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.     

Sulphonyurea as a cause of severe hypoglycaemia in the community

IntroductionHypoglycaemia is a well recognised side effect of insulin and sulphonyurea therapy in the treatment of, patients with diabetes mellitus.MethodsWe performed a retrospective analysis of patients who developed severe hypoglycaemia in Hull and, East Yorkshire, United Kingdom over a 4-month period to assess the different therapies that contribute the most to the problem and the patient groups who are at greatest risk.ResultsOf the 75 patients with diabetes mellitus who developed severe hypoglycaemia, 61 (80%) were taking, insulin, 5 in combination with metformin. Ten (13%) patients were taking SU therapy; 5 in, combination with metformin, 2 in combination with a thiazolidinedione and 1 in combination with, insulin. When the SU-treated and non-SU treated groups were compared, patients taking SU therapy were, significantly older and had significantly lower HbA1c levels.ConclusionsAll patients taking SU and insulin treatment are potentially at risk of developing hypoglycaemia. Our, analysis shows that almost 15% of patients in our region who suffered from severe hypoglycaemia, were on SU therapy. Patients in this group were older and had lower levels of HbA1c. Whilst national HbA1c targets may be useful for clinicians to define glycaemic targets for their, population, this has to be tempered by what is in the best interests of the patient and not what is, dictated by the Quality and Outcomes Framework. Possible alternatives to SU therapy should be, considered especially if hypoglycaemia is a concern.     

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.     

GLP‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self‐regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β‐cells by glucagon‐like peptide 1 receptor (GLP‐1R) agonists is known to be glucose‐dependent. GLP‐1R agonists potentiate glucose‐stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This ‘glucose‐regulated’ activity of GLP‐1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non‐regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP‐1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP‐1R agonists occur in patients treated with a concomitant SU. This review aims to discuss the current understanding of the mechanisms by which GLP‐1R signalling promotes insulin secretion from pancreatic β‐cells via a glucose‐dependent process.     

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.     

Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes

Hypoglycaemia is the limiting factor in the glycaemic management of diabetes. Iatrogenic hypoglycaemia is typically the result of the interplay of insulin excess and compromised glucose counterregulation in Type I (insulin-dependent) diabetes mellitus. Insulin concentrations do not decrease and glucagon and epinephrine concentrations do not increase normally as glucose concentrations decrease. The concept of hypoglycaemia-associated autonomic failure (HAAF) in Type I diabetes posits that recent antecedent iatrogenic hypoglycaemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycaemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses). Perhaps the most compelling support for HAAF is the finding that as little as 2 to 3 weeks of scrupulous avoidance of hypoglycaemia reverses hypoglycaemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients. The mediator and mechanism of HAAF are not known but are under active investigation. The glucagon response to hypoglycaemia is also reduced in patients approaching the insulin deficient end of the spectrum of Type II (non-insulin-dependent) diabetes mellitus, and glycaemic thresholds for autonomic (including epinephrine) and symptomatic responses to hypoglycaemia are shifted to lower plasma glucose concentrations after hypoglycaemia in Type II diabetes. Thus, patients with advanced Type II diabetes are also at risk for HAAF. While it is possible to minimise the risk of hypoglycaemia by reducing risks -- including a 2 to 3 week period of scrupulous avoidance of hypoglycaemia in patients with hypoglycaemia unawareness -- methods that provide glucose-regulated insulin replacement or secretion are needed to eliminate hypoglycaemia and maintain euglycaemia over a lifetime of diabetes.     

Prevalence and reasons for insulin refusal in Bangladeshi patients with poorly controlled Type 2 diabetes in East London

Aims To determine the prevalence and reasons for refusal to commence insulin in Bangladeshi patients with Type 2 diabetes. Methods A survey of 212 Bangladeshi patients seen in a hospital diabetes unit, with poor glycaemic control (HbA_1c≥ 8.0%) on maximum oral glucose‐lowering therapy, in whom insulin was deemed necessary. Patients who refused insulin were invited to attend focus groups. Data were analysed by thematic content analysis using the constant comparative method. Results Of 212 patients offered insulin, 122 (57.5%) commenced insulin immediately, 47 (22.1%) started insulin within 6 months and 43 (20.3%) refused to commence insulin despite repeated counselling. Thirty‐six (83.7%) of those who refused insulin agreed to participate in focus groups. Reasons for insulin refusal included: disease severity—perceptions that requirement for insulin was an indicator of a more serious stage of their condition; insulin leading to premature death—common suggestion that commencing insulin led to early death; loss of control—including fear of hypoglycaemia, weight gain, loss of independence and reliance on others to give insulin or look for signs of hypoglycaemia; lack of perception of benefits—poor perception of the benefits of improved glycaemic control on quality of life and cardiovascular risk; needle anxiety—a significant proportion of subjects conveyed concern over frequent injections. Conclusions Insulin refusal is common in Bangladeshi subjects with Type 2 diabetes and poor glycaemic control. A number of factors contribute to this, and methods to overcome the barriers to insulin therapy need to be sought.     

Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration

Aims/hypothesis We explored the epidemiology of hypoglycaemia in individuals with insulin-treated diabetes by testing the hypothesis that diabetes type and duration of insulin treatment influence the risk of hypoglycaemia. Materials and methods This was an observational study over 9–12 months in six UK secondary care diabetes centres. Altogether 383 patients were involved. Patients were divided into the following three treatment groups for type 2 diabetes: (1) sulfonylureas, (2) insulin for <2 years and (3) insulin for >5 years, and into two treatment groups for type 1 diabetes, namely <5 years disease duration and >15 years disease duration. Self-reported (mild and severe) and biochemical episodes (interstitial glucose <2.2 mmol/l using continuous glucose monitoring) were recorded. Results Mild hypoglycaemia in type 2 diabetic patients on insulin for <2 years was less frequent than in type 1 patients with <5 years disease duration (mean rate: 4 vs 36 episodes per subject-year, p < 0.001). In type 2 diabetic patients treated with sulfonylureas or insulin for <2 years, no differences were observed in the proportion experiencing severe hypoglycaemia (7 vs 7%, difference 0 [95% CI: −7 to 9%]), mild symptomatic (39 vs 51%, difference 12 [−3 to 25%]) or interstitial glucose <2.2 mol/l (22 vs 20%, difference 2 [−13 to 10%]). Severe hypoglycaemia rates were comparable in patients with type 2 diabetes on sulfonylureas or insulin < 2 years (0.1 and 0.2 episodes per subject-year) and far less frequent than in type 1 diabetes (<5 years group, 1.1; >15 years group, 3.2.episodes per subject-year). Conclusions/interpretation During early insulin use in type 2 diabetes, the frequency of hypoglycaemia is generally equivalent to that observed in patients treated with sulfonylureas and considerably lower than during the first 5 years of treatment in type 1 diabetes. UK Hypoglycaemia Study Group: For a list of the members of this group and their affiliations, see the Appendix. UK Hypoglycaemia Study Group: For a list of each author’s contribution to this study, see the Electronic supplementary material (ESM) which is available to authorised users at doi:. Send any feedback or comments on this article to Simon Heller at the Academic Unit of Diabetes, Endocrinology and Metabolism, School of Medicine and Biomedical Sciences, Room OU141, Beech Hill Road, Sheffield S10 2RX, UK. s.heller@sheffield.ac.uk.     

Non‐insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions

Intensive insulin therapy is the mainstay of treatment for people with Type 1 diabetes, but hypoglycaemia and weight gain are often limiting factors in achieving glycaemic targets and decreasing the risk of diabetes‐related complications. The inclusion of pharmacological agents used traditionally in Type 2 diabetes as adjuncts to insulin therapy in Type 1 diabetes has been explored, with the goal of mitigating such drawbacks. Pramlintide and metformin result in modest HbA_1c and weight reductions, but their use is limited by poor tolerability and, in the case of pramlintide, by frequency of injections and cost. The addition of glucagon‐like peptide‐1 receptor agonists to insulin results in improved glycaemic control, reduced insulin doses and weight loss, but this is at the expense of higher rates of hypoglycaemia and hyperglycaemia with ketosis. Sodium‐glucose co‐transporter‐2 and dual sodium‐glucose co‐transporter‐2 and ‐1 inhibitors also improve glucose control, but with reductions in weight and insulin requirements potentiating the risk of acidosis‐related events and hypoglycaemia. The high proportion of people with Type 1 diabetes not achieving glycaemic targets, the negative clinical impact of intensive insulin therapy and the rise in obesity and cardiovascular disease and mortality, underline the need for individualized clinical care. The evaluation of new therapies, effective in Type 2 diabetes, as adjuncts to insulin therapy represents a promising strategy, particularly given the beneficial effects on cardiovascular and renal outcomes in people with Type 2 diabetes with or at high risk of complications that are also observed in patients with Type 1 diabetes. As the population with Type 1 diabetes ages, our mission is to evolve and provide better tools and improved therapies to excel, not only in glycaemic control but also in risk reduction and reduction of complications.     

How hypoglycaemia can affect the life of a person with diabetes

Hypoglycaemia is the commonest side-effect of insulin treatment for diabetes, and is the single greatest barrier to achieving and maintaining good glycaemic control. Severe hypoglycaemia (requiring assistance for recovery) is associated with significant morbidity and is feared by most people with type 1 diabetes and their families. It causes stress and anxiety and may influence self-management and glycaemic control. The annual prevalence of severe hypoglycaemia is around 30% in people with type 1 diabetes, and is higher in those with risk factors such as strict glycaemic control, impaired awareness of hypoglycaemia and increasing duration of diabetes. It is also common during sleep (nocturnal hypoglycaemia). Neurological manifestations include coma, convulsions, transient hemiparesis and stroke, while reduced consciousness and cognitive dysfunction may cause accidents and injuries. Cardiac events may be precipitated such as arrhythmias, myocardial ischaemia and cardiac failure. Hypoglycaemia can affect all aspects of life, including employment, driving, recreational activities involving exercise, and travel, and measures should be taken in all of these situations to avoid this potentially dangerous side-effect of insulin therapy.     

Insulin detemir lowers the risk of hypoglycaemia and provides more consistent plasma glucose levels compared with NPH insulin in Type 1 diabetes.

AIMS: Hypoglycaemia remains a major barrier preventing optimal glycaemic control in Type 1 diabetes due to the limitations of conventional insulin preparations. We investigated whether basal-bolus therapy with insulin detemir (detemir), a new soluble basal insulin analogue, was more effective in reducing the risk of hypoglycaemia compared with NPH insulin (NPH). METHODS: In this multinational, open-label, cross-over trial, 130 individuals with Type 1 diabetes received detemir and NPH twice daily in a randomized order in combination with premeal insulin aspart (IAsp) during two 16-week treatment periods. Risk of hypoglycaemia was based on self-measured plasma glucose (SMPG) and self-reported episodes during the last 10 weeks of each period. RESULTS: Risk of nocturnal and overall hypoglycaemia was, respectively, 50% and 18% lower with detemir than with NPH (P < 0.001). A total of 19 severe hypoglycaemic episodes occurred during treatment with detemir compared with 33 with NPH (NS). HbA(1c) decreased by 0.3% point with both treatments and was comparable at 7.6% (+/- sem 0.06%, 95% confidence interval -0.106, 0.108) after 16 weeks with similar doses of basal insulin. Within-person variation in mean plasma glucose was lower with detemir than with NPH (sd 3.00 vs. 3.33, P < 0.001), as was prebreakfast SMPG (P < 0.0001). CONCLUSIONS: Detemir was associated with a significantly lower risk of hypoglycaemia compared with NPH at similar HbA1c when used in combination with mealtime IAsp. The more consistent plasma glucose levels observed with detemir may allow people to aim for tighter glycaemic control without an increased risk of hypoglycaemia.     

A population-based study of risk factors for severe hypoglycaemia in a contemporary cohort of childhood-onset type 1 diabetes

Aims/hypothesis

Severe hypoglycaemia is a major barrier to optimising glycaemic control. Recent changes in therapy, however, may have altered the epidemiology of severe hypoglycaemia and its associated risk factors. The aim of this study was to examine the incidence rates and risk factors associated with severe hypoglycaemia in a contemporary cohort of children and adolescents with type 1 diabetes.

Methods

Subjects were identified from a population-based register containing data on >99% of patients (<16 years of age) who were being treated for type 1 diabetes in Western Australia. Patients attend the clinic approximately every 3 months, where data pertaining to diabetes management, demographics and complications including hypoglycaemia are prospectively recorded. A severe hypoglycaemic event was defined as an episode of coma or convulsion associated with hypoglycaemia. Risk factors assessed included age, duration of diabetes, glycaemic control, sex, insulin therapy, socioeconomic status and calendar year.

Results

Clinical visit data from 1,770 patients, providing 8,214 patient-years of data between 2000 and 2011 were analysed. During follow-up, 841 episodes of severe hypoglycaemia were observed. No difference in risk of severe hypoglycaemia was observed between age groups. Good glycaemic control (HbA_1c <7% [53 mmol/mol]) compared with the cohort average (HbA_1c 8–9% [64–75 mmol/mol]) was not associated with an increased risk of severe hypoglycaemia. When compared with patients on injection regimens, subjects aged 12–18 years on pump therapy were at reduced risk of severe hypoglycaemia (incidence risk ratio 0.6; 95% CI 0.4, 0.9).

Conclusions/interpretation

In this population-based sample of children and adolescents with type 1 diabetes, contemporary therapy is associated with a changed pattern and incidence of severe hypoglycaemia.     

Comparing hormonal and symptomatic responses to experimental hypoglycaemia in insulin‐ and sulphonylurea‐treated Type 2 diabetes

Aims Patients with diabetes rely on symptoms to identify hypoglycaemia. Previous data suggest patients with Type 2 diabetes develop greater symptomatic and hormonal responses to hypoglycaemia at higher glucose concentrations than non‐diabetic controls and these responses are lowered by insulin treatment. It is unclear if this is as a result of insulin therapy itself or improved glucose control. We compared physiological responses to hypoglycaemia in patients with Type 2 diabetes patients treated with sulphonylureas (SUs) or insulin (INS) with non‐diabetic controls (CON). Methods Stepped hyperinsulinaemic hypoglycaemic clamps were performed on 20 subjects with Type 2 diabetes, 10 SU‐treated and 10 treated with twice‐daily premixed insulin, and 10 age‐ and weight‐matched non‐diabetic controls. Diabetic subjects were matched for diabetes duration, glycated haemoglobin (HbA_1c) and hypoglycaemia experience. We measured symptoms, counterregulatory hormones and cognitive function at glucose plateaux of 5, 4, 3.5, 3 and 2.5 mmol/l. Results Symptomatic responses to hypoglycaemia occurred at higher blood glucose concentrations in SU‐treated than INS‐treated patients [3.5 (0.4) vs. 2.6 (0.5) mmol/l SU vs. INS; P = 0.001] or controls [SU vs. CON 3.5 (0.4) vs. 3.0 (0.6) mmol/l; P = 0.05]. They also had a greater increase in symptom scores at hypoglycaemia [13.6 (11.3) vs. 3.6 (6.1) vs. 5.1 (4.3) SU vs. INS vs. CON; P = 0.017]. There were no significant differences in counterregulatory hormone responses or impairment of cognitive function among groups. Conclusions Sulphonylurea‐treated subjects are more symptomatic of hypoglycaemia at a higher glucose level than insulin‐treated subjects. This may protect them from severe hypoglycaemia but hinder attainment of glycaemic goals.     

Lower levels of circulating IGF‐I in Type 1 diabetic women with frequent severe hypoglycaemia during pregnancy

Aims Severe hypoglycaemia is a significant problem in pregnant women with Type 1 diabetes. We explored whether frequent severe hypoglycaemia during pregnancy in women with Type 1 diabetes is related to placental growth hormone (GH) and insulin‐like growth factor I (IGF‐I) levels. Methods A prospective, observational study of 107 consecutive pregnant women with Type 1 diabetes. Blood samples were drawn for IGF‐I and placental GH analyses at 8, 14, 21, 27 and 33 weeks. Severe hypoglycaemic events were reported within 24 h. Results Eleven women (10%) experienced frequent severe hypoglycaemia (≥ 5 events), accounting for 60% of all events. Throughout pregnancy, IGF‐I levels were 25% lower in these women (P < 0.005) compared with the remaining women, despite similar placental GH levels. Eighty per cent of the severe hypoglycaemic events occurred before 20 weeks when IGF‐I levels were at their lowest. This finding was not explained by differences in insulin dose, median plasma glucose levels or glycated haemoglobin. History of severe hypoglycaemia the year preceding pregnancy and impaired hypoglycaemia awareness—being the only predictors of frequent severe hypoglycaemia in a logistic regression analysis—were not associated with IGF‐I or placental GH levels at 8 weeks. Conclusions In women with Type 1 diabetes experiencing frequent severe hypoglycaemia during pregnancy, IGF‐I levels are significantly lower compared with the remaining women despite similar placental GH levels. IGF‐I levels are lowest in early pregnancy where the incidence of severe hypoglycaemia is highest. IGF‐I may be a novel factor of interest in the investigation of severe hypoglycaemia in patients with Type 1 diabetes.     

Diabetic hypoglycaemia.

Hypoglycaemia is a major factor preventing insulin-treated patients from achieving normoglycaemia. This reflects the inadequacy of current insulin treatment, which causes high insulin concentrations in the post-absorptive period. Physiological defences to hypoglycaemia include autonomic activation, which limits the fall in glucose level and causes symptoms, alerting patients to an impending episode. Many patients develop defective responses and hypoglycaemia unawareness after longstanding disease or with tight glycaemic control and are then prone to severe attacks. This may be the result of repeated hypoglycaemic episodes, which by altering cerebral glucose uptake, disturb the mechanisms that activate the central response to hypoglycaemia. Preventing further hypoglycaemia can partially reverse these defects and restore symptomatic awareness. Clinical hypoglycaemia has also been implicated in the 'dead in bed' syndrome and in chronic cognitive impairment. The problem of hypoglycaemia will eventually be solved by better insulin delivery and non-invasive glucose meters, but until then, more focused education may have a more substantial impact.     

Influence of preprandial vs. postprandial insulin glulisine on weight and glycaemic control in patients initiating basal-bolus regimen for type 2 diabetes: a multicenter, randomized, parallel, open-label study (NCT00135096)

Aim: Insulin therapy is commonly associated with weight gain. The timing of prandial insulin administration may enhance its efficacy/safety and maintain effective weight control. This study examined the effect of postprandial vs. preprandial insulin glulisine on weight gain and glycaemic control in type 2 diabetes patients taking basal insulin. Methods: This was a multicenter, randomized, open‐label trial conducted in 45 centres in the USA. A total of 716 patients with type 2 diabetes and glycated haemoglobin A_1c (HbA_1c) ≥7.5% and ≤10.0% were screened; 345 were randomized and 322 comprised the intent‐to‐treat group (premeal, 163; postmeal, 159). Insulin glargine once daily, ±metformin and subcutaneous injections of premeal or postmeal insulin glulisine were given for 52 weeks. Main outcome measures included changes in HbA_1c, fasting plasma glucose and weight from study baseline to endpoint (week 52). Results: At study end, insulin glulisine achieved similar glycaemic control whether it was administered before or after meals (HbA_1c: 7.04% premeal vs. 7.16% postmeal, p = NS). Overall hypoglycaemia incidence and severe hypoglycaemia rates were not significantly different between premeal and postmeal groups; however, symptomatic and nocturnal hypoglycaemia rates were higher in the postprandial group. Mean body weight was lower in the postmeal group, with the difference between postmeal and premeal weight change from baseline to week 52 of ?0.87 kg (p = 0.243). Conclusion: Postprandial glulisine administration provided similar glycaemic control and was non‐inferior to preprandial administration on weight gain, without additional risk of severe hypoglycaemia, showing dosing flexibility and the feasibility of such approach when clinically indicated.     

Glycaemia and cardiac arrhythmias in people with type 1 diabetes: A prospective observational study

Aim

To investigate the impact of hypoglycaemia, hyperglycaemia and glycaemic variability on arrhythmia susceptibility in people with type 1 diabetes.

Materials and Methods

Thirty adults with type 1 diabetes were included in a 12-month observational exploratory study. Daytime and night-time incident rate ratios (IRRs) of arrhythmias were determined for hypoglycaemia (interstitial glucose [IG] <3.9 mmol/L), hyperglycaemia (IG >10.0 mmol/L) and glycaemic variability (standard deviation and coefficient of variation).

Results

Hypoglycaemia was not associated with an increased risk of arrhythmias compared with euglycaemia and hyperglycaemia combined (IG ≥ 3.9 mmol/L). However, during daytime, a trend of increased risk of arrhythmias was observed when comparing time spent in hypoglycaemia with euglycaemia (IRR 1.08 [95% CI: 0.99-1.18] per 5 minutes). Furthermore, during daytime, both the occurrence and time spent in hyperglycaemia were associated with an increased risk of arrhythmias compared with euglycaemia (IRR 2.03 [95% CI: 1.21-3.40] and IRR 1.07 [95% CI: 1.02-1.13] per 5 minutes, respectively). Night-time hypoglycaemia and hyperglycaemia were not associated with the risk of arrhythmias. Increased glycaemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during night-time.

Conclusions

Acute hypoglycaemia and hyperglycaemia during daytime may increase the risk of arrhythmias in individuals with type 1 diabetes. However, no such associations were found during night-time, indicating diurnal differences in arrhythmia susceptibility.     

Use of insulin in type 2 diabetes: What we learned from recent clinical trials on the benefits of early insulin initiation

The majority of people with type 2 diabetes mellitus (T2DM) require insulin therapy to maintain HbA_1c levels < 7% during the first decade of diagnosis. Large prospective trials investigating the cardiovascular (CV) benefits of intensive glycaemic control have produced inconsistent results; however, meta-analyses have suggested that intensive glycaemic control provides both micro- and macrovascular benefits. The ORIGIN study investigated the impact of basal insulin glargine therapy targeting ≤ 5.3 mmol/L for fasting plasma glucose compared with standard care on CV outcomes in people with pre- or early diabetes, and demonstrated a neutral effect on CV outcomes with long-term use of insulin glargine early in the course of diabetes, with a low rate of severe hypoglycaemia and modest weight gain. The EARLY, GLORY and EASIE studies also demonstrated that insulin use earlier in the treatment pathway led to improved glycaemic control, reduced weight gain and fewer hypoglycaemic episodes than when insulin was added later in the course of disease. The beneficial effect of early transient intensive insulin therapy (TIIT) at diagnosis has been demonstrated in a number of trials; it rapidly limits the damage caused by gluco- and lipotoxicity, improving residual β-cell function and potentially slowing disease progression. The evidence suggests that people newly diagnosed with T2DM and HbA_1c > 9% should be given early TIIT to achieve normoglycaemia within weeks, after which standard care should then be adopted. Insulin use earlier in the treatment pathway should be considered, as it reduces the risk of hypoglycaemia as well as allows β-cell rest, which can help preserve β-cell function.     

Hypoglycaemia in insulin-treated Type 2 diabetes: frequency,symptoms and impaired awareness

Aims Hypoglycaemia is considered to be less common in people with insulin-treated Type 2 diabetes than in Type 1 diabetes. A retrospective survey was made of 215 people with insulin-treated Type 2 diabetes to quantify the frequency and nature of hypoglycaemia experienced. Methods The frequencies of mild (self-treated) and severe (required assistance) hypoglycaemia during the preceding year were estimated retrospectively. The usual symptoms of hypoglycaemia and state of awareness of hypoglycaemia were scored using validated questionnaires and any history suggestive of impaired hypoglycaemia awareness was documented. Results In this cohort, 157 (73%) had experienced hypoglycaemia since commencing insulin, the frequency of which increased with duration of diabetes and of insulin therapy and was inversely related to current HbA_1c (all P < 0.05). During the preceding year, 32 individuals (15%) had experienced severe hypoglycaemia, with an estimated incidence for the entire group of 0.28 episodes/patient/year. Principal components analysis revealed two underlying symptom groups (autonomic and neuroglycopenic), similar to those reported previously by young adults with Type 1 diabetes, but the total symptom score declined with advancing age. Of the 157 with a history of hypoglycaemia, the 13 (8%) individuals who gave a history of impaired awareness of hypoglycaemia had experienced a ninefold higher incidence of severe hypoglycaemia than those with normal awareness, and reported experiencing mainly neuroglycopenic symptoms. Conclusions While the overall frequencies of mild and severe hypoglycaemia were lower in insulin-treated Type 2 diabetes than have been reported previously in Type 1 diabetes, the risk of hypoglycaemia was greater with increasing duration of diabetes and of insulin therapy. Although impaired awareness of hypoglycaemia was uncommon, it was associated with a higher incidence of severe hypoglycaemia. Diabet. Med. 20, ***–*** (2003)