Frequency and Symptoms of Hypoglycaemia Experienced by Patients with Type 2 Diabetes Treated with Insulin

This study ascertained the prevalence of severe hypoglycaemia and loss of awareness of hypoglycaemia in patients with Type 2 diabetes treated with insulin. One hundred and four sequentially selected Type 2 diabetic patients were compared with 104 patients with Type 1 diabetes who were matched for duration of insulin therapy. The patients were interviewed using a standardized questionnaire. During treatment with insulin, 18 Type 2 patients had experienced fewer than two episodes of hypoglycaemia, while 86 had experienced two or more episodes; 80 (93%) reported normal awareness, six (7%) reported partial awareness, and none had absent awareness of hypoglycaemia. All 86 Type 1 diabetic patients matched to the 86 Type 2 patients had experienced multiple episodes of hypoglycaemia; 71 (83%) had normal awareness, 14 (16%) had partial awareness and one patient (1%) reported absent awareness of hypoglycaemia. The Type 1 patients who had altered awareness of hypoglycaemia had longer duration of diabetes and insulin therapy (normal awareness: 5 (1–17) years (median (range)) vs partial awareness: 9 (3–18) years, p < 0.01). Similarly, Type 2 patients with altered awareness had longer duration of diabetes (normal awareness: 11 (2–25) years vs partial awareness: 19 (8–24) years, p < 0.02) and had received insulin for longer (normal awareness: 3 (1–18) years vs partial awareness: 12 (6–17) years, p < 0.001). Severe hypoglycaemia in the preceding year had occurred with a similar prevalence in the Type 2 patients (9 (10%)) and Type 1 patients (14 (16%)), but was more frequent in those patients with partial awareness both in Type 1 patients (normal awareness: 3 (4%) vs partial awareness: 11 (73%), p < 0.001) and in Type 2 patients (normal awareness: 3 (4%) vs partial awareness: 6 (100%), p < 0.001). Although the symptoms of hypoglycaemia were idiosyncratic in individual Type 2 patients, the range and prevalence of specific symptoms were similar to those described by the patients with Type 1 diabetes.     

Hypoglycaemia in Type 2 diabetes

The primary cause of hypoglycaemia in Type 2 diabetes is diabetes medication—in particular, those which raise insulin levels independently of blood glucose, such as sulphonylureas (SUs) and exogenous insulin. The risk of hypoglycaemia is increased in older patients, those with longer diabetes duration, lesser insulin reserve and perhaps in the drive for strict glycaemic control. Differing definitions, data collection methods, drug type/regimen and patient populations make comparing rates of hypoglycaemia difficult. It is clear that patients taking insulin have the highest rates of self‐reported severe hypoglycaemia (25% in patients who have been taking insulin for > 5 years). SUs are associated with significantly lower rates of severe hypoglycaemia. However, large numbers of patients take SUs in the UK, and it is estimated that each year > 5000 patients will experience a severe event caused by their SU therapy which will require emergency intervention. Hypoglycaemia has substantial clinical impact, in terms of mortality, morbidity and quality of life. The cost implications of severe episodes—both direct hospital costs and indirect costs—are considerable: it is estimated that each hospital admission for severe hypoglycaemia costs around £1000. Hypoglycaemia and fear of hypoglycaemia limit the ability of current diabetes medications to achieve and maintain optimal levels of glycaemic control. Newer therapies, which focus on the incretin axis, may carry a lower risk of hypoglycaemia. Their use, and more prudent use of older therapies with low risk of hypoglycaemia, may help patients achieve improved glucose control for longer, and reduce the risk of diabetic complications.     

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. Copyright © 2013 John Wiley & Sons, Ltd.     

Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes—the ‘dead in bed’ syndrome revisited

Aims/hypothesis  Sudden nocturnal death in type 1 diabetes (‘dead in bed’ syndrome) is thought to be due to ECG QT prolongation with subsequent ventricular tachyarrhythmia in response to nocturnal hypoglycaemia. We investigated this theoretical mechanism using continuous ECG and continuous glucose monitoring in a group of patients with type 1 diabetes. Methods  Twenty-five patients with type 1 diabetes (age 20–50 years) underwent two separate 24 h ECG and continuous glucose monitoring periods. Patients were fully ambulant and carried out normal daily activities. Results  There were 13 episodes (26% of recordings) of nocturnal hypoglycaemia, eight of <2.2 mmol/l and five of 2.2–3.4 mmol/l. Corrected QT interval (QTc) was longer during nocturnal hypoglycaemia compared with normoglycaemic control periods (445 ± 40 vs 415 ± 23 ms; p = 0.037). Cardiac rate and rhythm disturbances (excluding sinus tachycardia) were seen in eight of the 13 nocturnal hypoglycaemia episodes (62%). These were sinus bradycardia (<40 beats/min; three episodes), ventricular ectopics (three episodes), atrial ectopics (one) and P wave abnormalities (one). Conclusions/interpretation  This study demonstrates QTc prolongation and cardiac rate/rhythm disturbances in response to episodes of nocturnal hypoglycaemia in ambulant patients with type 1 diabetes. This may support an arrhythmic basis for the ‘dead in bed’ syndrome.     

The impact of insulin type on severe hypoglycaemia events requiring inpatient and emergency department care in patients with type 2 diabetes

Aims

To evaluate the risk from different insulin types on severe hypoglycaemia (SHG) events requiring inpatient (IP) or emergency department (ED) care in patients with type 2 diabetes.

Methods

Type 2 diabetes patients newly started on insulin in a large commercial claims database were evaluated for SHG events. Patients were classified into an insulin group based on their most frequently used insulin type. Multivariable Cox models assessed the association between insulin type and the risk of SHG events.

Results

We identified 8626 patients (mean age 53.5 years; 55% female) with type 2 diabetes followed for an average of 4.0 years after insulin initiation. Of these, 161 (1.9%) had a SHG event at an average of 3.1y after insulin initiation. Patients with SHG events were slightly older (56.4 vs. 53.4 years), used a similar number of OADs (1.1 vs. 1.2) but had more co-morbidities compared with those without SHG events. In multivariate Cox models, premixed insulin (HR 2.12; p < 0.01), isophane insulin (NPH) (HR 2.02; p < 0.01), and rapid acting insulin (HR 2.75; p < 0.01) had significantly higher risks of SHG events compared with glargine. No statistically significant difference in SHG events was seen with detemir (HR 1.20; p = 0.73).

Conclusions

Among patients with type 2 diabetes, the use of newer basal insulin analogues was associated with lower rates of SHG events requiring IP or ED care compared with users of other insulin formulations. Future research should examine the impact of hypoglycaemia events of different severity levels.     

Severe hypoglycaemia in children and adolescents during multiple-dose insulin therapy

Episodes of severe hypoglycaemia, resulting in coma and/or convulsions, were documented in an unselected, population-based group of 376 children and adolescents with Type 1 diabetes mellitus (Type 1 DM) treated at the Aurora Hospital, City of Helsinki. A prospective study in 1994–95 yielded 493 patient-years and a retrospective study in 1990–93, 904 patient-years of data. Of these patients, 77–85 % received insulin in three or more daily doses. During 1990–95, 43 patients had a total of 48 severe hypoglycaemic episodes. For each episode (n = 48), one control Type 1 DM patient who had never experienced any severe hypoglycaemia, matched by age, diabetes duration and puberty, was sought from the study population. Incidence of severe hypoglycaemia was 3.1/100 patient years prospectively and 3.6/100 retrospectively. At the time of the episode, median age was 13.3 (range 2.2–21) years, and median diabetes duration 6.1 (0.5–14.6) years. Rates were similar in different age groups (<6, 6–12.9 and ≥ 13 years). A potential explanation for the hypoglycaemia was found in 79 % of the episodes. Insulin dose was higher (p = 0.04) and HbA_1c lower (p = 0.005) in patients with severe hypoglycaemia than in controls. In conclusion, multiple-dose insulin therapy in young patients with Type 1 DM can be associated with a low rate of severe hypoglycaemia. The majority of such episodes seem to be preventable. © 1998 John Wiley & Sons, Ltd.     

Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with Type 1 diabetes

Aims/hypothesis Experimental hypoglycaemia leads to abnormal cardiac repolarization manifest by a lengthened QT interval and caused by adrenergic stimulation. However it is less clear whether spontaneous clinical episodes lead to similar changes. We have therefore measured cardiac ventricular repolarization and counterregulatory responses in patients with Type 1 diabetes during hypoglycaemic and euglycaemic nights.Methods We studied 22 patients with Type 1 diabetes (mean age 40.4±17.2 years, duration of diabetes 17.2±9.3 years, HbA1c 8.2±1.2% overnight). Measurements were taken hourly of blood glucose, plasma potassium, catecholamines and high resolution electrocardiograms.Results Hypoglycaemia (blood glucose level <2.5 mmol/l) occurred on 7 of the 22 nights. During overnight hypoglycaemia, QTc interval increased by 27 ms (±15) above baseline, compared with 9 ms (±19) during nights with no nocturnal hypoglycaemia (p=0.034, 95%CI 2, 35). Adrenaline increased by 0.33 nmol/l (±0.21) above baseline during hypoglycaemia, compared with –0.05 nmol/l (±0.08) during euglycaemia (p=0.001, 95%CI 0.19, 0.56 nmol/l). There was no significant difference between potassium, and noradrenaline concentrations between the two groups.Conclusion/interpretation QTc interval lengthens significantly during spontaneous nocturnal hypoglycaemia. Increases are generally less than those observed during experimental hypoglycaemia and could reflect attenuated sympathoadrenal responses during clinical episodes. The clinical relevance of these changes is uncertain but is consistent with the hypothesis that clinical hypoglycaemia can cause abnormal cardiac repolarization and an attendant risk of cardiac arrhythmia.Abbreviations ECG electrocardiogram     

A pilot study using flash continuous glucose monitoring in patients with type-2 diabetes on multiple anti-diabetic agents during Ramadan

Background

This study aims to examine the incidence of hypoglycaemia, based on activity, during Ramadan in patients with type 2 diabetes mellitus who were on were on three or more anti-diabetic medications.

Treatment and prevention of severe hypoglycaemia in people with diabetes: Current and new formulations of glucagon

Some therapies for diabetes increase the risk of hypoglycaemia, in particular all insulins and insulin secretagogues, including the glinides and sulfonylureas. Hypoglycaemia remains a major limiting factor to successful glycaemic management, despite the availability of prevention options such as insulin analogues, continuous glucose monitoring, insulin pumps, and dogs that have been trained to detect hypoglycaemia. Non-severe (self-treated) and severe (requiring assistance for recovery) hypoglycaemia rates are higher in people with type 1 diabetes, but those with insulin-treated type 2 diabetes are also at risk. Education and regular review are essential between people with diabetes and their caregivers and healthcare professionals about symptoms, prevention and treatment. Awareness of the potential dangers of hypoglycaemia is fundamental to the optimal management of diabetes. When therapy is intensified to achieve glycaemic targets, it is important that people at risk of severe hypoglycaemia, and particularly their caregivers, have ready access to effective treatment for hypoglycaemia emergencies. The current and potential formulations of glucagon available for treatment of severe hypoglycaemia are reviewed.     

Random non-fasting C-peptide testing can identify patients with insulin-treated type 2 diabetes at high risk of hypoglycaemia

Aims/hypothesis

The aim of this study was to determine whether random non-fasting C-peptide (rCP) measurement can be used to assess hypoglycaemia risk in insulin-treated type 2 diabetes.

Methods

We compared continuous glucose monitoring-assessed SD of blood glucose and hypoglycaemia duration in 17 patients with insulin-treated type 2 diabetes and severe insulin deficiency (rCP < 200 pmol/l) and 17 matched insulin-treated control patients with type 2 diabetes but who had preserved endogenous insulin (rCP > 600 pmol/l). We then assessed the relationship between rCP and questionnaire-based measures of hypoglycaemia in 256 patients with insulin-treated type 2 diabetes and a comparison group of 209 individuals with type 1 diabetes.

Results

Continuous glucose monitoring (CGM)-assessed glucose variability and hypoglycaemia was greater in individuals with rCP < 200 pmol/l despite similar mean glucose. In those with low vs high C-peptide, SD of glucose was 4.2 (95% CI 3.7, 4.6) vs 3.0 (2.6, 3.4) mmol/l (p < 0.001). In the low-C-peptide vs high-C-peptide group, the proportion of individuals experiencing sustained hypoglycaemia ≤ 4 mmol/l was 94% vs 41% (p < 0.001), the mean rate of hypoglycaemia was 5.5 (4.4, 6.7) vs 2.1 (1.4, 2.9) episodes per person per week (p = 0.004) and the mean duration was 630 (619, 643) vs 223 (216, 230) min per person per week (p = 0.01). Hypoglycaemia ≤ 3 mmol/l was infrequent in individuals with preserved C-peptide (1.8 [1.2, 2.6] episodes per person per week vs 0.4 [0.1, 0.8] episodes per person per week for low vs high C-peptide, p = 0.04) and only occurred at night. In a population-based cohort with insulin-treated type 2 diabetes, self-reported hypoglycaemia was twice as frequent in those with rCP < 200 pmol/l (OR 2.0, p < 0.001) and the rate of episodes resulting in loss of consciousness or seizure was five times higher (OR 5.0, p = 0.001). The relationship between self-reported hypoglycaemia and C-peptide was similar in individuals with type 1 and type 2 diabetes.

Conclusions/interpretation

Low rCP is associated with increased glucose variability and hypoglycaemia in patients with insulin-treated type 2 diabetes and represents a practical, stable and inexpensive biomarker for assessment of hypoglycaemia risk.

     

Hyperinsulinaemia during exercise does not suppress hepatic glycogen concentrations in patients with type 1 diabetes: a magnetic resonance spectroscopy study

Aims/hypothesis We compared in vivo changes in liver glycogen concentration during exercise between patients with type 1 diabetes and healthy volunteers. Methods We studied seven men with type 1 diabetes (mean ± SEM diabetes duration 10 ± 2 years, age 33 ± 3 years, BMI 24 ± 1 kg/m², HbA_1c 8.1 ± 0.2% and VO₂ peak 43 ± 2 ml [kg lean body mass]⁻¹ min⁻¹) and five non-diabetic controls (mean ± SEM age 30 ± 3 years, BMI 22 ± 1 kg/m², HbA_1c 5.4 ± 0.1% and VO₂ peak 52 ± 4 ml [kg lean body mass]⁻¹ min⁻¹, before and after a standardised breakfast and after three bouts (EX1, EX2, EX3) of 40 min of cycling at 60% VO₂ peak. ¹³C Magnetic resonance spectroscopy of liver glycogen was acquired in a 3.0 T magnet using a surface coil. Whole-body substrate oxidation was determined using indirect calorimetry. Results Blood glucose and serum insulin concentrations were significantly higher (p < 0.05) in the fasting state, during the postprandial period and during EX1 and EX2 in subjects with type 1 diabetes compared with controls. Serum insulin concentration was still different between groups during EX3 (p < 0.05), but blood glucose concentration was similar. There was no difference between groups in liver glycogen concentration before or after the three bouts of exercise, despite the relative hyperinsulinaemia in type 1 diabetes. There were also no differences in substrate oxidation rates between groups. Conclusions/interpretation In patients with type 1 diabetes, hyperinsulinaemic and hyperglycaemic conditions during moderate exercise did not suppress hepatic glycogen concentrations. These findings do not support the hypothesis that exercise-induced hypoglycaemia in patients with type 1 diabetes is due to suppression of hepatic glycogen mobilisation. K. Chokkalingam and K. Tsintzas contributed equally to this study.     

Assessment of hypoglycaemia awareness using continuous glucose monitoring.

AIMS: To investigate the possibility of assessing hypoglycaemia awareness in patients with Type 1 diabetes using continuous glucose monitoring. METHODS: Twenty patients with Type 1 diabetes were investigated. Ten patients with Type 1 diabetes and strongly impaired hypoglycaemia awareness were compared with 10 patients with intact hypoglycaemia awareness regarding quality of hypoglycaemia perception (number of undetected hypoglycaemic episodes per 24 h, glucose level < 3.3 mmol/l). Hypoglycaemia detection was assessed using the event function of the Continuous Glucose Monitoring System (CGMS; Medtronic MiniMed, Northridge, CA, USA). Patients were instructed to enter an event upon suspecting being hypoglycaemic. RESULTS: Satisfactory CGMS performance could be achieved [mean r = 0.893 between calibration measurements and CGMS data, mean absolute difference (MAD) = 20.6%], although artefacts were observable and had to be controlled. Hypoglycaemia unaware patients showed a significantly higher total number of hypoglycaemic episodes (P < 0.05), number of undetected hypoglycaemic episodes (P < 0.01), and mean glucose levels (P < 0.05). Even in aware patients, undetected hypoglycaemia was observable. No significant differences regarding occurrence of nocturnal hypoglycaemia were observable. CONCLUSIONS: The possibility of direct assessment of hypoglycaemia awareness using continuous glucose monitoring was demonstrated. Its application in clinical practice could be of use for assessing hypoglycaemia perception and evaluating the impact of treatment changes on hypoglycaemia awareness.     

Renal hyperfiltration in type 2 diabetes: effect of age-related decline in glomerular filtration rate

Aims/hypothesis We sought to characterise the effect of the age-related decline of GFR on hyperfiltration in type 2 diabetes and to identify clinical characteristics associated with hyperfiltration. Materials and methods GFR was measured in 662 type 2 diabetic patients by plasma disappearance of 99 m-technetium-diethylene-triamine-penta-acetic acid. The prevalence of hyperfiltration was calculated using both an age-unadjusted GFR threshold of >130 ml min⁻¹ 1.73 m⁻² and an age-adjusted threshold incorporating a decline of 1 ml min⁻¹ year⁻¹ after the age of 40. The hyperfiltering patients were compared with type 2 diabetic subjects who had a GFR between 90 and 130 ml min⁻¹ 1.73 m⁻² and were matched for age, sex and disease duration to allow for identification of modifiable factors associated with hyperfiltration. Results The prevalence of hyperfiltration was 7.4% when age-unadjusted and 16.6% when age-adjusted definitions were used. The age-unadjusted vs -adjusted prevalence rates for hyperfiltration were 50 vs 50%, 12.9 vs 23.4% and 0.3 vs 9.0% for patients aged <40 years, 40 to 65 years and >65 years, respectively. Both the age-unadjusted and -adjusted hyperfiltration groups had lower mean diastolic blood pressure and lower serum creatinine levels than the control groups. Although the age-unadjusted hyperfiltration group had larger kidneys compared to the control group, this difference was no longer significant when the age-adjusted definition was used. There were no differences in HbA₁c, mean arterial pressure, antihypertensive use, insulin therapy, dyslipidaemia, frequency of macro- or microvascular complications, BMI, urinary sodium, urea and albumin excretion between the groups. Conclusions/interpretation Hyperfiltration was still more common among younger patients with type 2 diabetes even after adjusting for the expected age-related decline in GFR. Hyperfiltration was associated with a lower mean diastolic blood pressure independent of age.     

Fulminant type 1 diabetes as a high risk group for diabetic microangiopathy—a nationwide 5-year-study in Japan

Aims/hypothesis The aim of the present study was to assess the development of microangiopathy in patients with fulminant type 1 diabetes, a novel subtype of type 1B diabetes. Materials and methods In a nationwide survey, we followed 41 patients with fulminant type 1 diabetes and 76 age- and sex-matched patients with type 1A diabetes for 5 years. The following data were recorded every 12 months after the onset of diabetes: seven-point blood glucose concentrations, HbA_1c level, urinary albumin excretion, serum C-peptide level, blood pressure, daily dosages of insulin, frequency of severe hypoglycaemic episodes, and neurological and fundoscopic examination. Results The 5-year cumulative incidence of microangiopathy was 24.4% in fulminant type 1 diabetes and 2.6% in type 1A diabetes. In longitudinal studies using the Kaplan–Meier method, the cumulative incidence of each form of microangiopathy was significantly higher in fulminant type 1 diabetes than in type 1A diabetes; retinopathy was 9.8% vs 0% (p = 0.014), nephropathy 12.2% vs 2.6% (p = 0.015) and neuropathy 12.2% vs 1.3% (p = 0.010), respectively. Mean HbA_1c levels were similar in the fulminant and type 1A diabetes groups during the follow-up periods. However, the mean M-value, mean insulin dosages and the frequency of severe hypoglycaemic episodes were significantly higher, and the mean postprandial C-peptide level was significantly lower in the fulminant type 1 diabetes group. Conclusions/interpretation These data suggest that patients with fulminant type 1 diabetes are a high-risk subgroup for diabetic microangiopathy associated with the lack of endogenous insulin secretion from the onset of diabetes.     

Nocturnal hypoglycaemia in type 1 diabetes--consequences and assessment

Hypoglycaemia is inevitable when striving for low HbA1c values. Nocturnal hypoglycaemia often occurs without symptoms, but results in diminished next day well-being and hypoglycaemia unawareness. Frequency of nocturnal hypoglycaemia was first assessed in research ward settings, but suffered from insufficient glucose sampling frequency. This may have resulted in overestimation of the duration of hypoglycaemic episodes. The advent of the first continuous glucose sensor, the needle-type MedtronicMiniMed Continuous Glucose Measurement System, revolutionized the assessment of glucose values. However, on scrutiny, the first version of this sensor showed a drift into the hypoglycaemic area and delayed recovery from hypoglycaemia. Using the microdialysis-based GlucoDay system, our group reported a lower frequency of nocturnal hypoglycaemia in type 1 diabetes patients using an insulin pump, than that expected from the existing literature. Today, more than 80 years after the introduction of insulin for the treatment of type 1 diabetes, the associated frequency of nocturnal hypoglycaemia still awaits its definitive assessment.     

Severe hypoglycaemia is a major predictor of incident diabetic retinopathy in Japanese patients with type 2 diabetes

AimHypoglycaemia is a common complication in diabetes patients. However, its relationship with retinopathy has not been well documented in patients with type 2 diabetes (T2D). This study aimed to investigate the associations between hypoglycaemia and the incidence and progression of diabetic retinopathy (DR).MethodsIn this longitudinal cohort study, which was part of the Japan Diabetes Complications Study (JDCS), adult patients with T2D were recruited at 59 diabetes clinics across Japan. Their history of hypoglycaemia was assessed by standardized self-reported questionnaires. Severe hypoglycaemia was defined as having at least one episode with coma requiring an outpatients visit or hospitalization. Adjusted hazard ratios (HRs) for incidence and progression of DR over 8 years of follow-up were determined.ResultsOf 1221 patients without DR, 127 (10.4%) had experienced non-severe hypoglycaemia within the previous year, whereas 10 (0.8%) reported severe hypoglycaemia episodes. During the 8-year follow-up involving 8492 person-years, 329 patients developed DR. In 410 patients with prevalent DR, the adjusted HRs for incident DR were 4.35 (95% CI: 1.98–9.56; P < 0.01) and, for progression of DR, 2.29 (95% CI: 0.45–11.78; P = 0.32) with severe hypoglycaemia.ConclusionHaving a history of severe hypoglycaemia was one of the strongest predictors of incident DR in patients with T2D, with a fourfold increased risk. Identifying patients with greater risks of DR based on their history of hypoglycaemia may help to personalize risk evaluation in patients with diabetes.     

Incident and recurrent hypoglycaemia with linagliptin and glimepiride over a median of 6 years in the CAROLINA cardiovascular outcome trial

Aim

The CAROLINA trial established non-inferiority of linagliptin versus glimepiride for major adverse cardiovascular events in patients with relatively early type 2 diabetes at increased cardiovascular risk. In pre-specified and post-hoc analyses, we investigated treatment effects on total hypoglycaemic burden in CAROLINA.

Materials and methods

Patients were randomized and treated with 5 mg linagliptin (n = 3014) or 1-4 mg glimepiride (n = 3000) once daily added to standard care. Hypoglycaemia captured from investigator-reported adverse events was analysed with Poisson and negative binomial regressions for the first and total (first plus recurrent) events, respectively. The influence of insulin initiation and glycated haemoglobin (HbA1c) change on the treatment effect for hypoglycaemia was also explored.

Results

Over 6.3 years median follow-up, average HbA1c over time did not differ between linagliptin versus glimepiride (weighted mean difference [95% confidence interval]: 0.00%, [−0.05, 0.05]), nor did insulin initiation (18.6% vs. 19.2% of patients, respectively), whereas body weight was lower with linagliptin (−1.54 kg, [−1.80, −1.28]). Hypoglycaemia frequency was lower with linagliptin across all hypoglycaemia categories, including severe episodes. Rate ratios (95% confidence interval) for first and total events for investigator-reported hypoglycaemia were 0.21 (0.19-0.24) and 0.12 (0.10-0.14), respectively, with 8.7 first and 60.8 total estimated events prevented/100 patient-years with linagliptin versus glimepiride. These differences occurred during night-time and daytime, and in subgroup analyses of total events. Treatment differences in hypoglycaemia were neither impacted by HbA1c changes nor insulin initiation.

Conclusions

Across the severity spectrum, linagliptin substantially reduced the hypoglycaemic burden versus glimepiride in patients with relatively early type 2 diabetes at increased cardiovascular risk.     

Omitting breakfast and lunch after injection of different long-acting insulin preparations at bedtime: a prospective study in patients with type 2 diabetes

Aims/hypothesis  The aim of this prospective trial was to compare the effect of different long-acting insulin preparations injected at bedtime on glucose concentrations in patients with type 2 diabetes omitting breakfast and lunch the next day. Methods  Twenty patients (ten women) with type 2 diabetes who were on an intensified insulin therapy participated. Mean (±SD) age was 63 ± 10 years, diabetes duration 18 ± 9 years, BMI 32.5 ± 5 kg/m², and HbA_1c 7.3 ± 0.7%. Patients received neutral protamine Hagedorn (NPH) insulin, insulin detemir or insulin glargine for at least 2 months; doses were adjusted to achieve morning blood glucose levels of <7 mmol/l. At the end of the respective treatment period, the long-acting insulin was injected at bedtime (at 22:45 hours) as usual but patients refrained from breakfast and lunch the next day; glucose was measured by a continuous glucose monitoring system (CGMS). Results   Comparable glucose target ranges were reached at midnight (5.8 to 6.1 mmol/l) and at 07:00 hours (6.7 to 6.9 mmol/l) with all three insulin preparations, using mean doses of 29 ± 10 U (NPH insulin), 33 ± 13 U (insulin detemir), and 32 ± 12 U (insulin glargine). Glucose levels between midnight and 07:00 hours were not significantly different for the three insulin preparations. Symptomatic hypoglycaemia did not occur from 08:00 to 16:00 hours; glucose concentrations during this time were slightly lower with NPH insulin than with insulin detemir (p = 0.012) and insulin glargine (p = 0.049). Conclusions/interpretation  Following bedtime injection of NPH insulin or of the analogues insulin detemir or insulin glargine, fasting glucose <7 mmol/l was achieved in the morning, without subsequent hypoglycaemia when participants continued to fast during the day.     

Severe hypoglycaemia in type 1 diabetes mellitus: underlying drivers and potential strategies for successful prevention

Hypoglycaemia remains an over‐riding factor limiting optimal glycaemic control in type 1 diabetes. Severe hypoglycaemia is prevalent in almost half of those with long‐duration diabetes and is one of the most feared diabetes‐related complications. In this review, we present an overview of the increasing body of literature seeking to elucidate the underlying pathophysiology of severe hypoglycaemia and the limited evidence behind the strategies employed to prevent episodes. Drivers of severe hypoglycaemia including impaired counter‐regulation, hypoglycaemia‐associated autonomic failure, psychosocial and behavioural factors and neuroimaging correlates are discussed. Treatment strategies encompassing structured education, insulin analogue regimens, continuous subcutaneous insulin infusion pumps, continuous glucose sensing and beta‐cell replacement therapies have been employed, yet there is little randomized controlled trial evidence demonstrating effectiveness of new technologies in reducing severe hypoglycaemia. Optimally designed interventional trials evaluating these existing technologies and using modern methods of teaching patients flexible insulin use within structured education programmes with the specific goal of preventing severe hypoglycaemia are required. Individuals at high risk need to be monitored with meticulous collection of data on awareness, as well as frequency and severity of all hypoglycaemic episodes. Copyright © 2013 John Wiley & Sons, Ltd.