Perceived symptoms of hypoglycaemia in elderly Type 2 diabetic patients treated with insulin

Elderly insulin-treated diabetic patients have a high risk of severe hypoglycaemia, yet their hypoglycaemic symptom profile has attracted little research. In this study, the frequency and intensity of symptoms of hypoglycaemia were recorded using a validated questionnaire in 132 insulin-treated diabetic patients, aged 70 years or more. Principal components analysis (PCA) was used to discover the factorial structure of the symptoms. Lightheadedness and unsteadiness were prominent symptoms in the elderly patients. PCA suggested three separate groups of symptoms: (1) those related specifically to impairment of co-ordination and articulation; (2) more general neuroglycopenic symptoms, and (3) autonomic symptoms. The frequency and classification of hypoglycaemic symptoms in this elderly population is different from those seen in younger diabetic patients treated with insulin. Neurological symptoms of hypoglycaemia were more commonly reported and may be misinterpreted as features of cerebrovascular disease. Health professionals and carers involved in the treatment and education of diabetic patients should be aware of the age-specific differences in hypoglycaemic symptoms. © 1998 John Wiley & Sons, Ltd.     

Counterregulatory hormonal response to insulin-induced hypoglycaemia in insulin-dependent diabetic patients: a comparison of equimolar amounts of porcine and semisynthetic human insulin

Abstract. The aim of the present study was to compare the degree of hypoglycaemia, the hypoglycaemic symptom score and counterregulatory responses to equimolar amounts of intravenously administered porcine and semisynthetic human insulin in a double-blind crossover study in insulin-dependent diabetic patients. After overnight stabilization of blood glucose to approximately 6 mmol l^?1 insulin was infused from 06.00 hours at such a rate as to keep the blood glucose concentration constant at 6 mmol l^?1. At 09.00 hours hypoglycaemia was induced by increasing the infusion rate to give a blood glucose level of 2 mmol l^?1 within about 60 min. The individual infusion rate from the first test was repeated in the second test, 1 week later. Blood glucose minimum levels were 2.1 (range, 1.3–2.9) and 2.1 (1.3–2.8) mmol l^?1 for porcine and human insulin, respectively. The insulin concentrations at blood nadirs were 107 (66–180) and 107 (56–184) pmol l^?1, respectively, for porcine compared to human insulin (NS). Symptom scores at minimum blood glucose concentrations were 43 and 46, respectively, with a maximal difference in intensity of 1 point in each patient. There were no statistical differences in the counterregulatory responses of glucagon, epinephrine, norepinephrine, Cortisol, growth hormone, prolactin, beta-endorphine or in serum-potassium decreases. Patients were unable to discriminate between the two forms of insulin. It is concluded that there are no differences between porcine and semisynthetic insulin with regard to glucose fall, hormonal counterregulation or symptom scores, when the two forms of insulin are administered intravenously in equimolar amounts.     

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.     

Clinical correlates of hypoglycaemia over 4 years in people with type 2 diabetes starting insulin: An analysis from the CREDIT study

Aim

To identify factors associated with documented symptomatic and severe hypoglycaemia over 4 years in people with type 2 diabetes starting insulin therapy.

Materials and methods

CREDIT, a prospective international observational study, collected data over 4 years on people starting any insulin in 314 centres; 2729 and 2271 people had hypoglycaemia data during the last 6 months of years 1 and 4, respectively. Multivariable logistic regression was used to select the characteristics associated with documented symptomatic hypoglycaemia, and the model was tested against severe hypoglycaemia.

Results

The proportions of participants reporting ≥1 non‐severe event were 18.5% and 16.6% in years 1 and 4; the corresponding proportions of those achieving a glycated haemoglobin (HbA1c) concentration <7.0% (<53 mmol/mol) were 24.6% and 18.3%, and 16.5% and 16.2% of those who did not. For severe hypoglycaemia, the proportions were 3.0% and 4.6% of people reaching target vs 1.5% and 1.1% of those not reaching target. Multivariable analysis showed that, for documented symptomatic hypoglycaemia at both years 1 and 4, baseline lower body mass index and more physical activity were predictors, and lower HbA1c was an explanatory variable in the respective year. Models for documented symptomatic hypoglycaemia predicted severe hypoglycaemia. Insulin regimen was a univariate explanatory variable, and was not retained in the multivariable analysis.

Conclusions

Hypoglycaemia occurred at significant rates, but was stable over 4 years despite increased insulin doses. The association with insulin regimen and with oral agent use declined over that time. Associated predictors and explanatory variables for documented symptomatic hypoglycaemia conformed to clinical impressions and could be extended to severe hypoglycaemia. Better achieved HbA1c was associated with a higher risk of hypoglycaemia.     

Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study.

AIMS: To ascertain the frequency and identify predictors of self-reported hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes. METHODS: A random sample of 267 people with insulin-treated diabetes were recruited from a population-based diabetes register in Tayside, Scotland. Each subject prospectively recorded the number of mild and severe hypoglycaemic episodes experienced over a 1-month period. Ordinal logistic regression was performed to identify potential predictors of hypoglycaemia. RESULTS: Five hundred and seventy-two hypoglycaemic events were reported by 155 patients. The participants with Type 1 diabetes had a total of 336 hypoglycaemic events with a rate of 42.89 events per patient per year. Of these, nine were severe hypoglycaemic events, with a rate of 1.15 events per patient per year. Participants with insulin-treated Type 2 diabetes experienced a total of 236 hypoglycaemic events with a rate of 16.37 events per patient per year. Of these, five were severe hypoglycaemic events, which would be equivalent to 0.35 events per patient per year. Predictors of hypoglycaemia in Type 1 diabetes were a history of previous hypoglycaemia (P = 0.006) and co-prescribing of any oral drug (P = 0.048). In patients with insulin-treated Type 2 diabetes, a history of previous hypoglycaemia (P < 0.0001) and duration of insulin treatment (P = 0.014) were significant predictors. CONCLUSION: The incidence of self-reported severe hypoglycaemia in insulin-treated Type 2 diabetes is lower than in Type 1 diabetes but does occur more often than previously reported and with sufficient frequency to cause significant morbidity. Duration of insulin treatment is a key predictor of hypoglycaemia in insulin-treated Type 2 diabetes.     

The relationship between symptomatic and biochemical hypoglycaemia in insulin-dependent diabetic patients

The relationship between symptomatic (subjective feelings) and biochemical (blood glucose concentration less than 3 mmol l-1) hypoglycaemia was studied in 66 randomly selected insulin-dependent diabetic out-patients under normal conditions of daily life with conventional insulin injection regimens. The patients (a) collected 7-point diurnal blood glucose profiles at home on three consecutive days and then once weekly for 3 weeks, (b) indicated whether they felt hypoglycaemic at sampling times, and (c) collected extra samples if they felt hypoglycaemic at any time during the study period. The weekly frequencies of symptomatic and biochemical hypoglycaemia were 0.99 and 1.75 per patient, respectively. Biochemical hypoglycaemia was present in 29% of the symptomatic episodes, and symptomatic hypoglycaemia accompanied 16% of the biochemical episodes. Symptomatic hypoglycaemia was experienced at a median blood glucose concentration of 3.4 mmol l-1 (range 1.4-14.9 mmol l-1). Fifty per cent of both symptomatic and biochemical episodes occurred before lunch, while the remainder were evenly distributed throughout the day. The occurrence of biochemical hypoglycaemia, but not of symptomatic hypoglycaemia, was inversely correlated with HbA1c and median blood glucose concentration. Thus symptomatic hypoglycaemia is an unreliable indicator of biochemical hypoglycaemia and of the degree of glycaemic control. Blood glucose measurements are a prerequisite for the diagnosis of hypoglycaemia.     

Exercise-induced hypoglycaemia in IDDM patients treated with a short-acting insulin analogue

Summary In order to examine the effect of short-acting insulin analogue on the exercise-induced hypoglycaemia in insulin-dependent diabetes mellitus (IDDM) patients we compared the glycaemic response of 40 min cycle ergometer exercise performed either shortly (40 min) or later (180 min) after a breakfast meal and subcutaneous injection of either short-acting insulin analogue [Lys(B28) Pro(B29)] or soluble human insulin (Humulin Regular) in ten IDDM patients with long duration of the disease. Both preparations had been used 1 month before respective studies. Changes in blood glucose, insulin and counterregulatory hormones were assayed. As compared to human insulin, after the analogue injection the peak insulin concentration came earlier, was 56 % higher (p < 0.05) and disappeared faster, and the postprandial blood glucose response was lower (p < 0.05). In the analogue-treated patients the exercise-induced hypoglycaemia was 2.2-fold greater (p < 0.01) during the early exercise, but 46 % less (p < 0.05) during late exercise as compared to the treatment with human insulin. Serum insulin or analogue concentration at the beginning of the exercise correlated closely with the fall in blood glucose during exercise (r = 0.74, p < 0.01; r = 0.73, p < 0.02, respectively). In the analogue-treated patients, fasting serum glucagon and adrenalin concentrations were higher than during human insulin therapy (p < 0.05) and remained so throughout the study. As compared to soluble human insulin, a much faster absorption of insulin analogue: 1) reduces post-prandial hyperglycaemia, 2) can either augment or reduce exercise-induced hypoglycaemia depending on the time interval between insulin injection and the time of exercise. Since exercise is usually not performed until 2–3 h after a meal, short-acting insulin analogue may be more feasible than soluble human insulin for active IDDM patients. [Diabetologia (1995) 38: 106–111] Received: 29 April 1994 and in revised Form: 29 July 1994     

Long‐term efficacy and safety of canagliflozin in combination with insulin in Japanese patients with type 2 diabetes mellitus

Aim

The aim of this study was to assess the long‐term efficacy and safety of canagliflozin as add‐on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin.

Materials and methods

The study comprised a 16‐week, double‐blind period in which patients were randomized to either placebo (P; N = 70) or canagliflozin (100 mg, CAN; N = 76), followed by a 36‐week open‐label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values.

Results

The changes from baseline (mean ± standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were ?1.09% ± 0.85% and ?0.88% ± 0.86% for HbA1c, ?1.40% ± 2.54% and ?2.14% ± 2.75% for body weight, and 7.84% ± 14.37% and 8.91% ± 10.80% for HOMA2‐%B (all, P < .001). Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post‐hoc ordinal logistic modelling/logistic modelling showed that lower serum C‐peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double‐blind period as well as in the canagliflozin all‐treatment period.

Conclusions

This study demonstrates the long‐term efficacy and safety of canagliflozin combined with insulin in Japanese patients.     

Insulin detemir used in basal-bolus therapy in people with type 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 months in comparison to NPH insulin

AIM: The aim of this study was to compare the long-term safety and efficacy of twice-daily insulin detemir or NPH insulin as the basal component of basal-bolus therapy in people with type 1 diabetes. METHODS: A multicentre, open-label, parallel-group study was conducted over 12 months and completed by 308 people (from an original randomized cohort of 428). Patients were randomized in a 2:1 ratio to receive insulin detemir or NPH insulin before breakfast and dinner, with insulin aspart at mealtimes. RESULTS: Glycaemic control improved in both groups with HbA(1c) decreasing by 0.64 and 0.56% point in the insulin detemir and NPH insulin groups, reaching baseline-adjusted final values of 7.53 +/- 0.10% and 7.59 +/- 0.13%, respectively. No significant difference was apparent between treatments in terms of HbA(1c), fasting plasma glucose or 9-point blood glucose profiles. Fewer hypoglycaemic events (major and minor) occurred in association with insulin detemir compared with NPH insulin, but the overall hypoglycaemic risk did not differ statistically significantly (RR for detemir, 0.78 [0.56-1.08]). However, the risk of nocturnal hypoglycaemia during the maintenance phase (month 2-12) was 32% lower in the detemir group (p = 0.02) and lower in every month. This risk reduction remained statistically significant after correction for HbA(1c). After 12 months, baseline-adjusted mean body weight was significantly lower in the insulin detemir group than in the NPH insulin group (p < 0.001). CONCLUSIONS: In long-term basal-bolus therapy, insulin detemir with insulin aspart as mealtime insulin is well tolerated and reduces the risks of nocturnal hypoglycaemia and weight gain compared to NPH insulin.     

The management of type 2 diabetes with fixed‐ratio combination insulin degludec/liraglutide (IDegLira) versus basal‐bolus therapy (insulin glargine U100 plus insulin aspart): A short‐term cost‐effectiveness analysis in the UK setting

Aim

To evaluate the cost‐effectiveness of IDegLira versus basal‐bolus therapy (BBT) with insulin glargine U100 plus up to 4 times daily insulin aspart for the management of type 2 diabetes in the UK.

Methods

A Microsoft Excel model was used to evaluate the cost‐utility of IDegLira versus BBT over a 1‐year time horizon. Clinical input data were taken from the treat‐to‐target DUAL VII trial, conducted in patients unable to achieve adequate glycaemic control (HbA1c <7.0%) with basal insulin, with IDegLira associated with lower rates of hypoglycaemia and reduced body mass index (BMI) in comparison with BBT, with similar HbA1c reductions. Costs (expressed in GBP) and event‐related disutilities were taken from published sources. Extensive sensitivity analyses were performed.

Results

IDegLira was associated with an improvement of 0.05 quality‐adjusted life years (QALYs) versus BBT, due to reductions in non‐severe hypoglycaemic episodes and BMI with IDegLira. Costs were higher with IDegLira by GBP 303 per patient, leading to an incremental cost‐effectiveness ratio (ICER) of GBP 5924 per QALY gained for IDegLira versus BBT. ICERs remained below GBP 20 000 per QALY gained across a range of sensitivity analyses.

Conclusions

IDegLira is a cost‐effective alternative to BBT with insulin glargine U100 plus insulin aspart, providing equivalent glycaemic control with a simpler treatment regimen for patients with type 2 diabetes inadequately controlled on basal insulin in the UK.     

Severe hypoglycaemia in a person with insulin autoimmune syndrome accompanied by insulin receptor anomaly type B.

AIMS: A rare case of the insulin autoimmune syndrome (IAS) accompanied by insulin receptor anomaly is reported. METHODS: Antibodies to insulin and insulin receptor were determined in the patient with severe hypoglycaemia before and after the treatment with prednisolone. RESULTS: Titers of antibody to insulin and insulin receptors were 73.0% and 41.5%, respectively. Drug-induced lymphocyte stimulation tests were all negative for the suspicious drugs. Her HLA-DR was DRB1*0403/04051. Following steroid therapy, the formation of antibodies was suppressed and alleviated her symptoms. Scatchard analysis yielded findings specific to polyclonal antibodies. CONCLUSIONS: The changes in autoantibodies resulted in alleviation of the hypoglycemic symptoms as a result of steroid therapy.