Nocturnal Hypoglycemic Events Research Articles

Patient-related and Socio-economic Implications of Non-Severe Nocturnal Hypoglycaemia among Canadian Type 1 and Type 2 Diabetes Patients

Hypoglycemia is a common side-effect of treatment with certain diabetes drugs. Non-Severe Nocturnal Hypoglycemic Events (NSNHE) occur more frequently than severe events. The objective of this study was to identify how NSNHEs in a Canadian diabetes population affect disease self-management and disease-related costs.

Non-severe nocturnal hypoglycemic events: experience and impacts on patient functioning and well-being

PurposeNon-severe nocturnal hypoglycemic events (NSNHEs) are hypoglycemic events that occur during sleep but do not require medical assistance from another individual. This study was conducted to better understand the NSNHEs as patients actually experience them in their daily life, and how they impacted functioning and well-being.MethodsNine focus groups were held in four countries with diabetics (Type 1 and Type 2) who had experienced an NSNHE within the previous month: France (2 groups); Germany (2 groups); United Kingdom (2 groups); and United States (3 groups). These groups were audio-taped, translated to English where applicable, and analyzed thematically.ResultsSeventy-eight people with diabetes participated in the focus groups: 41 (53 %) were female and 37 (47 %) were male; 24 (31 %) had Type 1 diabetes, and 54 (69 %) had Type 2 diabetes. Participant reports were grouped into several major themes: next day effects, symptoms, sleep impacts, social impacts, corrective action, practical management, feelings about NSNHEs, and work impacts.ConclusionsPeople with both Type 1 and Type 2 diabetes experience NSNHEs. The range of impact on these patients is wide, from very mild to severe with a majority of participants experiencing strong impacts that limit their daily functioning. This finding suggests that NSNHEs are more impactful than previously believed.

A Prototype of a New Noninvasive Device to Detect Nocturnal Hypoglycemia in Adolescents with Type 1 Diabetes—A Pilot Study

Severe hypoglycemic events are a major consequence of tight diabetes control. Continuous glucose monitoring systems (CGMSs) were recently introduced in order to minimize the risk of hypoglycemia. However, the present CGMSs are invasive and costly and have been recently demonstrated to be intolerant for most children and adolescents. Hence there is a need for a simple, noninvasive, convenient, and inexpensive device to detect hypoglycemic events. The Gili Medical Hypoglycemia Non Invasive Monitoring System (GMHNIMS) (Gili Medical Ltd., Migdal HaEmek, Israel) has been currently developed for these purposes. Ten patients 14-18 years old with type 1 diabetes for at least 1 year participated in a pilot study that was held at the Meyer Children's Hospital, Rambam Medical Center, Haifa, Israel. All patients were either treated by insulin pump or by multiple daily injections. The GMHNIMS was connected to the study subjects during three consecutive nights in an inpatient setting while they received their usual insulin regimen. The system is composed of four sensors (heart rate, perspiration, skin temperature, and tremor) that detect physiologic changes during hypoglycemia. In addition, each patient was connected to a real-time CGMS for 3 nights. When a hypoglycemic event was suspected clinically by the patient, a bedside capillary glucose was checked by a glucometer. The system was found to be convenient without any disturbances to sleep quality. The sensitivity of the GMHNIMS for detection of true hypoglycemic events was 100% with specificity of 85.7%. The new device showed high detection rates of nocturnal hypoglycemic events with an acceptable degree of false-positive readings. Being inexpensive and noninvasive, this device has the potential for routine use in insulin-treated patients.

PDB69 the Impact of Nocturnal Hypoglycemic Events on Functioning, Well-Being and Diabetes Management

PDB69 the Impact of Nocturnal Hypoglycemic Events on Functioning, Well-Being and Diabetes Management

New insulins and insulin therapy

New insulins and insulin therapy

Impact of nocturnal hypoglycemic events on diabetes management, sleep quality, and next-day function: results from a four-country survey

Objectives:Non-severe nocturnal hypoglycemic events (NSNHEs) may have a major impact on patients. The objective was to determine how NSNHEs affect diabetes management, sleep quality, functioning, and to assess if these impacts differ by diabetes type or country.Methods:An internet survey to adults with diabetes in the US, UK, Germany, and France.Results:Of 6756 screened respondents, 1086 reported an NSNHE in the past month. For this last event, respondents with type 2 required significantly more time than type 1 to recognize and respond to the event (1.5 vs 1.1 hours), 25.7% (T1) and 18.5% (T2) decreased their normal insulin dose due to their most recent NSNHE. All respondents were likely to take 1–2 additional self-monitored blood glucose measurements on the day following. NSNHEs were associated with a high proportion of respondents contacting a healthcare professional (18.6% T1, 27.8% T2) reporting they could not return to sleep at night (13.3% T1, 13.4% T2), and tiredness on the day following the event (71.2% for both). Of the respondents working for pay, 18.4% T1 and 28.1% T2 reported being absent from work due to the NSNHE, and a substantial proportion of respondents (8.7% T1, 14.4% T2) also reported missing a meeting or work appointment or not finishing a task on time. Compared with other countries, respondents from France may experience a more substantial impact on diabetes management and daily functioning following an NSNHE. Potential limitations in this study include recall and selection bias; however, these biases are not believed to have impacted findings in any meaningful way.Conclusions:NSNHEs are associated with a substantial impact on diabetes management, sleep quality, and next-day functioning.

PDB59 Nocturnal Hypoglycemic Events: Impacts on Patients Functioing, Well-Being and Diabetes Management

PDB59 Nocturnal Hypoglycemic Events: Impacts on Patients Functioing, Well-Being and Diabetes Management

Use of continuous glucose monitoring to introduce adjunctive pramlintide therapy in a patient with type 1 diabetes: A case study

AbstractPurpose: To report the successful use of a continuous glucose monitoring system (CGMS) in helping a patient with type 1 diabetes initiate a new diabetes therapy, pramlintide, which improves glycemic control.Data sources: Case report, diagnostic evidence, and scientific literature.Conclusions: CGMS data before and 3 months after pramlintide initiation supported the changes felt by the patient. Diurnal and postprandial glucose excursions decreased with a resultant decrease in A1C from 9% to 7.4%. Additionally, body weight decreased by 8 lbs and hypoglycemic events declined markedly. No nocturnal hypoglycemic events occurred during the observation period.Implications for practice: Given the serious and chronic nature of diabetes, it is paramount for the patient and healthcare provider to develop and modify as needed treatment regimens that help the patient achieve and maintain glycemic control over time—a difficult task even in the motivated patient. In patients with type 1 diabetes, pramlintide can further improve glycemic control and CGMS can be a beneficial tool for monitoring that change.

Cost-effectiveness of insulin glargine versus NPH insulin for the treatment of Type 2 diabetes mellitus, modeling the interaction between hypoglycemia and glycemic control in Switzerland

The objective of this study was to evaluate the short-term and long-term clinical and economic outcomes associated with insulin glargine or NPH insulin in patients with Type 2 diabetes mellitus (T2DM) inadequately controlled with oral anti-diabetic drugs in Switzerland, modeling the interaction between hypoglycemia and glycemic control (HbA1c). A validated discrete event simulation model for T2DM was used to predict incidence of short-term complications (symptomatic, nocturnal and severe hypoglycemic events) and long-term complications (microvascular and macrovascular events), life expectancy, quality-adjusted life years (QALYs) and direct medical costs in patients treated with insulin glargine or NPH insulin. The model was populated with published Swiss patient characteristics with T2DM. Baseline risks of hypoglycemic events, utility decrements of diabetes-related long-term complications and the hypoglycemia fear score were derived from the literature. Relative risk reductions of hypoglycemia adjusted for HbA1c using insulin glargine compared with NPH insulin were based on a published negative binomial meta-regression analysis. Costs of severe hypoglycemia, micro- and macrovascular events were analyzed from literature whenever possible otherwise guideline-projected resource-use estimations were valued with Swiss official prices or tariffs in 2006 CHF. Simulations were run with 1,000 patients per cohort over a time horizon of 40 years. Incremental cost effectiveness ratios (ICERs) were presented as cost per QALY and per life year gained (LYG). Future costs and clinical benefits were discounted at 3.5%. Wide-range one-way sensitivity analyses were performed. Insulin glargine was associated with an improvement in quality of life (0.098 QALYs per patient) and additional life expectancy (0.05 life years gained per patient) compared to NPH insulin. Incremental costs of CHF 2,578 resulted in an ICER of CHF 26,271 per QALY and CHF 51,100 per LYG. The cost per QALY was most sensitive to changes in costs, utility decrements and relative risk reductions of hypoglycemia. This study evaluated, for the first time, the cost effectiveness of insulin glargine versus NPH insulin for the treatment of T2DM considering the interaction between glycemic control and hypoglycemia in Switzerland. The base case and sensitivity analyses demonstrated that insulin glargine proved to be cost-effective with respect to accepted willingness to pay thresholds and therefore represents good value for money.

A New-Generation Ultra-Long-Acting Basal Insulin With a Bolus Boost Compared With Insulin Glargine in Insulin-Naïve People With Type 2 Diabetes

OBJECTIVEInsulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the novel basal analog insulin degludec (IDeg: 70%) and insulin aspart (IAsp: 30%). We compared the safety and efficacy of IDegAsp, an alternative formulation (AF) (55% IDeg and 45% IAsp), and insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes inadequately controlled with oral antidiabetic drugs.RESEARCH DESIGN AND METHODSIn this 16-week, open-label trial, subjects (mean age 59.1 years, A1C 8.5%, BMI 30.3 kg/m2) were randomized to once-daily IDegAsp (n = 59), AF (n = 59), or IGlar (n = 60), all in combination with metformin. Insulin was administered before the evening meal and dose-titrated to a fasting plasma glucose (FPG) target of 4.0–6.0 mmol/L.RESULTSAfter 16 weeks, mean A1C decreased in all groups to comparable levels (IDegAsp: 7.0%; AF: 7.2%; IGlar: 7.1%). A similar proportion of subjects achieved A1C <7.0% without confirmed hypoglycemia in the last 4 weeks of treatment (IDegAsp: 51%; AF: 47%; IGlar: 50%). Mean 2-h postdinner plasma glucose increase was lower for IDegAsp (0.13 mmol/L) and AF (0.24 mmol/L) than IGlar (1.63 mmol/L), whereas mean FPG was similar (IDegAsp: 6.8 mmol/L; AF: 7.4 mmol/L; IGlar: 7.0 mmol/L). Hypoglycemia rates were lower for IDegAsp and IGlar than AF (1.2, 0.7, and 2.4 events/patient year). Nocturnal hypoglycemic events occurred rarely for IDegAsp (1 event) and IGlar (3 events) compared with AF (27 events).CONCLUSIONSIn this proof-of-concept trial, once-daily IDegAsp was safe, well tolerated, and provided comparable overall glycemic control to IGlar at similar low rates of hypoglycemia, but better postdinner plasma glucose control.

Multicenter, open‑label, nonrandomized, observational safety study in subjects using insulin aspart in basal‑bolus regimen for the treatment of diabetes

Basal-bolus insulin therapy is a standard method of intensifying diabetes treatment. A common adverse effect of such treatment is hypoglycemia. Data on frequency of hypoglycemia when fast-acting insulin analogue is used in everyday clinical practice is scarce. The aim of the study was to investigate the risk of hypoglycemia after the use of insulin aspart in basal-bolus therapy in patients with type 1 and 2 diabetes. It was a multicenter, open-label, noninterventional study. It involved 950 patients with type 1 and 1332 patients with type 2 diabetes who started preprandial insulin aspart in basal-bolus regimen. Patients were followed for 13 weeks. The primary endpoint was the incidence of major daytime and nocturnal hypoglycemic events assessed on the basis of patients' self-reports during follow-up compared with a 4-week period before the baseline visit. Secondary endpoints were: incidence of minor daytime and nocturnal hypoglycemia, hemoglobin A1c (HbA1c), fasting and postprandial glycemia. The rate of major hypoglycemia decreased in patients with type 1 diabetes--the incidence rate ratio (IRR) was 0.14 for daytime and 0.03 for nocturnal episodes (P <0.0001) and did not change in patients with type 2 diabetes. The rate of minor episodes decreased in patients with type 1 diabetes (IRR = 0.44 for daytime and IRR = 0.24 for nocturnal episodes, P <0.0001) and in patients with type 2 diabetes (IRR= 0.57, P <0.0001 for daytime and IRR = 0.89, P <0.05 for nocturnal episodes). HbA1c decreased by 1.28 ± 1.64% in type 1 and 1.25 ± 1.10% in type 2 diabetes (both P <0.0001). Self-measured fasting and postprandial blood glucose levels were significantly lower at the final visit compared with baseline, irrespective of diabetes type. In clinical practice, treatment with insulin aspart in basal-bolus regimen is associated with low risk of hypoglycemia and leads to a significant improvement in glucose control, irrespective of diabetes type.

Efficacy of combined use of miglitol in Type 2 diabetes patients receiving insulin therapy-placebo-controlled double-blind comparative study

Combination therapy with an α-glucosidase inhibitor and insulin is commonly performed for type 2 diabetes mellitus. We conducted a placebo-controlled double-blind comparative study to investigate the efficacy of combination therapy with miglitol and insulin. The patients with T2DM on insulin therapy were randomly assigned to either a miglitol treatment group (Group M) or a placebo group (Group P) and treated for 12weeks. Meal tolerance tests were conducted at the observation period, week 0 and week 12 of the treatment period. Mean values of decrease in 1-h- and 2-h postprandial plasma glucose level were significantly larger in Group M than in Group P (60.3±70.1mg/dl vs. -5.1±68.2mg/dl (P<0.001)), as was HbA1c as well (0.36±0.66% vs. -0.03±0.56% (P<0.001)). Adverse events included abdominal distension and flatulence, which were significantly more frequent in Group M. The frequency of nocturnal hypoglycemia events tended to be reduced in Group M. Combined use of insulin and miglitol is useful for postprandial glucose regulation and improves glycemic control.

Glycemic Control with Preprandial Versus Basal Insulin in Patients with Type 2 Diabetes Mellitus Poorly Controlled by Oral Antidiabetes Agents

This study was designed to compare glycemic control (glycated hemoglobin [A1C] level) with either once-daily basal insulin (BI) (insulin glargine) or preprandial insulin (PPI) (Exubera) [insulin human (recombinant DNA origin)] inhalation powder, Pfizer Inc., New York, NY) in patients with type 2 diabetes mellitus (T2DM) poorly controlled on at least two oral antidiabetes agents (OADs). This was a 26-week, open-label, parallel-group, randomized study where 257 patients (mean A1C 8.6%) on OAD treatment for > or = 3 months were treated with either BI (n = 122) or PPI (n = 135). Based on self-monitored blood glucose levels, PPI dose was adjusted before each major meal, whereas BI dose was titrated in the morning or before bedtime. Prestudy OADs were continued, but doses could be modified. At 26 weeks, change from baseline in A1C was greater with PPI (-1.7 vs. -1.4%, P = 0.0389). Numerically, more patients achieved A1C <6.5% (28% vs. 19%) and A1C <7.0% (63% vs. 55%) with PPI compared with BI. PPI had lower postmeal glucose increments, but higher prebreakfast glucose and weight gain (1.1kg), than BI. Mild or moderate hypoglycemic events were more frequent with PPI (6.2 vs. 2.9 events/months), but nocturnal hypoglycemic events were less frequent (22% vs. 30%). PPI improved postprandial glucose and A1C levels significantly more than BI. More patients achieved A1C targets with PPI, at the expense of more hypoglycemia and body weight gain. These results illustrate the potential benefits and detriments of prandial insulin supplementation in patients with T2DM poorly controlled on OADs alone.

Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain: 52-week data from the PREDICTIVE™ study in a cohort of French patients with type 1 or type 2 diabetes

Aim PREDICTIVE™ (an ongoing multinational observational study) provides an opportunity to explore the impact of insulin detemir use in routine clinical practice. Here, we report on long-term (52-week) data from a French cohort of patients ( n = 1772), comprising 643 with type 1 diabetes and 1129 with type 2 diabetes. Methods Patients were prescribed insulin detemir at their physician's discretion and assessed at various visits (baseline, 12 weeks, 26 weeks and 52 weeks). The primary endpoint was the frequency of serious adverse drug reactions, including major hypoglycaemia. Secondary endpoints included minor and nocturnal hypoglycaemia, glycaemic control (HbA 1c, fasting blood glucose and variability of fasting blood glucose) and weight change. Results The incidence of serious adverse drug reactions was low throughout the study, seen in 10 patients with type 1 diabetes (14 events, 1.6%) and seven with type 2 diabetes (seven events, 0.6%). In both type 1 and type 2 diabetes cohorts, the overall minor and nocturnal hypoglycaemic events were reduced from baseline ( P < 0.001), with no clinically significant changes in weight from baseline to endpoint. After 52 weeks of treatment with insulin detemir, glycaemic control improved, with reductions in: HbA 1c, by −0.6% and −0.8% in type 1 and type 2 diabetes patients, respectively; fasting blood glucose, by −1.4 mmol/L and −1.9 mmol/L respectively; and FBG variability, by −0.8 mmol/L and −0.3 mmol/L, respectively ( P < 0.0001 for all). Conclusion Patients treated with insulin detemir in a clinical healthcare setting improved their glycaemic control with no increases in hypoglycaemia, adverse events or weight compared with baseline.

Preclinical and clinical studies on safety and tolerability of repaglinide.

Repaglinide, an insulinotropic benzoic acid derivative, has been tested extensively in the preclinical and clinical setting for safety and tolerability. In preclinical safety trials, no clinically relevant laboratory or histopathological changes were found and repaglinide was not found to be genotoxic, immunogenic, teratogenic or tumorigenic at levels 50 times greater than the exposure in humans. In an ascending-dose tolerability study in Type 2 diabetic patients, no clinically relevant changes in liver enzymes or ECG occurred during the trial. A total of five active-controlled, long-term trials of identical design have been carried out (with 12 months of maintenance on a fixed, pretitrated dose), including 1228 patients on repaglinide and 597 on sulphonylureas, 417 of whom were on glibenclamide. The most common adverse event in the phase II studies was hypoglycaemia. The frequency of hypoglycaemia was identical for repaglinide and sulphonylureas; however, fewer nocturnal hypoglycaemic events were observed with repaglinide and no increase in the frequency of hypoglycaemic events occurred in elderly patients (> 65 years) compared with younger patients. Severe reactions (assistance required) were approximately twice as frequent in the comparator group. During these studies, two serious hypoglycaemic reactions were reported (coma, seizure or hospitalization), both occurring in patients on glibenclamide. The frequency of serious adverse events and serious cardiovascular events was comparable between repaglinide and sulphonylureas.

Once-daily insulin detemir in a cohort of insulin-naïve patients with type 2 diabetes: a sub-analysis from the PREDICTIVE study

ABSTRACTObjective: PREDICTIVE is a large, observational study of the empirical use of insulin detemir in patients with type 1 or type 2 diabetes (T1DM/T2DM). This post hoc analysis evaluates insulin-naïve patients with T2DM uncontrolled on oral antidiabetic drugs (OADs) who were initiated and remained on once-daily insulin detemir for 12 weeks.* Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation; Novo Nordisk A/S, Bagsvaerd, DenmarkResearch design and methods: This observational, multinational, multi-center, open-label prospective study evaluated the efficacy and safety of insulin detemir in 1653 insulin-naïve patients with T2DM (mean age 60.8 ± 10.9 years, BMI 29.8 ± 4.8 kg/m2, and HbA1C 8.82 ± 1.50%). Statistical comparisons were made between baseline and 12-week follow up data. Our study was subject to the usual limitations of observational studies.Main outcome measures: Endpoints were: incidence of serious adverse drug reactions, including number of hypoglycemic events (total, major, and nocturnal), glycemic parameters, and weight change.Results: Following insulin initiation, no significant change occurred in the number of nocturnal hypoglycemic events or total hypoglycemic events (p = 0.4513), and no serious adverse drug reactions were observed during the 12 weeks of treatment. HbA1C decreased by a mean 1.25% (SD ± 1.25%; p < 0.0001), with 30% of patients (n = 383) achieving HbA1C <7% at 12 weeks. Mean changes in fasting blood glucose and fasting blood glucose variability were –3.62 mmol/L (SD ± 2.93; p < 0.0001) and −0.48 mmol/L (SD ± 1.03; p < 0.0001), respectively. Body weight decreased by a mean 0.5 kg (SD ± 3.3; p < 0.0001), with weight loss or no weight change occurring in a substantial percentage of patients in each BMI category (<25, 25–30, 30–35, and >35 kg/m2). Patients with higher baseline BMI lost the most weight, with the greatest weight loss (–1.20 kg) reported in those with BMI >35 kg/m2.Conclusions: Empirical use of insulin detemir as an insulin initiation strategy can improve glycemic control with good tolerability, including a low risk of hypoglycemia and a weight benefit, in a majority of insulin-naïve patients uncontrolled on OADs.

Insulin detemir improves glycemic control and reduces hypoglycemia in children with type 1 diabetes: findings from the Turkish cohort of the PREDICTIVE™ observational study

Insulin detemir is a basal insulin analog designed to produce a superior pharmacokinetic profile to basal formulations of human insulin. It has shown consistently improved tolerability in comparison to neutral protamine Hagedorn (NPH) insulin in adult cohorts, but there are relatively few publications involving pediatric cohorts. The efficacy and safety of insulin detemir in children with type 1 diabetes was assessed using data from the Turkish cohort of PREDICTIVE (a large, multinational, observational) study. The children investigated were using basal-bolus therapy involving NPH insulin or insulin glargine at baseline but were switched to insulin detemir as part of routine clinical care by their physicians. Twelve weeks of treatment with insulin detemir significantly reduced mean hemoglobin A1c (9.7-8.9%, p < 0.001) and mean fasting glucose [185-162 mg/dL (10.3-9 mmol/L), p < 0.01]. Fasting glucose variability was also lower after treatment with insulin detemir than previously (on either NPH or glargine, p < 0.05). The frequencies of total, major and nocturnal hypoglycemic events were significantly reduced with insulin detemir relative to baseline, with an estimated mean of 6.89 fewer events/patient/yr overall (p < 0.001) and 2.6 fewer nocturnal events/patient/yr (p < 0.01). Weight and insulin dose remained relatively unchanged. Twelve weeks of treatment with insulin detemir improved glycemic control and reduced hypoglycemia in children with type 1 diabetes. This improved tolerability might allow further dose titration and therefore additional improvements in glucose control.

Switching patients from insulin glargine-based basal-bolus regimens to a once daily insulin detemir-based basal-bolus regimen: results from a subgroup of the PREDICTIVE™ study

The aim of the PREDICTIVE study, a large, multinational observational trial, was to evaluate the efficacy and safety of insulin detemir (IDet) in routine clinical practice. Twelve-week follow-up data from patients with type 1 (T1D) or type 2 (T2D) diabetes in the European cohort switched from once (qd) or twice (bid) daily insulin glargine (IGlarg) (+/-oral antidiabetic therapy) to qd IDet in a basal-bolus regimen. End-points, assessed from patient recall/diaries, included incidence of serious adverse drug reactions, glycaemic parameters, hypoglycaemia and weight change. The analysis included 1285 patients with T1D (n = 508) or T2D (n = 777). At 12 weeks, glycosylated haemoglobin (HbA1c) was significantly reduced (qd IGlarg to qd IDet: T1D, -0.47%; T2D, -0.51%; p < 0.0001 for both; bid IGlarg to qd IDet: T1D, -0.31%; T2D, -0.89%, p < 0.05 for both). Fasting blood glucose (FBG) and FBG variability were also reduced. Reductions in overall, major and nocturnal hypoglycaemic events were observed after switching from qd IGlarg to qd IDet (overall, T1D, 39.7-18.85 episodes/patient-year; overall, T2D, 11.57-2.99 episodes/patient-year, p < 0.0001 for both). Similar reductions were observed in bid IGlarg to qd IDet patients. Mean weight change was -0.3 to -0.4 kg across patient groups. Switching from IGlarg to qd IDet was associated with improvements in glycaemic parameters with no associated increase in hypoglycaemic episodes or weight gain. Patients with T1D and T2D may be switched from IGlarg to qd IDet as part of a basal-bolus regimen.

Nocturnal Glucose Metabolism after Bedtime Injection of Insulin Glargine or Neutral Protamine Hagedorn Insulin in Patients with Type 2 Diabetes

Insulin glargine is a long-acting human insulin analog often administered at bedtime to patients with type 2 diabetes. It reduces fasting blood glucose levels more efficiently and with less nocturnal hypoglycemic events compared with human neutral protamine Hagedorn (NPH) insulin. Therefore, bedtime injections of insulin glargine and NPH insulin were compared overnight and in the morning. In 10 type 2 diabetic patients, euglycemic clamps were performed, including [6,6'](2)H(2) glucose, to study the rate of disappearance (Rd) and endogenous production (EGP) of glucose during the night. On separate days at bedtime (2200 h), patients received a sc injection of insulin glargine, NPH insulin, or saline in a randomized, double-blind fashion. Similar doses of both insulins had different metabolic profiles. NPH insulin had a greater effect on both Rd and EGP in the night compared with insulin glargine. By contrast, in the morning, insulin glargine was more effective, increasing Rd by 5.8 micromol/kg(-1).min(-1) (95% confidence interval 4.7-6.9) and reducing EGP -5.7 (-5.0 to -6.4) compared with NPH insulin. Nearly 80% of the glucose lowering effect in the morning was due to insulin glargine's reduction of EGP. Its injection was associated with one-third lower morning glucagon levels compared with NPH insulin (P = 0.021). Nocturnal variations of EGP and Rd explain the reduced incidence of hypoglycemia and lower fasting glucose levels reported for insulin glargine compared with human NPH insulin.

Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus

Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer insulin analogues might result in fewer macrovascular and microvascular events. To assess the effects of long-term treatment with long-acting insulin analogues (insulin glargine and insulin detemir) compared to NPH insulin in patients with type 2 diabetes mellitus. Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as insulin producing companies. Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Six studies comparing insulin glargine to NPH (Neutral Protamine Hagedorn) insulin and two studies comparing insulin detemir to NPH insulin were identified. In these trials, 1715 patients were randomised to insulin glargine and 578 patients to insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2 treated with "basal" insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with insulin glargine or detemir.