Effects of sitagliptin on counter-regulatory and incretin hormones during acute hypoglycaemia in patients with type 1 diabetes: a randomized double-blind placebo-controlled crossover study.

AIMS: To assess whether the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin affects glucagon and other counter-regulatory hormone responses to hypoglycaemia in patients with type 1 diabetes. METHODS: We conducted a single-centre, randomized, double-blind, placebo-controlled, three-period crossover study. We studied 16 male patients with type 1 diabetes aged 18-52 years, with a diabetes duration of 5-20 years and intact hypoglycaemia awareness. Participants received sitagliptin (100 mg/day) or placebo for 6 weeks and attended the hospital for three acute hypoglycaemia studies (at baseline, after sitagliptin treatment and after placebo). The primary outcome was differences between the three hypoglycaemia study days with respect to plasma glucagon responses from the initialization phase of the hypoglycaemia intervention to 40 min after onset of the autonomic reaction. RESULTS: Sitagliptin treatment significantly increased active levels of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. No significant differences were observed for glucagon or adrenergic counter-regulatory responses during the three hypoglycaemia studies. Growth hormone concentration at 40 min after occurrence of autonomic reaction was significantly lower after sitagliptin treatment [median (IQR) 23 (0.2-211.0) mEq/l] compared with placebo [median (IQR) 90 (8.8-180) mEq/l; p = 0.008]. CONCLUSIONS: Sitagliptin does not affect glucagon or adrenergic counter-regulatory responses in patients with type 1 diabetes, but attenuates the growth hormone response during late hypoglycaemia.

Factors that drive insulin-dosing decisions of diabetes care providers: a vignette-based study in the Netherlands.

AIM: To test how certain patient factors would influence the decision of Dutch care providers regarding insulin dose adjustments. We hypothesize that some of these decisions would diverge from recent evidence and consensus statements. METHODS: We developed narrative vignettes describing clinical scenarios of patients receiving basal insulin therapy. For each vignette, the respondents were asked to indicate whether they would advise a change in insulin dose. A total of 520 paper questionnaires were distributed among physicians and nurses in primary and secondary care in the Netherlands. Multivariate linear and logistic regression analyses were performed to identify factors associated with dosing decisions. RESULTS: A total of 190 (37%) questionnaires were returned. In cases of a severe rather than mild hypoglycaemic event, care providers were nearly five times more likely to decrease the dose (odds ratio 4.77, 95% CI 1.65-13.75). Care providers were six times more likely to increase the dose when the patient's current dose was low (30 units) rather than high (90 units) (odds ratio 6.38, 95% CI 3.04-13.37). The plasma glucose concentration during a hypoglycaemic event and a known history of cardiovascular disease did not influence the care providers' dosing decisions. CONCLUSION: Evidence regarding the optimum insulin titration is not always translated into clinical practice. When formulating guidelines, misconceptions should be identified and addressed.

The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis.

Patients with type 2 diabetes mellitus using sulfonylurea derivatives or insulin may experience hypoglycaemia. However, recent data regarding the incidence of hypoglycaemia are scarce. We conducted a systematic review and meta-analysis to determine the proportion of patients with type 2 diabetes mellitus that experience hypoglycaemia when treated with sulfonylurea or insulin. We searched MEDLINE and EMBASE for randomized controlled trials that compared incretin-based drugs to sulfonylureas or insulin and assessed hypoglycaemia incidence in the latter therapies. Subgroup and meta-regression analyses were performed to study possible associations with potential risk factors for hypoglycaemia. Data of 25 studies were extracted, 22 for sulfonylurea and 3 for insulin. Hypoglycaemia with glucose ≤3.1 mmol/L or ≤2.8 mmol/L was experienced by 10.1% [95% confidence interval (CI) 7.3-13.8%] and 5.9% (95% CI 2.5-13.4%) of patients with any sulfonylurea treatment. Severe hypoglycaemia was experienced by 0.8% (95% CI 0.5-1.3%) of patients. Hypoglycaemia with glucose ≤3.1 mmol/L and severe hypoglycaemia occurred least frequently with gliclazide: in 1.4% (95% CI 0.8-2.4%) and 0.1% (95% CI 0-0.7%) of patients, respectively. None of the risk factors were significant in a stepwise multivariate meta-regression analysis. Too few studies had insulin as comparator, so these data could not be meta-analysed. The majority of patients with type 2 diabetes mellitus on sulfonylurea therapy in clinical trials remain free of any relevant hypoglycaemia. Gliclazide was associated with the lowest risk of hypoglycaemia. Because participants in randomized controlled trials differ from the general population, care should be taken when translating these data into clinical practice.

Frequency of symptomatic and asymptomatic hypoglycaemia in Type 1 diabetes: effect of impaired awareness of hypoglycaemia.

AIMS: To characterize the frequency and the nature (symptomatic vs. asymptomatic) of hypoglycaemia in people with Type 1 diabetes with impaired awareness of hypoglycaemia. METHODS: A group of 19 patients with Type 1 diabetes with normal hypoglycaemia awareness were matched for age, sex, duration of diabetes and glycaemic control with 19 patients with impaired awareness of hypoglycaemia. Frequency of severe hypoglycaemia in the preceding year was estimated retrospectively. Capillary blood glucose was monitored prospectively four times daily, over a 4-week period. All blood glucose values < 3 mmol/l were recorded and classified by symptom response. RESULTS: The patients with impaired awareness of hypoglycaemia exhibited twice the frequency of all episodes of hypoglycaemia over the 4-week monitoring period than those with normal awareness (mean ±sd 7.9 ± 5.4 vs. 3.7 ± 3.6, P = 0.003). No differences between the two subgroups were observed in the total number of symptomatic hypoglycaemia episodes (4.2 ± 3.3 vs. 3.2 ± 3.4, P = 0.25). The group with impaired awareness of hypoglycaemia had a sevenfold higher incidence of asymptomatic hypoglycaemia than those with normal awareness (3.7 ± 5.3 vs. 0.5 ± 1.2, P = 0.001); these episodes comprised 47% of all glucose values < 3.0 mmol/l in this group, compared with 14% in the normal awareness group. The annual prevalence of severe hypoglycaemia for patients with impaired awareness of hypoglycaemia was 53% compared with 5% for patients with normal awareness, and these patients had a significantly higher incidence of severe events (1.6 ± 2.8 vs. 0.1 ± 0.3, P = 0.001). CONCLUSIONS: Adults with Type 1 diabetes who have impaired awareness of hypoglycaemia are exposed to a much higher incidence of asymptomatic hypoglycaemia than those with normal awareness and are at higher risk of developing severe hypoglycaemia.

Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes.

AIMS: Impaired awareness of hypoglycaemia (IAH) is thought to affect approximately 25% of people with Type 1 diabetes. While this estimate was based on retrospective information from patients in several small studies performed several years ago, validated methods of assessment have not been used in a large hospital clinic-based population to ascertain the prevalence in the present era. METHODS: Five hundred and eighteen people with Type 1 diabetes were recruited by random selection over a 2-year period. Participants completed a questionnaire documenting baseline characteristics and assessment of their awareness status using the method described by Gold et al. The number of episodes of severe hypoglycaemia they had experienced in the preceding year was recorded retrospectively. RESULTS: IAH was present in 19.5% of the cohort. Compared to those with normal awareness of hypoglycaemia, those with IAH were significantly older [mean +/- standard deviation (sd); 39.3 +/- 12.9 vs. 45.9 +/- 13.5 years, P < 0.001], had a longer duration of diabetes [median (interquartile range) 14 (8-22) vs. 23 (14-32) years, P < 0.001], and had a six-fold higher frequency of severe hypoglycaemia in the previous year [0.38 +/- 1.04 (25th-75th centile 0-0) vs. 2.36 +/- 4.81 (25th-75th centile 0-2) episodes per person, P < 0.001]. CONCLUSIONS: The present survey of a large hospital-based clinic population has confirmed that a significant proportion of people with Type 1 diabetes (19.5%) continue to have IAH. Despite improvements in insulin therapies, intensification of insulin regimens and innovative patient education, the prevalence of IAH remains high in Type 1 diabetes.