Skip to main content
Top
Published in: Diabetologia 3/2006

01-03-2006 | Article

Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study

Authors: H. Yki-Järvinen, R. Kauppinen-Mäkelin, M. Tiikkainen, M. Vähätalo, H. Virtamo, K. Nikkilä, T. Tulokas, S. Hulme, K. Hardy, S. McNulty, J. Hänninen, H. Levänen, S. Lahdenperä, R. Lehtonen, L. Ryysy

Published in: Diabetologia | Issue 3/2006

Login to get access

Abstract

Aims/hypothesis

In type 2 diabetic patients we compared 9 months of combination therapy with insulin glargine and metformin with 9 months of NPH insulin combined with metformin. The primary focus was changes in HbA1c; secondary focus was diurnal glucose profiles and symptomatic hypoglycaemia.

Methods

In this investigator-initiated open, parallel-group clinical trial involving seven centres, 110 insulin-naive type 2 diabetic patients with poor glycaemic control (HbA1c ≥8.0%) on oral hypoglycaemic agents (90% using sulfonylurea plus metformin) were randomised to receive bedtime insulin glargine with metformin (G+MET) or bedtime NPH with metformin (NPH+MET) for 36 weeks. The patients were taught how to self-adjust their insulin dose and use a modem to send the results of home glucose monitoring to treatment centres. The goal was to achieve a fasting plasma glucose (FPG) of 4.0 to 5.5 mmol/l in both groups.

Results

During the last 12 weeks, FPGs averaged 5.75±0.02 and 5.96±0.03 mmol/l (p<0.001) and insulin doses were 68±5 and 70±6 IU/day (0.69±0.05 and 0.66±0.04 IU kg–1 day–1, NS) in the G+MET and NPH+MET groups, respectively. At 36 weeks, mean HbA1c was 7.14±0.12 and 7.16±0.14%, respectively (NS). Symptomatic, but not confirmed symptomatic, hypoglycaemia was significantly lower during the first 12 weeks in the G+MET group (4.1±0.8 episodes/patient-year) than in the NPH+MET group (9.0±2.3 episodes/patient-year, p<0.05), but not significantly different thereafter. Glucose levels before dinner were higher in the NPH+MET group (10.1±0.3 mmol/l) than in the G+MET group (8.6±0.3 mmol/l, p=0.002) throughout the 36-week study. With regard to baseline characteristics such as initial glycaemia or C-peptide, there was no difference between patients who achieved good glycaemic control (HbA1c <7.0%) and those who did not. Differences were seen in the following: between study centres, weight gain during the run-in period and insulin therapy, and FPG during the last 12 weeks (5.7±0.2 vs 6.7±0.3 mmol/l for patients reaching vs those not reaching target, p<0.01).

Conclusions/interpretation

Good glycaemic control can be achieved with both G+MET and NPH+MET. Use of G+MET reduces symptomatic hypoglycaemia during the first 12 weeks and dinnertime hyperglycaemia compared with NPH+MET.
Literature
1.
go back to reference Pugh JA, Wagner ML, Sawyer J, Ramirez G, Tuley M, Friedberg SJ (1992) Is combination sulfonylurea and insulin therapy useful in NIDDM patients? Diabetes Care 15:953–959PubMedCrossRef Pugh JA, Wagner ML, Sawyer J, Ramirez G, Tuley M, Friedberg SJ (1992) Is combination sulfonylurea and insulin therapy useful in NIDDM patients? Diabetes Care 15:953–959PubMedCrossRef
2.
go back to reference Peters AL, Davidson MB (1991) Insulin plus a sulfonylurea agent for treating type 2 diabetes. Ann Intern Med 115:45–53PubMed Peters AL, Davidson MB (1991) Insulin plus a sulfonylurea agent for treating type 2 diabetes. Ann Intern Med 115:45–53PubMed
3.
go back to reference Wright A, Burden AC, Paisey RB, Cull CA, Holman RR (2002) Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 25:330–336PubMedCrossRef Wright A, Burden AC, Paisey RB, Cull CA, Holman RR (2002) Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 25:330–336PubMedCrossRef
4.
go back to reference Riddle MC, Rosenstock J, Gerich JE, Insulin glargine 4002 study investigators (2003) The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy in type 2 diabetic patients. Diabetes Care 26:3080–3086PubMedCrossRef Riddle MC, Rosenstock J, Gerich JE, Insulin glargine 4002 study investigators (2003) The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy in type 2 diabetic patients. Diabetes Care 26:3080–3086PubMedCrossRef
5.
go back to reference Yki-Järvinen H, Ryysy L, Nikkilä K, Tulokas T, Vanamo R, Heikkilä M (1999) Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 130:389–396PubMed Yki-Järvinen H, Ryysy L, Nikkilä K, Tulokas T, Vanamo R, Heikkilä M (1999) Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 130:389–396PubMed
6.
go back to reference Aviles-Santa L, Sinding J, Raskin P (1999) Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 131:182–188PubMed Aviles-Santa L, Sinding J, Raskin P (1999) Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 131:182–188PubMed
7.
go back to reference Wulffele MG, Kooy A, Lehert P et al (2002) Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 25:2133–2140PubMedCrossRef Wulffele MG, Kooy A, Lehert P et al (2002) Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 25:2133–2140PubMedCrossRef
8.
go back to reference Lepore M, Pampanelli S, Fanelli C et al (2000) Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 49:2142–2148PubMedCrossRef Lepore M, Pampanelli S, Fanelli C et al (2000) Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 49:2142–2148PubMedCrossRef
9.
go back to reference Yki-Jarvinen H, Dressler A, Ziemen M (2000) Less nocturnal glycaemia/hypoglycaemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care 23:1130–1136PubMedCrossRef Yki-Jarvinen H, Dressler A, Ziemen M (2000) Less nocturnal glycaemia/hypoglycaemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care 23:1130–1136PubMedCrossRef
10.
go back to reference Fritsche A, Schweitzer MA, Haring HU (2003) Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med 138:952–959 Fritsche A, Schweitzer MA, Haring HU (2003) Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med 138:952–959
11.
go back to reference DeFronzo RA, Goodman AM (1995) Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicentre Metformin Study Group. N Engl J Med 333:541–549CrossRefPubMed DeFronzo RA, Goodman AM (1995) Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicentre Metformin Study Group. N Engl J Med 333:541–549CrossRefPubMed
12.
go back to reference Yki-Järvinen H (2001) Combination therapies with insulin in type 2 diabetes. Diabetes Care 24:758–767PubMedCrossRef Yki-Järvinen H (2001) Combination therapies with insulin in type 2 diabetes. Diabetes Care 24:758–767PubMedCrossRef
13.
go back to reference Taves DR (1974) Minimization: a new method of assessing patients to treatment and control groups. Clin Pharmacol Ther 15:443–453PubMed Taves DR (1974) Minimization: a new method of assessing patients to treatment and control groups. Clin Pharmacol Ther 15:443–453PubMed
14.
go back to reference Tuomi TM, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR (1993) Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with non-insulin-dependent onset of disease. Diabetes 42:359–362PubMedCrossRef Tuomi TM, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR (1993) Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with non-insulin-dependent onset of disease. Diabetes 42:359–362PubMedCrossRef
15.
go back to reference Kuzuya H, Blix PM, Horwitz DL, Steiner DF, Rubenstein AH (1977) Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes 26:22–29PubMedCrossRef Kuzuya H, Blix PM, Horwitz DL, Steiner DF, Rubenstein AH (1977) Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes 26:22–29PubMedCrossRef
16.
go back to reference DeFronzo RA, Hendler R, Christensen N (1980) Stimulation of counterregulatory hormonal response in diabetic man by a fall in glucose concentration. Diabetes 29:125–131PubMed DeFronzo RA, Hendler R, Christensen N (1980) Stimulation of counterregulatory hormonal response in diabetic man by a fall in glucose concentration. Diabetes 29:125–131PubMed
17.
go back to reference Mäkimattila S, Nikkilä K, Yki-Järvinen H (1999) Causes of weight gain during insulin therapy with and without metformin in patients with non-insulin-dependent diabetes mellitus. Diabetologia 42:406–412CrossRefPubMed Mäkimattila S, Nikkilä K, Yki-Järvinen H (1999) Causes of weight gain during insulin therapy with and without metformin in patients with non-insulin-dependent diabetes mellitus. Diabetologia 42:406–412CrossRefPubMed
18.
go back to reference Yki-Järvinen H, Helve E, Sane T, Nurjhan N, Taskinen M-R (1989) Insulin inhibition of overnight glucose production and gluconeogenesis from lactate in NIDDM. Am J Physiol 256:E732–E739PubMed Yki-Järvinen H, Helve E, Sane T, Nurjhan N, Taskinen M-R (1989) Insulin inhibition of overnight glucose production and gluconeogenesis from lactate in NIDDM. Am J Physiol 256:E732–E739PubMed
19.
go back to reference Gerich JE, Mitrakou A, Kelley D et al (1990) Contribution of impaired muscle glucose clearance to reduced postabsorptive systemic glucose clearance in NIDDM. Diabetes 39:211–216PubMedCrossRef Gerich JE, Mitrakou A, Kelley D et al (1990) Contribution of impaired muscle glucose clearance to reduced postabsorptive systemic glucose clearance in NIDDM. Diabetes 39:211–216PubMedCrossRef
20.
go back to reference Mitrakou A, Kelley D, Veneman T et al (1990) Contribution of abnormal muscle and liver metabolism to postprandial hyperglycaemia in NIDDM. Diabetes 39:1381–1390PubMedCrossRef Mitrakou A, Kelley D, Veneman T et al (1990) Contribution of abnormal muscle and liver metabolism to postprandial hyperglycaemia in NIDDM. Diabetes 39:1381–1390PubMedCrossRef
21.
go back to reference Pehling G, Tessari P, Gerich JE, Haymond MW, Service FJ, Rizza RA (1984) Abnormal meal carbohydrate disposition in insulin-dependent diabetes. Relative contributions of endogenous glucose production and initial splanchnic uptake and effect of intensive insulin therapy. J Clin Invest 74:985–991PubMedCrossRef Pehling G, Tessari P, Gerich JE, Haymond MW, Service FJ, Rizza RA (1984) Abnormal meal carbohydrate disposition in insulin-dependent diabetes. Relative contributions of endogenous glucose production and initial splanchnic uptake and effect of intensive insulin therapy. J Clin Invest 74:985–991PubMedCrossRef
22.
go back to reference Westerbacka J, Corner A, Tiikkainen M et al (2004) Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia 47:1360–1369CrossRefPubMed Westerbacka J, Corner A, Tiikkainen M et al (2004) Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia 47:1360–1369CrossRefPubMed
23.
go back to reference Ryysy L, Häkkinen AM, Goto T et al (2000) Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749–758PubMedCrossRef Ryysy L, Häkkinen AM, Goto T et al (2000) Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749–758PubMedCrossRef
24.
go back to reference Seppala-Lindroos A, Vehkavaara S, Hakkinen AM et al (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87:3023–3028CrossRefPubMed Seppala-Lindroos A, Vehkavaara S, Hakkinen AM et al (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87:3023–3028CrossRefPubMed
Metadata
Title
Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study
Authors
H. Yki-Järvinen
R. Kauppinen-Mäkelin
M. Tiikkainen
M. Vähätalo
H. Virtamo
K. Nikkilä
T. Tulokas
S. Hulme
K. Hardy
S. McNulty
J. Hänninen
H. Levänen
S. Lahdenperä
R. Lehtonen
L. Ryysy
Publication date
01-03-2006
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 3/2006
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-005-0132-0

Other articles of this Issue 3/2006

Diabetologia 3/2006 Go to the issue