- Email: [email protected]
Insulin analogs versus human insulin in type 2 diabetes
DIABETES RESEARCH A N D CLINICAL PRACTICE
9 3S (2011) S102–S104
Insulin analogs versus human insulin in type 2 diabetes Ilias N. Migdalis * 2nd Medical Department and Diabetes Centre, NIMTS Hospital, Athens, Greece
AR TI C L E
I NF O
A B S T R A C T
Keywords:
Oral hypoglycaemic agents become less effective as beta cell function declines. Thus many
Insulin therapy
patients with type 2 diabetes will ultimately require treatment with insulin. There are two
Diabetes mellitus type 2
main approaches to starting insulin: (a) as a basal supplement with an intermediate to
Human insulin
long-acting preparation (NPH, glargine or detemir) plus oral agents; (b) as a premixed in-
Insulin analogs
sulin regimen. Almost all the studies have shown similar glucose control with both NPH and the new insulin analogs. Further analyses between these insulins have documented significant reductions in hypoglycaemia especially at night with the insulin analogs. The weight gain is an important issue in patients with diabetes. It appears that insulin detemir studies have reported weight neutrality or less weigh gain or even weight loss. However, most insulin glargine studies have reported a weight gain. On the other hand insulin analogs have the important disadvantage of high cost. It is important to take in to account all the above factors such as cost, weight gain, number of insulin injections and hypoglycaemia while prescribing insulin. © 2011 Elsevier Ireland Ltd. All rights reserved.
Insulin is used in the treatment of patients with diabetes of all types. The need for insulin depends upon the balance between insulin secretion and insulin resistance. All patients with type 1 diabetes need insulin treatment permanently and many patients with type 2 diabetes will require insulin as their beta cell function declines over time. Type 2 diabetes is characterized by both insulin resistance and relative insulin deficiency. Therapy should begin with diet, weight reduction and exercise, which can frequently induce normoglycaemia. Patients with persistent hyperglycaemia are often started on one or more oral hypoglycaemic drugs. Metformin is a good early choice, based on safety profile, neutral effect with regard to weight gain, and ability to lower glycaemia. Insulin is added if goal glycaemic control is not attained. Initiation of insulin therapy, however, is often unnecessarily delayed, owing to physician or patient reluctance and other factors, thus exposing patients to the physiological consequences of prolonged hyperglycaemia [1]. Patients * Correspondence to: Ilias N. Migdalis, 2nd Medical Department and Diabetes Centre, NIMTS Hospital, 115 21 Athens, Greece. Tel.: +30 210 7288401; fax: +30 210 7297958. E-mail address: [email protected]
should be made aware that initiating insulin does not represent a personal failure and that most patients with type 2 diabetes will eventually require exogenous insulin, due to the decline in endogenous insulin production. In type 2 diabetes there are two main approaches to starting insulin: (a) As a basal supplement with an intermediate to longacting preparation (NPH, glargine or detemir) plus oral agents. The long-acting preparation insulin suppresses hepatic glucose production and maintains near normoglycaemia in the fasting state. (b) As a premixed insulin regimen. Most premixed preparations contain an intermediate acting insulin and either a short or a rapid acting insulin. The initial regimen is not always the most physiologic yet may be the best choice for behavioral reasons. NPH insulin has been available for many years and its availability has decreased the need for number of injections [2]. Many recent studies have compared NPH insulin with new long-acting insulin analogs (glargine and detemir) in patients with both type 1 and type 2 diabetes. Almost all the studies have shown similar glucose control with both NPH and the new insulin analogs. Further analyses between these insulins have documented significant reductions in
0168-8227/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
DIABETES RESEARCH A N D CLINICAL PRACTICE
hypoglycaemia, especially at night, with the insulin analogs [3–5]. Since hypoglycaemia is an important barrier either for the initiation of insulin therapy or for the intensification of diabetes treatment and can possibly result in an increase in health care cost through emergency room visits, this fact may need to be considered. In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycaemic control (HbA1c >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. Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA1c in a majority of overweight patients with type 2 diabetes with HbA1c between 7.5 and 10.0% on oral agents alone. In doing this, glargine causes significantly less nocturnal hypoglycaemia than NPH, thus reducing a leading barrier to initiating insulin [6]. In an other trial, individuals (n=476) with HbA1c 7.5–10.0% were randomized to addition of twice-daily insulin detemir or NPH insulin in a parallel-group multicenter trial. Over 24 weeks, insulin doses were titrated toward pre-breakfast and predinner plasma glucose targets of ≤6.0 mmol/l (≤108 mg/dl). Outcomes assessed included HbA1c, percentage achieving HbA1c ≤7.0%, risk of hypoglycaemia, and body weight. At 24 weeks HbA1c had decreased by 1.8 and 1.9% (from 8.6 to 6.8 and from 8.5 to 6.6%) for detemir and NPH, respectively (NS). In both groups, 70% of the participants achieved an HbA1c ≤7.0%, but the proportion achieving this without hypoglycaemia was higher with insulin detemir than with NPH insulin (26 vs 16%, p=0.008). Compared with NPH insulin, the risk for all hypoglycaemia with insulin detemir was reduced by 47% (p < 0.001) and nocturnal hypoglycaemia by 55% (p <0.001). Mean weight gain was 1.2 Kg with insulin detemir and 2.8 Kg with NPH insulin (p < 0.001), and the difference in baseline-adjusted final weight was –1.58 (p < 0.001) [7]. In a recent study, supplementation of oral agents with detemir or glargine achieved clinically important improvements in glycaemic control with low risk of hypoglycaemia. Non-inferiority was demonstrated for detemir using higher insulin doses (mainly patients on twice daily dosing); weight gain was somewhat reduced with once daily insulin detemir [8]. Meta-analyses of trials in patients with type 2 diabetes comparing once daily insulin glargine or detemir to once or twice daily NPH insulin [9–11], report similar glycaemic control between groups. However, the rates of symptomatic overall and nocturnal hypoglycaemia, while relatively infrequent with either basal insulin, were lower in patients treated with either insulin glargine or detemir comparing with NPH. Thus, insulin glargine and detemir may have some relatively modest clinical advantages over NPH (less symptomatic and nocturnal hypoglycaemia) with the important disadvantage of high cost. The newer rapid-acting insulins may have a minor glycaemic advantage over short-acting (regular) insulin in patients with type 1 diabetes, but not in patients with type 2 diabetes. This was illustrated in a meta-analysis of 42 randomized, controlled trials (involving 1,901 patients with type 2 diabetes) that compared rapid-acting insulin analogs to regular insulin as pre-meal bolus doses [12]. No signifi-
9 3S (2011) S102–S104
S103
cant differences were seen in HbA1c levels or the number of hypoglycaemic episodes. However, the ability to inject the rapid-acting insulins immediately before meals, as opposed to the 30 to 45 minutes before the meal recommended for short-acting insulins, may provide improved convenience for patients. Adding basal insulin to prior oral treatments is very successful for many patients. However, a consistent finding from various studies is that 30–50% of the patients starting insulin therapy with basal insulin did not achieve the <7% HbA1c target [13]. Thus, even patients who initially achieve excellent control of HbA1c with basal insulin may need to address post-prandial hyperglycaemia at a later time. Most premixed (biphasic) preparations contain an intermediate acting insulin and either a short or a rapid-acting insulin. The results of the IMPROVE™ subgroup analysis demonstrated that patients with type 2 diabetes inadequately controlled on basal insulins, may improve their glycaemic control by intensification to biphasic insulin aspart 30/70 (BIAsp 30) therapy. Regardless of their prior basal insulin regimen, switching to BIAsp 30-bid in the majority of cases, enabled many patients to achieve the HbA1c target without hypoglycaemia. Similarly, switching patients to BIAsp 30 from human premix insulin resulted in significant improvements in glycaemic control combined with a reduced risk of hypoglycaemia [14]. Insulin is now recommended by the American Diabetes Association as the second agent added after metformin. In treatment-naïve patients with newly diagnosed type 2 diabetes, insulin (insulin NovoLog Mix 70/30 with Flex Pen delivery) and metformin were initiated for a 3-month leadin period, then patients were randomly assigned to insulin and metformin (insulin group) or metformin, pioglitazone and glyburide (oral group) for 36 months. In conclusion, when compared with a clinically equivalent treatment regimen, insulin-based therapy is effective and did not cause greater weight gain or hypoglycaemia nor decrease compliance, treatment satisfaction or quality of life [15]. It is important to take into account all the above factors such as cost, weight gain, number of insulin injections and hypoglycaemia while prescribing a given basal insulin, premixed insulin preparation or short-acting and rapid-acting insulin.
Conflict of interest The author has no conflicts of interest to report.
references [1] Brunton S. Insulin regimens for type 2 diabetes mellitus. J Fam Pract 2006;55:10S–7. [2] Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet 2001:358:739–46. [3] Peterson GE. Intermediate and long-acting insulin: a review of NPH insulin, insulin glargine and insulin detemir. Curr Med Res Opin 2006;22:2613–9. [4] Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily
S104
[5] [6]
[7]
[8]
[9]
DIABETES RESEARCH A N D CLINICAL PRACTICE
insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006;28:1569–81. Garg SK, Naik RG. Long-acting insulin analogs versus human insulins. Diabetes Techn Ther 2008;10:331–2. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26:3080–6. Hermansen K, Davies M, Derezinski T, Ravn GM, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy as oral glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetes Care 2006;29:1269–74. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised 52 week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetologia 2008; 51:408–16. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A. Reduced hypoglycaemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care 2005; 28:950–5.
9 3S (2011) S102–S104
[10] Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007;2:CD 005613. [11] Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues versus NPH human insulin in type 2 diabetes. A meta-analysis. Diabetes Res Clin Pract 2008;81:184–9. [12] Plank J, Siebenhofer A, Berghold A, Jeitler K, Horvath K, Mrak P, et al. Systemic review and meta-analysis of short-acting insulin analogues in patients with diabetes mellitus. Arch Intern Med 2005;165:1337–44. [13] Raccah D, Bretzel RG, Owens D, Riddle M. When basal insulin therapy in type 2 diabetes mellitus is not enough – what next? Diabetes Metab Res Rev 2007;23:257–64. [14] Shah S, Benroubi M, Borzi V, Gumprecht J, Kawamori R, Shaban J, et al. Safety and effectiveness of biphasic insulin aspart 30/70 (NOVOMIX 30) when switching from human penmix insulin in patients with type 2 diabetes: subgroup analysis from the 6-month IMPROVE™ observational study. Int J Clin Pract 2009;63:574–82. [15] Lingvay L, Legendre JL, Kaloyanova PF, Zhang S, Adams-Huet B, Raskin P. Insulin-based versus triple oral therapy for newly diagnosed type 2 diabetes. Diabetes Care 2009;32:1789–95.
9 3S (2011) S102–S104
Insulin analogs versus human insulin in type 2 diabetes Ilias N. Migdalis * 2nd Medical Department and Diabetes Centre, NIMTS Hospital, Athens, Greece
AR TI C L E
I NF O
A B S T R A C T
Keywords:
Oral hypoglycaemic agents become less effective as beta cell function declines. Thus many
Insulin therapy
patients with type 2 diabetes will ultimately require treatment with insulin. There are two
Diabetes mellitus type 2
main approaches to starting insulin: (a) as a basal supplement with an intermediate to
Human insulin
long-acting preparation (NPH, glargine or detemir) plus oral agents; (b) as a premixed in-
Insulin analogs
sulin regimen. Almost all the studies have shown similar glucose control with both NPH and the new insulin analogs. Further analyses between these insulins have documented significant reductions in hypoglycaemia especially at night with the insulin analogs. The weight gain is an important issue in patients with diabetes. It appears that insulin detemir studies have reported weight neutrality or less weigh gain or even weight loss. However, most insulin glargine studies have reported a weight gain. On the other hand insulin analogs have the important disadvantage of high cost. It is important to take in to account all the above factors such as cost, weight gain, number of insulin injections and hypoglycaemia while prescribing insulin. © 2011 Elsevier Ireland Ltd. All rights reserved.
Insulin is used in the treatment of patients with diabetes of all types. The need for insulin depends upon the balance between insulin secretion and insulin resistance. All patients with type 1 diabetes need insulin treatment permanently and many patients with type 2 diabetes will require insulin as their beta cell function declines over time. Type 2 diabetes is characterized by both insulin resistance and relative insulin deficiency. Therapy should begin with diet, weight reduction and exercise, which can frequently induce normoglycaemia. Patients with persistent hyperglycaemia are often started on one or more oral hypoglycaemic drugs. Metformin is a good early choice, based on safety profile, neutral effect with regard to weight gain, and ability to lower glycaemia. Insulin is added if goal glycaemic control is not attained. Initiation of insulin therapy, however, is often unnecessarily delayed, owing to physician or patient reluctance and other factors, thus exposing patients to the physiological consequences of prolonged hyperglycaemia [1]. Patients * Correspondence to: Ilias N. Migdalis, 2nd Medical Department and Diabetes Centre, NIMTS Hospital, 115 21 Athens, Greece. Tel.: +30 210 7288401; fax: +30 210 7297958. E-mail address: [email protected]
should be made aware that initiating insulin does not represent a personal failure and that most patients with type 2 diabetes will eventually require exogenous insulin, due to the decline in endogenous insulin production. In type 2 diabetes there are two main approaches to starting insulin: (a) As a basal supplement with an intermediate to longacting preparation (NPH, glargine or detemir) plus oral agents. The long-acting preparation insulin suppresses hepatic glucose production and maintains near normoglycaemia in the fasting state. (b) As a premixed insulin regimen. Most premixed preparations contain an intermediate acting insulin and either a short or a rapid acting insulin. The initial regimen is not always the most physiologic yet may be the best choice for behavioral reasons. NPH insulin has been available for many years and its availability has decreased the need for number of injections [2]. Many recent studies have compared NPH insulin with new long-acting insulin analogs (glargine and detemir) in patients with both type 1 and type 2 diabetes. Almost all the studies have shown similar glucose control with both NPH and the new insulin analogs. Further analyses between these insulins have documented significant reductions in
0168-8227/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
DIABETES RESEARCH A N D CLINICAL PRACTICE
hypoglycaemia, especially at night, with the insulin analogs [3–5]. Since hypoglycaemia is an important barrier either for the initiation of insulin therapy or for the intensification of diabetes treatment and can possibly result in an increase in health care cost through emergency room visits, this fact may need to be considered. In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycaemic control (HbA1c >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. Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA1c in a majority of overweight patients with type 2 diabetes with HbA1c between 7.5 and 10.0% on oral agents alone. In doing this, glargine causes significantly less nocturnal hypoglycaemia than NPH, thus reducing a leading barrier to initiating insulin [6]. In an other trial, individuals (n=476) with HbA1c 7.5–10.0% were randomized to addition of twice-daily insulin detemir or NPH insulin in a parallel-group multicenter trial. Over 24 weeks, insulin doses were titrated toward pre-breakfast and predinner plasma glucose targets of ≤6.0 mmol/l (≤108 mg/dl). Outcomes assessed included HbA1c, percentage achieving HbA1c ≤7.0%, risk of hypoglycaemia, and body weight. At 24 weeks HbA1c had decreased by 1.8 and 1.9% (from 8.6 to 6.8 and from 8.5 to 6.6%) for detemir and NPH, respectively (NS). In both groups, 70% of the participants achieved an HbA1c ≤7.0%, but the proportion achieving this without hypoglycaemia was higher with insulin detemir than with NPH insulin (26 vs 16%, p=0.008). Compared with NPH insulin, the risk for all hypoglycaemia with insulin detemir was reduced by 47% (p < 0.001) and nocturnal hypoglycaemia by 55% (p <0.001). Mean weight gain was 1.2 Kg with insulin detemir and 2.8 Kg with NPH insulin (p < 0.001), and the difference in baseline-adjusted final weight was –1.58 (p < 0.001) [7]. In a recent study, supplementation of oral agents with detemir or glargine achieved clinically important improvements in glycaemic control with low risk of hypoglycaemia. Non-inferiority was demonstrated for detemir using higher insulin doses (mainly patients on twice daily dosing); weight gain was somewhat reduced with once daily insulin detemir [8]. Meta-analyses of trials in patients with type 2 diabetes comparing once daily insulin glargine or detemir to once or twice daily NPH insulin [9–11], report similar glycaemic control between groups. However, the rates of symptomatic overall and nocturnal hypoglycaemia, while relatively infrequent with either basal insulin, were lower in patients treated with either insulin glargine or detemir comparing with NPH. Thus, insulin glargine and detemir may have some relatively modest clinical advantages over NPH (less symptomatic and nocturnal hypoglycaemia) with the important disadvantage of high cost. The newer rapid-acting insulins may have a minor glycaemic advantage over short-acting (regular) insulin in patients with type 1 diabetes, but not in patients with type 2 diabetes. This was illustrated in a meta-analysis of 42 randomized, controlled trials (involving 1,901 patients with type 2 diabetes) that compared rapid-acting insulin analogs to regular insulin as pre-meal bolus doses [12]. No signifi-
9 3S (2011) S102–S104
S103
cant differences were seen in HbA1c levels or the number of hypoglycaemic episodes. However, the ability to inject the rapid-acting insulins immediately before meals, as opposed to the 30 to 45 minutes before the meal recommended for short-acting insulins, may provide improved convenience for patients. Adding basal insulin to prior oral treatments is very successful for many patients. However, a consistent finding from various studies is that 30–50% of the patients starting insulin therapy with basal insulin did not achieve the <7% HbA1c target [13]. Thus, even patients who initially achieve excellent control of HbA1c with basal insulin may need to address post-prandial hyperglycaemia at a later time. Most premixed (biphasic) preparations contain an intermediate acting insulin and either a short or a rapid-acting insulin. The results of the IMPROVE™ subgroup analysis demonstrated that patients with type 2 diabetes inadequately controlled on basal insulins, may improve their glycaemic control by intensification to biphasic insulin aspart 30/70 (BIAsp 30) therapy. Regardless of their prior basal insulin regimen, switching to BIAsp 30-bid in the majority of cases, enabled many patients to achieve the HbA1c target without hypoglycaemia. Similarly, switching patients to BIAsp 30 from human premix insulin resulted in significant improvements in glycaemic control combined with a reduced risk of hypoglycaemia [14]. Insulin is now recommended by the American Diabetes Association as the second agent added after metformin. In treatment-naïve patients with newly diagnosed type 2 diabetes, insulin (insulin NovoLog Mix 70/30 with Flex Pen delivery) and metformin were initiated for a 3-month leadin period, then patients were randomly assigned to insulin and metformin (insulin group) or metformin, pioglitazone and glyburide (oral group) for 36 months. In conclusion, when compared with a clinically equivalent treatment regimen, insulin-based therapy is effective and did not cause greater weight gain or hypoglycaemia nor decrease compliance, treatment satisfaction or quality of life [15]. It is important to take into account all the above factors such as cost, weight gain, number of insulin injections and hypoglycaemia while prescribing a given basal insulin, premixed insulin preparation or short-acting and rapid-acting insulin.
Conflict of interest The author has no conflicts of interest to report.
references [1] Brunton S. Insulin regimens for type 2 diabetes mellitus. J Fam Pract 2006;55:10S–7. [2] Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet 2001:358:739–46. [3] Peterson GE. Intermediate and long-acting insulin: a review of NPH insulin, insulin glargine and insulin detemir. Curr Med Res Opin 2006;22:2613–9. [4] Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily
S104
[5] [6]
[7]
[8]
[9]
DIABETES RESEARCH A N D CLINICAL PRACTICE
insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006;28:1569–81. Garg SK, Naik RG. Long-acting insulin analogs versus human insulins. Diabetes Techn Ther 2008;10:331–2. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26:3080–6. Hermansen K, Davies M, Derezinski T, Ravn GM, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy as oral glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetes Care 2006;29:1269–74. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised 52 week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetologia 2008; 51:408–16. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A. Reduced hypoglycaemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care 2005; 28:950–5.
9 3S (2011) S102–S104
[10] Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007;2:CD 005613. [11] Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues versus NPH human insulin in type 2 diabetes. A meta-analysis. Diabetes Res Clin Pract 2008;81:184–9. [12] Plank J, Siebenhofer A, Berghold A, Jeitler K, Horvath K, Mrak P, et al. Systemic review and meta-analysis of short-acting insulin analogues in patients with diabetes mellitus. Arch Intern Med 2005;165:1337–44. [13] Raccah D, Bretzel RG, Owens D, Riddle M. When basal insulin therapy in type 2 diabetes mellitus is not enough – what next? Diabetes Metab Res Rev 2007;23:257–64. [14] Shah S, Benroubi M, Borzi V, Gumprecht J, Kawamori R, Shaban J, et al. Safety and effectiveness of biphasic insulin aspart 30/70 (NOVOMIX 30) when switching from human penmix insulin in patients with type 2 diabetes: subgroup analysis from the 6-month IMPROVE™ observational study. Int J Clin Pract 2009;63:574–82. [15] Lingvay L, Legendre JL, Kaloyanova PF, Zhang S, Adams-Huet B, Raskin P. Insulin-based versus triple oral therapy for newly diagnosed type 2 diabetes. Diabetes Care 2009;32:1789–95.