Hypoglycaemia: An overview

Hypoglycaemia is a frequent side-effect of treatment with insulin and sulfonylureas for people with diabetes, threatening potentially serious morbidity and preventing optimal glycaemic control. Fear of hypoglycaemia and development of syndromes such as impaired awareness and counterregulatory deficiency provide additional hazards for intensification of treatment. Rapid lowering of HbA1c may be potentially dangerous in type 2 diabetes because of the adverse cardiovascular effects induced by hypoglycaemia. Hypoglycaemia can disrupt many everyday activities such as driving, work performance and recreational pursuits. Measures to reduce the risk of hypoglycaemia are labour-intensive and require substantial resources.     

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.     

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.     

Reporting of hypoglycaemia in clinical trials of basal insulins: A need for consensus

Hypoglycaemia is a common side-effect of diabetes therapies, particularly insulin, and imposes a substantial burden on individuals and healthcare systems. Consequently, regulatory approval of newer basal insulin (BI) therapies has relied on demonstration of a balance between achievement of good glycaemic control and less hypoglycaemia. Randomized controlled trials (RCTs) are the gold standard for assessing efficacy and safety, including hypoglycaemia risk, of BIs and are invaluable for obtaining regulatory approval. However, their highly selected patient populations and their conditions lead to results that may not be representative of real-life situations. Real-world evidence (RWE) studies are more representative of clinical practice, but they also have limitations. As such, data both from RCTs and RWE studies provide a fuller picture of the hypoglycaemia risk with BI therapies. However, substantial differences exist in the way hypoglycaemia is reported across these studies, which confounds comparisons of hypoglycaemia frequency among different BIs. This problem is ongoing and persists in recent trials of second-generation BI analogues. Although they provide a lower risk of hypoglycaemia when compared with earlier BIs, they do not eliminate it. This review describes differences in the way hypoglycaemia is reported across RCTs and RWE studies of second-generation BI analogues and examines potential reasons for these differences. For studies of BIs, there is a need to standardize aspects of design, analysis and methods of reporting to better enable interpretation of the efficacy and safety of such insulins among studies; such aspects include length of follow-up, glycaemic targets, hypoglycaemia definitions and time intervals for determining nocturnal events.     

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.     

Hypoglycaemia and gastric emptying

Hypoglycaemia is arguably the most important complication of insulin therapy in type 1 and type 2 diabetes. Counter-regulation of hypoglycaemia is dependent on autonomic function and frequent hypoglycaemia may lead to reductions in both autonomic warning signals and the catecholamine response, the so-called “impaired awareness of hypoglycaemia”. It is now appreciated that gastric emptying is a major determinant of the glycaemic response to carbohydrate-containing meals in both health and diabetes, that disordered (especially delayed) gastric emptying occurs frequently in diabetes, and that acute hypoglycaemia accelerates gastric emptying substantially. However, the potential relevance of gastric emptying to the predisposition to, and counter-regulation of, hypoglycaemia has received little attention. In insulin-treated patients, the rate of gastric emptying influences the timing of the postprandial insulin requirement, and gastroparesis is likely to predispose to postprandial hypoglycaemia. Conversely, the marked acceleration of gastric emptying induced by hypoglycaemia probably represents an important counter-regulatory response to increase the rate of carbohydrate absorption. This review summarizes the current knowledge of the inter-relationships between hypoglycaemia and gastric emptying, with a focus on clinical implications.     

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.     

Symptoms of hypoglycaemia in people with diabetes.

The symptoms of hypoglycaemia are fundamental to the early detection and treatment of this side-effect of insulin and oral hypoglycaemic therapy in people with diabetes. The physiology of normal responses to hypoglycaemia is described and the importance of symptoms of hypoglycaemia is discussed in relation to the treatment of diabetes. The symptoms of hypoglycaemia are described in detail. The classification of symptoms is considered and the usefulness of autonomic and neuroglycopenic symptoms for detecting hypoglycaemia is discussed. The many external and internal factors involved in the perception of symptoms are reviewed, and symptoms of hypoglycaemia experienced by people with Type 2 diabetes are addressed. Age-specific differences in the symptoms of hypoglycaemia have been identified, and are important for clinical and research practice, particularly with respect to the development of acquired hypoglycaemia syndromes in people with Type 1 diabetes that can result in impaired awareness of hypoglycaemia. In addition, the routine assessment of hypoglycaemia symptoms in the diabetic clinic is emphasized as an important part of the regular review of people with diabetes who are treated with insulin.     

The importance of the initial period of basal insulin titration in people with diabetes

Achieving target glycaemic control is essential in people with diabetes to minimize the risk of long-term complications, and many people with type 2 diabetes will ultimately require basal insulin (BI) therapy to achieve their individualized glycaemic targets. Usually, the first 12 weeks following initiation of BI therapy represents the period when the greatest dose increases and glycaemic reductions occur. Effective glycaemic control combined with minimizing the risk of hypoglycaemia is important to enable the achievement of glycaemic control in the longer term. However, substantial therapeutic inertia exists in clinical practice, both in initiation and up-titration of BI, owing to patient-, physician- and healthcare system-related barriers, including fear of hypoglycaemia and the perception of a burdensome regimen. The more prolonged duration of action, reduced glycaemic variability and lower risk of hypoglycaemia seen with second-generation versus first-generation BI analogues may help alleviate patients’ and physicians’ concerns and facilitate titration. In turn, optimal BI titration and subsequent metabolic benefits may help improve therapy adherence and self-management. This review details the clinical implications of prompt titration of BI to achieve early glycaemic control, and the importance of minimizing hypoglycaemia risk within the initial titration period. Facilitation of patients’ self-management of BI is also 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. Copyright © 2013 John Wiley & Sons, Ltd.     

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.     

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.     

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)     

Insulin glargine in type 2 diabetes in everyday clinical practice: 7 years experience

Insulin therapy is often essential in people with type 2 diabetes mellitus (T2DM) but is typically not initiated early enough or aggressive enough, leading to worsening of glycaemic control and the majority of people staying above recommended haemoglobin A_1c (HbA_1c) targets of <7%. The extensive clinical experience gained with insulin glargine, in particular, the low risk of hypoglycaemia and consistent improvements in HbA_1c, suggests that insulin glargine can be initiated aggressively to help patients reach such HbA_1c targets. However, many clinicians may be unaware of how easy it is to initiate insulin glargine. Indeed, the once-daily injection of insulin glargine plus once-daily measurement of blood glucose should provide little difficulty for patients. In the current review, the options for the initiation of insulin glargine in T2DM and how the patient can become more involved in management of their diabetes are discussed. The advantages of insulin glargine in randomized controlled trials and how these have translated into everyday clinical practice are also discussed.     

Central pontine myelinolysis and ataxia: an unusual manifestation of hypoglycaemia

Hypoglycaemia is common in people with diabetes who aim to achieve good blood glucose control. Severe hypoglycaemia presents with evidence of neurological dysfunction, such as inability to concentrate, confusion, siezures, and coma. Such disturbances are reversible on correction of the hypoglycaemia. Infrequently there may be a focal neurological deficit and we report one such case presenting with cerebellar symptoms following an episode of severe hypoglycaemia. A magnetic resonance scan showed features consistent with the presence of central pontine myelinolysis. The symptoms resolved within a few months with only minimal residual neurological deficit. © 1998 John Wiley & Sons, Ltd.     

The mechanisms that underlie glucose sensing during hypoglycaemia in diabetes

Hypoglycaemia is a frequent and greatly feared side-effect of insulin therapy, and a major obstacle to achieving near-normal glucose control. This review will focus on the more recent developments in our understanding of the mechanisms that underlie the sensing of hypoglycaemia in both non-diabetic and diabetic individuals, and how this mechanism becomes impaired over time. The research focus of my own laboratory and many others is directed by three principal questions. Where does the body sense a falling glucose? How does the body detect a falling glucose? And why does this mechanism fail in Type 1 diabetes? Hypoglycaemia is sensed by specialized neurons found in the brain and periphery, and of these the ventromedial hypothalamus appears to play a major role. Neurons that react to fluctuations in glucose use mechanisms very similar to those that operate in pancreatic B- and A-cells, in particular in their use of glucokinase and the K_ATP channel as key steps through which the metabolic signal is translated into altered neuronal firing rates. During hypoglycaemia, glucose-inhibited (GI) neurons may be regulated by the activity of AMP-activated protein kinase. This sensing mechanism is disturbed by recurrent hypoglycaemia, such that counter-regulatory defence responses are triggered at a lower glucose level. Why this should occur is not yet known, but it may involve increased metabolism or fuel delivery to glucose-sensing neurons or alterations in the mechanisms that regulate the stress response.     

Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with Type 1 diabetes.

AIMS: To compare the effects of the rapid-acting insulin analogue insulin aspart and soluble human insulin on hypoglycaemia and glycaemic control in patients with Type 1 diabetes when injected immediately before meals as part of intensive insulin therapy. METHODS: In this multinational, double-blind, randomised, crossover trial, 155 patients with Type 1 diabetes (HbA(1c) < 8.0%) were symmetrically randomised to two 16-week treatment periods on either type of insulin, both injected 0-5 min before meals. NPH insulin was given as basal insulin once or twice daily as needed, and insulin dosages were regularly adjusted using pre-defined algorithms to maintain tight glycaemic control. Treatment periods were separated by a 4-week washout. RESULTS: The rate of major nocturnal (24.00-06.00 h) hypoglycaemic episodes was 72% lower with insulin aspart than with human insulin (0.067 vs. 0.225 events/month; P = 0.001). Total rate of major hypoglycaemia did not differ significantly between treatments (insulin aspart/human insulin relative risk 0.72; 95% CI 0.47-1.09, P = 0.12). The rate of minor events was significantly reduced by 7% with insulin aspart (P = 0.048). Reductions in rate of hypoglycaemia were achieved with maintained overall glycaemic control: Mean HbA(1c) remained constant, slightly below 7.7% on both treatments. CONCLUSIONS: The use of insulin aspart in an intensive insulin regimen in patients with tightly controlled Type 1 diabetes led to clinically significant reductions in major nocturnal hypoglycaemia with no deterioration in glycaemic control. Major nocturnal hypoglycaemia appears to be a strong clinical indication for the use of rapid-acting insulin analogues during intensive insulin therapy.     

Insulin glargine 300 units/mL for the treatment of individuals with type 2 diabetes in the real world: A review of the DELIVER programme

Evidence from randomized controlled trials (RCTs) has shown that second-generation basal insulin (BI) analogues, insulin glargine 300 U/mL (Gla-300) and insulin degludec (IDeg), provide similar glycaemic control, with a lower risk of hypoglycaemia compared with the first-generation BI analogue insulin glargine 100 U/mL (Gla-100) in people with type 2 diabetes (T2D). However, the highly selected participants and frequent follow-up of RCTs may not be truly representative of real-life clinical practice. It is important to assess the safety and effectiveness of these second-generation BI analogues in real-life clinical practice settings. The DELIVER programme utilized electronic healthcare records from the United States to compare clinical outcomes in people with T2D who received either Gla-300 or other BI analogues in real-world clinical practice. This review provides a concise overview of the results of the DELIVER studies. Overall, Gla-300 provided similar antihyperglycaemic effectiveness and a lower risk of hypoglycaemia versus the first-generation BI analogues Gla-100 and insulin detemir in people with T2D who had switched BIs. In those who were insulin-naïve, initiation with Gla-300 versus Gla-100 was associated with significantly better antihyperglycaemic effectiveness and similar or lower hypoglycaemic risk. Both glycaemic control and hypoglycaemia risk were also shown to be similar with Gla-300 and IDeg, in people who had switched BIs and in those who were insulin-naïve. In addition, the DELIVER 2 study reported that people with T2D who switched to Gla-300 had reduced healthcare resource utilization, with an overall saving of US$1439 per person per year compared with those who switched to another BI analogue. Overall, the real-world DELIVER programme showed that the glycaemic control with a low risk of hypoglycaemia observed with Gla-300 in RCTs was also seen in standard clinical practice.     

Hypoglycaemia as a function of HbA1c in type 2 diabetes: Insulin glargine 300 U/mL in a patient-level pooled analysis of EDITION 1, 2 and 3

Basal insulin therapy often involves a compromise between achievement of glycaemic targets and avoidance of hypoglycaemia, dependent on how intensively insulin is titrated. In the Phase 3a EDITION 1, 2 and 3 studies, insulin glargine 300 U/mL (Gla-300) provided glycaemic control equivalent to that of insulin glargine 100 U/mL (Gla-100), with less hypoglycaemia in individuals with type 2 diabetes mellitus (T2DM). The current study evaluated the rates of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia over six months of treatment with Gla-300 or Gla-100 in the EDITION studies, as a function of HbA1c. Analysis was performed on patient-level data pooled from the three EDITION studies, and annualized hypoglycaemia rate as a function of HbA1c at Month 6 was fitted using a negative binomial regression model. Participants treated with Gla-300 experienced a consistently lower rate of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia as compared with those treated with Gla-100, regardless of HbA1c at Month 6. Results suggest that treatment with Gla-300 vs Gla-100 could allow individuals with T2DM to achieve equivalent glycaemic control with less hypoglycaemia.     

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.