative risk of all hypoglycemic episodes (insulin detemir/NPH insulin) was 0.59 (95% CI-0.42-0.83) for older persons and 0.75 (95% CI-0.59-0.96) for younger persons. Adverse events were similar between treatments. Fasting plasma glucose was similar between treatments (mean treatment difference 0.97 mg/dL, 95% CI=-8.01-9.95, and 4.69 mg/dL, 95% CI=-2.30-11.67, for older and younger persons, respectively). Mean treatment difference for weight was -1.02 kg (95% CI -1.61 to -0.42) and -1.13 (95% CI -1.58 to -0.69) for older and younger persons, respectively. CONCLUSION: Previously reported benefits of insulin detemir, particularly less hypoglycemia and less weight gain, compared with NPH insulin, were the same for older and younger persons with DM at similar levels of HbA(1c).

The effect of exercise on the absorption of inhaled human insulin via the AERx insulin diabetes management system in people with type 1 diabetes.

OBJECTIVE: This study investigated the effect of moderate exercise on the absorption of inhaled insulin via the AERx insulin diabetes management system (iDMS). RESEARCH DESIGN AND METHODS: In this randomized, open-label, four-period, crossover, glucose clamp study 23 nonsmoking subjects with type 1 diabetes received a dose of 0.19 units/kg inhaled human insulin followed in random order by either 1) no exercise (NOEX group) or 30 min exercise starting, 2) 30 min after dosing (EX30), 3) 120 min after dosing (EX120), or 4) 240 min after dosing (EX240). RESULTS: Exercise changed the shape of the free plasma insulin curves, but compared with the NOEX group the area under the curve for free plasma insulin (AUC(ins)) for the first 2 h after the start of exercise was unchanged for EX30 and EX240, while it was 15% decreased for EX120 (P < 0.01). The overall insulin absorption during 6 and 10 h after dosing was 13% decreased for EX30 (P < 0.005), 11% decreased for EX120 (P < 0.01), and unchanged for EX240. Exercise did not influence the maximum insulin concentration (Cmax), while the time to Cmax was 22 min earlier for EX30 (P = 0.04). The AUC for the glucose infusion rate (AUC(GIR)) for 2 h after the start of exercise increased by 58% for EX30, 45% for EX120, and 71% for EX240 (all P < 0.02) compared with the NOEX group. CONCLUSIONS: Thirty minutes of moderate exercise led to unchanged or decreased absorption of inhaled insulin via AERx iDMS and faster Cmax for early exercise. Thus, patients using AERx iDMS can adjust insulin dose as usual independent of time of exercise, but they should be aware of the faster effect if exercising early after dosing.

A critical review of the literature on fear of hypoglycemia in diabetes: Implications for diabetes management and patient education.

OBJECTIVE: In many individuals with diabetes, the unpleasant symptoms and negative consequences associated with hypoglycemia may result in significant anxiety or even a fear of hypoglycemia (FoH). This fear may have significant clinical implications for diabetes management. The aim of this review is to integrate existing research on FoH (its measurement, predictors, correlates, impact and treatment) and discuss its implications for diabetes management and patient education. METHODS: A literature search was conducted using Medline and Embase. The search was limited to journal articles published in English from 1985 to 2007 inclusive. Three hundred and one abstracts were reviewed and 273 were rejected on the basis of non-relevance. In addition to the 28 papers included, six additional papers were identified by further searches and were added to this review. RESULTS: FoH appears to be a widespread phenomenon. It is measured primarily through the use of a specific scale, the Hypoglycemic Fear Survey (HFS). There are a number of factors that relate to whether an individual is likely to develop FoH including whether there is a history of hypoglycemia in an individual, length of time since first insulin treatment, and a higher level of variability in blood glucose level. FoH has been linked to both state and trait anxiety although the relationship is complex. CONCLUSIONS: There is evidence that FoH may have a significant negative impact on diabetes management, metabolic control and subsequent health outcomes. There is evidence that blood glucose (BG) awareness training and CBT can reduce levels of fear and improve disease management. More research is needed on how FoH arises and the individual variables which predict its development. In addition, well designed research is required to better understand the behavioral and medical impact of FoH, and interventions to reduce it. PRACTICE IMPLICATIONS: There is some evidence to suggest that interventions including BG awareness training and cognitive behavioral therapy can reduce levels of fear and improve disease management. While many aspects of FoH require further well-designed research, it is evident that this phenomenon can have a major impact on diabetes management and needs to be specifically addressed in patient education programs.

Insulin detemir results in less weight gain than NPH insulin when used in basal-bolus therapy for type 2 diabetes mellitus, and this advantage increases with baseline body mass index.

OBJECTIVE: Weight gain during insulin therapy can be a challenging problem in already overweight type 2 diabetes mellitus patients, affecting treatment compliance and long-term prognosis. The analogue insulin detemir has been reported to have a weight-sparing effect compared with other basal insulins. This pooled analysis investigated whether this potential advantage is related to body mass index (BMI) when insulin detemir is used as the basal component of basal-bolus therapy. METHODS: Data were pooled from two randomised, parallel group trials of 22 and 24 weeks' duration, in which 900 insulin-treated patients with type 2 diabetes mellitus had their treatment intensified to basal-bolus therapy. Patients received once- or twice-daily insulin detemir or neutral protamine Hagedorn (NPH) insulin in conjunction with insulin aspart or human soluble insulin at meal times. RESULTS: Patients treated with insulin detemir had minimal weight gain (mean <1 kg), regardless of their BMI at entry (estimated slope -0.032), whereas, in patients treated with NPH insulin, weight gain increased as baseline BMI increased (estimated slope 0.075, p = 0.025). Indeed, NPH insulin-treated patients with the largest BMI (>35 kg/m(2)) gained the most weight (mean of ~2.4 kg). In contrast, insulin detemir-treated patients with a BMI >35 kg/m(2) lost weight (mean of ~ -0.5 kg). Glycaemic control was similar with the two treatments. CONCLUSION: Insulin detemir may provide a clinical advantage in terms of reduced weight gain in the treatment of overweight patients with type 2 diabetes.

The impact of large tidal volume ventilation on the absorption of inhaled insulin in rabbits.

Previous studies have shown that ventilation patterns affect absorption of inhaled compounds. Thus, the aim of this study was to investigate the effect of large tidal volume ventilation (LTVV) on the absorption of inhaled insulin in rabbits. Mechanically ventilated rabbits were given human insulin via a nebuliser system, and plasma insulin was measured for the following 120min. Ventilation was adjusted to (1) normal tidal volume ventilation (NTVV) for the entire period after dosing (NTVV group), to (2) LTVV for the entire period after dosing (LTVV group), to (3) NTVV except for 15min LTVV immediately after dosing (Early LTVV group), or to (4) NTVV except for 15min LTVV starting at 60min after dosing (late LTVV group). Insulin absorption (AUC(ins(0-120min))) was increased by 149% for the LTVV group compared to NTVV group (p<0.01) with increased maximal insulin concentration (106%, p=0.03). The Early LTVV group showed a changed absorption profile. For the late LTVV group an increase in insulin levels was observed after the LTVV period (not significant compared to the NTVV group). These data could potentially have implications for patients using inhaled insulin in situations where a change in breathing pattern is seen, such as exercise.

Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes.

BACKGROUND: Many patients with poorly controlled type 2 diabetes mellitus (DM) receive, as initial insulin treatment, the addition of a basal formulation to an existing regimen of oral antidiabetic drug (OAD) therapy. Used this way, the insulin analogue detemir has been associated with improved glycemic control of a magnitude similar to neutral protamine Hagedorn (NPH), with lower rates of hypoglycemia and weight gain. Initial studies investigated detemir administered BID, but pharmacologic data suggest that detemir might be effective with QD administration. OBJECTIVES: The aims of this study were to compare the effectiveness and tolerability of detemir versus NPH administered QD together with > or =1 OAD in poorly controlled type 2 DM, and to compare different administration times of detemir. METHODS: This 20-week, multicenter, randomized, open-label, 3-arm, parallel-group trial was conducted at 91 centers across Europe and the United States. Men and women were eligible for participation if they were aged > or =18 years, had a body mass index (BMI) < or =40 kg/m(2), had a diagnosis of type 2 DM of at least 12 months' duration, and were insulin naive. Eligible patients also had a glycosylated hemoglobin (HbA(1c)) concentration value not outside the range of 7.5% to 11.0% following at least 3 months' treatment with > or =10 AD. Patients were randomly assigned to receive an evening SC injection of detemir, a prebreakfast injection of detemir, or an evening injection of NPH insulin (1:1:1), administered at initial doses of 10 IU (U). RESULTS: A total of 504 patients were enrolled 5 men, 219 women; mean [SD] age, 59 [11] years; mean [SD] BMI, 30 [5] kg/m2; insulin detemir before breakfast, 168; insulin detemir evening, 170; NPH insulin evening, 166). The intent-to-treat population comprised 498 patients. Morning and evening detemir were associated with reductions in HbA(1c) similar to those with evening NPH (raw mean decreases, -1.58%, -1.48%, and -1.74%, respectively). Nine-point profile and fasting and predinner plasma glucose data found morning detemir to be associated with a different diurnal glycemic profile compared with the evening regimens. Compared with evening NPH, 24-hour and nocturnal hypoglycemia were reduced by 53% (P = 0.019) and 65% (P = 0.031), respectively, with evening detemir. Incidences of hypoglycemia did not differ significantly between groups that received morning and evening detemir, but nocturnal hypoglycemia was reduced further, by 87%, with morning detemir compared with evening NPH (P < 0.001). Weight gain was 1.2, 0.7, and 1.6 kg with morning detemir, evening detemir, and NPH, respectively (P = 0.005 for evening detemir vs NPH). No between-treatment differences were seen in other tolerability end points. CONCLUSIONS: The results of this study in patients whose type 2 DM was poorly controlled with > or =1 OAD suggest that insulin detemir QD in the morning or evening can be used to improve glycemic control. Compared with NPH, insulin detemir may offer some tolerability advantages in this role.

A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes.

OBJECTIVE: To assess efficacy and tolerability of insulin detemir or NPH insulin added to oral therapy for type 2 diabetes in a treat-to-target titration protocol. RESEARCH DESIGN AND METHODS: Individuals (n = 476) with HbA(1c) (A1C) 7.5-10.0% were randomized to addition of twice-daily insulin detemir or NPH insulin in a parallel-group, multicenter trial. Over 24 weeks, insulin doses were titrated toward prebreakfast and predinner plasma glucose targets of < or =6.0 mmol/l (< or =108 mg/dl). Outcomes assessed included A1C, percentage achieving A1C < or =7.0%, risk of hypoglycemia, and body weight. RESULTS: At 24 weeks, A1C had decreased by 1.8 and 1.9% (from 8.6 to 6.8 and from 8.5 to 6.6%) for detemir and NPH, respectively (NS). In both groups, 70% of participants achieved an A1C

Influence of acute upper respiratory tract infection on the absorption of inhaled insulin using the AERx insulin Diabetes Management System.

AIMS: To assess the effects due to an uncomplicated acute upper respiratory tract infection (URTI) on the pharmacokinetics and glucose response of insulin when delivered by oral pulmonary absorption. METHODS: Normally healthy adult men (n = 11) and women (n = 9) received a single dose of inhaled human insulin, equivalent to approximately 6 IU subcutaneous, using the AERx insulin Diabetes Management System (iDMS), during and following recovery from an URTI. The first dose was administered with ongoing symptoms of < 3 days' duration, the second dose following recovery, and within 3 weeks of the first. Blood sampling for determination of insulin pharmacokinetics (serum AUC(0-6 h), AUC(0-8), C(max),t(max), t(1/2), MRT) and glucose response (plasma AOC(0-6 h)) was performed from 15 min predose to 6 h postdose. RESULTS: Insulin pharmacokinetics were not different for subjects during and following recovery from URTI [e.g. URTI: no URTI ratio in serum AUC(0-6 h) = 0.92 (95% confidence interval 0.81, 1.05)]; this was reflected by a similar glucose response. Inhaled insulin delivered by AERx iDMS was well tolerated by all subjects; no significant changes were observed in pulmonary function tests. No safety concerns arising from the mode of insulin administration were raised by either dose. CONCLUSIONS: The results suggest that insulin can be administered via AERx iDMS to nondiabetic subjects experiencing a URTI without any statistically significant changes in insulin pharmacokinetics or pharmacodynamics, and that the necessity for dose adjustments will not differ from subjects with an acute URTI who are receiving subcutaneous insulin.