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      Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials

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          Abstract

          Aim

          Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec (IDeg) has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. This pre-planned meta-analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM).

          Methods

          Pooled patient-level data for self-reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily (OD) vs. IGlar OD were analysed.

          Results

          Four thousand three hundred and thirty subjects (2899 IDeg OD vs. 1431 IGlar OD) were analysed. Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs. IGlar: estimated rate ratio (RR):0.83[0.70;0.98] 95% CI, RR:0.64[0.48;0.86] 95% CI and RR:0.14[0.03;0.70] 95% CI. In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar [RR:0.83[0.74;0.94] 95% CI and RR:0.68[0.57;0.82] 95% CI). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment (RR:0.75[0.60;0.94] 95% CI). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations.

          Conclusions

          The limitations of this study include the open-label design and exclusion of subjects with recurrent severe hypoglycaemia. This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes.

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          Most cited references19

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          Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group.

          Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. Outpatient diabetes clinics in 15 UK hospitals. A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. Fasting plasma glucose and HbA1c levels, and the proportion of patients who achieved target levels below 7% HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.
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            The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients.

            To compare the abilities and associated hypoglycemia risks of insulin glargine and human NPH insulin added to oral therapy of type 2 diabetes to achieve 7% HbA(1c). In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycemic control (HbA(1c) >7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target fasting plasma glucose (FPG)
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              Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes.

              P Cryer (2002)
              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.
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                Author and article information

                Journal
                Diabetes Obes Metab
                Diabetes Obes Metab
                dom
                Diabetes, Obesity & Metabolism
                Blackwell Publishing Ltd (Oxford, UK )
                1462-8902
                1463-1326
                February 2013
                03 December 2012
                : 15
                : 2
                : 175-184
                Affiliations
                [1 ]Division of Endocrinology, Department of Medicine, Georgetown University School of Medicine Washington, DC, USA
                [2 ]Oxford Centre for Diabetes, Endocrinology and Metabolism and NIHR Oxford Biomedical Research Centre Oxford, UK
                [3 ]University Hospitals (UZ) Leuven, KU Leuven Leuven, Belgium
                [4 ]University of Pisa Pisa, Italy
                [5 ]Atlanta Diabetes Associates Atlanta, GA, USA
                [6 ]Novo Nordisk Søborg, Denmark
                [7 ]University of Toronto, Mount Sinai Hospital Toronto, ON, Canada
                Author notes
                Correspondence to: Robert E. Ratner, MD, FACP, FACE, Chief Scientific and Medical Officer, American Diabetes Association, 1701 N. Beauregard St., Alexandria, VA 22311, USA. E-mail: rratner@ 123456diabetes.org
                Article
                10.1111/dom.12032
                3752969
                23130654
                9a9d7b22-dacb-4cd6-be93-d753b3129c3e
                © 2013 Blackwell Publishing Ltd

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                : 14 August 2012
                : 23 August 2012
                : 01 November 2012
                Categories
                Original Articles

                Endocrinology & Diabetes
                confirmed hypoglycaemia,insulin degludec,insulin glargine,nocturnal hypoglycaemia,severe hypoglycaemia

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