Adding metformin versus insulin dose increase in insulin-treated but poorly controlled Type 2 diabetes mellitus: an open-label randomized trial

To compare the effect of adding metformin to insulin therapy with a moderate increase in insulin dose alone in insulin-treated, poorly controlled Type 2 diabetic patients, 47 consecutive such patients (baseline daily dose >0.5 IU kg⁻¹ and HbA_1c >8 %) were openly randomized either to a combination of their previous insulin schedule plus metformin (2.55 g daily in three divided doses, n = 24) or to a moderate insulin dose increase (20 % of baseline, n = 23). The patient status/biochemical profile was assessed at entry and at 4 months. Among those assigned to insulin + metformin, 18 took the drug. Upon an intention-to-treat basis, patients assigned to insulin dose increase had a statistically significant weight gain (1.16 + 1.9 vs 0.3 ± 4.5 kg, p < 0.05). Patients assigned to the insulin + metformin regimen experienced a significantly greater fall in HbA_1c (−1.87 ± 2.16 vs 0.03 ± 1.68 %, p < 0.01), total cholesterol (−0.56 ± 0.89 vs 0.14 ± 0.72 mmol l⁻¹, p < 0.05) and LDL-cholesterol (−0.51 ± 0.73 vs 0.19 ± 0.6 mmol l⁻¹, p < 0.01). These data suggest that adding metformin to insulin in poorly controlled Type 2 DM patients offers an advantage in terms of glycaemic control and lipid plasma profile. Copyright © 1998 John Wiley & Sons, Ltd.     

A double-blind randomized study comparing the effects of continuing or not continuing rosiglitazone + metformin therapy when starting insulin therapy in people with Type 2 diabetes.

AIMS: To compare the efficacy and safety of either continuing or discontinuing rosiglitazone + metformin fixed-dose combination when starting insulin therapy in people with Type 2 diabetes inadequately controlled on oral therapy. METHODS: In this 24-week double-blind study, 324 individuals with Type 2 diabetes inadequately controlled on maximum dose rosiglitazone + metformin therapy were randomly assigned to twice-daily premix insulin therapy (target pre-breakfast and pre-evening meal glucose < or = 6.5 mmol/l) in addition to either rosiglitazone + metformin (8/2000 mg) or placebo. RESULTS: Insulin dose at week 24 was significantly lower with rosiglitazone + metformin (33.5 +/- 1.5 U/day, mean +/- se) compared with placebo [59.0 +/- 3.0 U/day; model-adjusted difference -26.6 (95% CI -37.7, -15,5) U/day, P < 0.001]. Despite this, there was greater improvement in glycaemic control [HbA(1c) rosiglitazone + metformin vs. placebo 6.8 +/- 0.1 vs. 7.5 +/- 0.1%; difference -0.7 (-0.8, -0.5)%, P < 0.001] and more individuals achieved glycaemic targets (HbA(1c) < 7.0% 70 vs. 34%, P < 0.001). The proportion of individuals reporting at least one hypoglycaemic event during the last 12 weeks of treatment was similar in the two groups (rosiglitazone + metformin vs. placebo 25 vs. 27%). People receiving rosiglitazone + metformin in addition to insulin reported greater treatment satisfaction than those receiving insulin alone. Both treatment regimens were well tolerated but more participants had oedema [12 (7%) vs. 4 (3%)] and there was more weight gain [3.7 vs. 2.6 kg; difference 1.1 (0.2, 2.1) kg, P = 0.02] with rosiglitazone + metformin. CONCLUSIONS: Addition of insulin to rosiglitazone + metformin enabled more people to reach glycaemic targets with less insulin, and was generally well tolerated.     

A randomized controlled trial examining combinations of repaglinide, metformin and NPH insulin.

AIMS: To compare combination use of repaglinide, metformin and bedtime Neutral Protamine Hagedorn (NPH) insulin with conventional approaches of insulin initiation in patients with Type 2 diabetes (T2DM). METHODS: Eighty-two patients with T2DM with suboptimal glycaemic control on oral glucose-lowering agents were randomized to one of three treatment regimens for 4 months. Group 1 received metformin and twice daily biphasic 30/70 human insulin mixture (n = 27), group 2 metformin and bedtime NPH insulin (n = 26) and group 3 metformin, bedtime NPH insulin and mealtime repaglinide (n = 25). RESULTS: Seventy-five patients completed the study. Baseline and end-point mean HbA1c levels fell from 9.0 +/- 1.1 to 7.9 +/- 1.1% in group 1, 10.0 +/- 2.2 to 9.2 +/- 1.4% group 2 and 10.0 +/- 1.7 to 8.1 +/- 1.5% in group 3, respectively. All groups showed improvements in HbA1c. There was no significant difference between groups in the proportions of patients experiencing hypoglycaemia (29.6, 25.0 and 16.7%, respectively; P = 0.55) or in mean weight gain (2.9, 0.7 and 2.2 kg, respectively; P = 0.06). By 4 months, insulin doses were 0.63 +/- 0.32 IU/kg in group 1, 0.58 +/- 0.21 IU/kg in group 2 and 0.37 +/- 0.22 IU/kg in group 3 (group 3 vs. groups 1 and 2: P < 0.002). CONCLUSIONS: The approach using repaglinide, metformin and NPH insulin improved glycaemic control with a similar safety profile to conventional insulin initiation in T2DM and produced final glycaemic control similar to metformin and a twice daily biphasic insulin mixture.     

Insulin glargine in combination with nateglinide in people with Type 2 diabetes: a randomized placebo-controlled trial.

OBJECTIVE: To determine the effect of adding nateglinide to therapy with insulin glargine in adults with Type 2 diabetes previously treated with insulin and with poor blood glucose control. RESEARCH DESIGN AND METHODS: In this 16-week, double-blind, placebo-controlled study, people with Type 2 diabetes [n = 55, HbA(1c) 8.2 +/- 1.0 (+/- sd)%, duration of diabetes 12.8 +/- 6.0 years, duration of insulin treatment 6.0 +/- 4.0 years] were transferred to single bedtime injection of insulin glargine for a titration period of 4 weeks, and then randomized to nateglinide or matching placebo before meals in addition to insulin glargine. Metformin was continued if taken. Doses of insulin and oral medication were titrated to protocol for the treatment period of 12 weeks. RESULTS: Baseline-adjusted self-monitored capillary blood glucose concentration at 12 weeks was significantly lower with nateglinide + insulin glargine compared with placebo + insulin glargine after breakfast [difference -2.3 (95% confidence interval -4.4, -0.2) mmol/l, P = 0.030], before lunch [-2.5 (-4.6, -0.3) mmol/l, P = 0.029], and after lunch [-2.3 (-4.3, -0.4) mmol/l, P = 0.021], but not at other times. Baseline-adjusted HbA(1c) was not lower with nateglinide + insulin glargine as compared with placebo + insulin glargine [7.8 +/- 1.4 vs. 8.3 +/- 1.0%, difference -0.43 (-0.98, 0.12)%]. CONCLUSIONS: Addition of nateglinide before meals to once-daily insulin glargine in people with long-standing diabetes already requiring insulin therapy improves blood glucose control in the early part of the day after breakfast and lunch, but does not provide good control of blood glucose levels overall.     

Comparison of acarbose and metformin in patients with Type 2 diabetes mellitus insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study.

AIMS: To compare the efficacy and safety of acarbose and metformin when added to sulphonylurea therapy in diabetic patients insufficiently controlled with sulphonylureas alone. METHODS: A 12-week, single-centre, placebo-controlled study, with 89 patients randomized to receive acarbose (100 mg t.d.s.), metformin (850 mg b.d.) or placebo in addition to their sulphonylurea therapy. The study was double-blinded with respect to acarbose/placebo and single-blinded for metformin/ acarbose and metformin/placebo. Patients started a strict dietary regimen 1 week before receiving their first dose of acarbose, metformin or placebo. This regimen was individually adjusted to metabolic status and energy requirements. RESULTS: The primary endpoint, HbA1c, decreased from baseline in all three groups after 12 weeks. The decrease was greater in the two groups receiving active therapy compared with placebo (acarbose -2.3+/-0.32%; metformin -2.5+/-0.16%; placebo -1.3+/-0.34%). There was no significant difference between acarbose and metformin (P=0.65). Differences between both active therapies and placebo were statistically significant (acarbose P < or = 0.01; metformin P < or = 0.004). Reductions in body weight over the treatment period were seen in all three groups and were greatest in the acarbose group (median weight reduction: acarbose 3.5 kg; metformin, 1.0 kg; placebo 1.4 kg). There were no significant differences in the incidence of gastrointestinal side-effects between the three groups and all regimens were generally well tolerated. CONCLUSION: The results of the study demonstrate the equivalence of acarbose and metformin for improving metabolic control in patients insufficiently controlled with diet and sulphonylureas.     

Evaluation of the weight-increasing effects of biphasic analog and regular NPH insulin mixtures in patients with Type 2 diabetes mellitus

Background: Weight gain is a significant problem in diabetic patients in terms of worsening glycemic control, increasing diabetic and cardiovascular morbidity and mortality, and contributing to social and psychological problems. In the present study, we evaluated the effects of a biphasic analog and regular NPH insulin mixtures on weight gain in patients with Type 2 diabetes mellitus (T2DM) over 1 year. Methods: Group I consisted of 71 patients (29 men and 42 women) being treated with analog mixtures (insulin lispro 75/25 mix and biphasic insulin aspart 70/30 mix) twice daily; Group II consisted of 69 patients (23 men and 46 women) being treated with a regular insulin mixture (70/30) twice daily. Starting weight, body mass index, HbA1c, and hypoglycemic episodes were evaluated after 6 and 12 months. Results: Weight gain in Group I at 6 and 12 months was 1.41 ± 2.70 and 2.08 ± 3.74 kg, respectively. In Group II, weight gain at 6 and 12 months was 1.5 ± 3.0 and 2.29 ± 3.85 kg, respectively. Intragroup comparisons indicated that, for both groups, weight gain at 6 and 12 months differed significantly from the starting weight. However, no significant differences in weight gain were found between the two groups (P > 0.05). Conclusions: The weight‐increasing effects of an analog mixture of insulin and the NPH regular mixture of insulin appear to be similar. This should be taken into account when determining the type of insulin to use in treating T2DM patients.     

Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial

PURPOSE: To assess the efficacy and safety of adding rosiglitazone to an established regimen of glyburide/metformin in patients with type 2 diabetes who had not achieved adequate glycemic control (glycosylated hemoglobin [HbA1C] levels >7.0% and < or =10.0%). METHODS: Following an open-label, lead-in phase to optimize the dosing of glyburide/metformin tablets, 365 patients randomly received additive therapy comprising rosiglitazone (4 mg once daily) or placebo for 24 weeks. Based on glycemic response, rosiglitazone dose was maintained or increased to 4 mg twice daily. Glyburide/metformin dose was maintained or reduced by 2.5/500 mg for symptomatic hypoglycemia. The primary endpoint was the change in HbA1C level from baseline to week 24. The proportions of patients achieving HbA1C levels <7% and a fasting plasma glucose level <126 mg/dL were also assessed. RESULTS: After 24 weeks, therapy with glyburide/metformin plus rosiglitazone resulted in a greater reduction in HbA1C levels (-1.0%, P<0.001) compared with combination therapy that included placebo, and in a larger proportion of patients (42% vs. 14%) who attained levels <7%. The difference in fasting plasma glucose levels between groups was -48 mg/dL (P<0.001), favoring glyburide/metformin plus rosiglitazone. The adverse event profile in the rosiglitazone-treated group included mild-to-moderate edema (8%), hypoglycemia (22%), and weight gain of 3 kg. No patient experienced hypoglycemia requiring third-party assistance. CONCLUSION: In patients with inadequate glycemic control despite established glyburide/metformin therapy, the addition of rosiglitazone improves glycemic control, allowing more patients to achieve an HbA1C level <7% and perhaps delaying the need for insulin treatment.     

Lack of effect of simvastatin on insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia: results from a double-blind, randomized, placebo-controlled crossover study.

AIMS: To evaluate the effects of simvastatin on serum lipids and insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia. METHODS: A double-blind, randomized, placebo-controlled and two-period crossover study. After a 2-month run-in, 19 eligible Type 2 diabetic patients with hypercholesterolaemia were randomized to receive either simvastatin or placebo for 3 months, exchanging their treatment thereafter for another 3 months. Blood samples were taken in month 0 and at monthly intervals to measure serum lipids and indices of glycaemic control. An euglycaemic insulin clamp was performed in months 0, 3 and 6 to assess change of insulin sensitivity. The amount of glucose infused during 90-120 min of the clamp (M), and the mean values of serum insulin during 90-120 min (I) were measured. The M and M/I ratio were used to represent the in vivo insulin sensitivity of the subject. RESULTS: Simvastatin significantly reduced serum total cholesterol (TC) by 23+/-18% and low density lipoprotein-cholesterol (LDL-C) by 30+/-26%. It did not alter glycaemic control. The M-values and M/I ratios were similar in both groups in each period and no drug effect on insulin sensitivity could be identified. CONCLUSIONS: Simvastatin significantly reduced the serum TC and LDL-C levels without alteration of insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia.     

Fulminant lactic acidosis in two patients with Type 2 diabetes treated with metformin.

Lactic acidosis is a known adverse risk of metformin treatment. We report two cases in whom fulminant lactic acidosis developed during treatment. There were no contraindications to metformin treatment and both were admitted with abdominal discomfort for some days, causing dehydration. Both patients had renal failure on admission, developed multiple organ failure and both suffered a massive stroke. One patient died and the other survived but is severely disabled. We suggest, in both cases, that acute renal failure developed as a result of dehydration, causing metformin accumulation and lactic acidosis. We recommend that all patients on metformin should consider discontinuation of metformin treatment in the event of a severe medical condition causing dehydration.     

Preprandial vs. postprandial insulin lispro-a comparative crossover trial in patients with Type 1 diabetes.

AIMS: Administration of bolus insulin after eating may be a useful therapeutic option for some patients. This 6-month, crossover study compared metabolic effects of routine use of preprandial vs. postprandial injection of bolus insulin lispro. METHODS: Thirty-one patients with Type 1 diabetes injected insulin lispro either preprandially or postprandially for a 3-month period followed by the alternate regimen for a further 3 months. HbA1c, fructosamine and eight-point self-determined blood glucose profiles were measured and analysed using an anova model appropriate for a crossover design. RESULTS: Mean HbA1c decreased slightly from baseline with preprandial (-0.15 +/- 0.41%) and increased slightly with postprandial (0.11 +/- 0.48%) insulin lispro so that there was a significant (P = 0.008) difference between treatments in final HbA1c level. Mean fructosamine also decreased slightly with preprandial (-15 +/- 31 micro mol/l) but was almost unchanged (1 +/- 39 micro mol/l) with postprandial insulin lispro. Overall daily blood glucose was not different (P = 0.312) for preprandial compared with postprandial administration. However, mean preprandial glucose was lower (7.5 +/- 2.01 vs. 6.6 +/- 1.22 mmol/l; P = 0.026), whereas mean postprandial glucose was higher (7.7 +/- 1.8 vs. 8.7 +/- 2.1 mmol/l; P = 0.031) with postprandial insulin lispro administration. Mean blood glucose excursions were higher with postprandial compared with preprandial insulin lispro, indicating greater daily fluctuations. No difference in incidence of hypoglycaemia was observed with the two treatment regimens. CONCLUSIONS: Postprandial insulin lispro administration appeared to be an acceptable treatment regimen and may be of benefit in certain situations. However, the benefits of postprandial administration may have to be balanced against poorer glycaemic control with continuous long-term use.     

Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study

Aims: To evaluate the efficacy and safety of initial combination therapy with linagliptin plus metformin versus linagliptin or metformin monotherapy in patients with type 2 diabetes. Methods: In this 24‐week, double‐blind, placebo‐controlled, Phase III trial, 791 patients were randomized to one of six treatment arms. Two free combination therapy arms received linagliptin 2.5 mg twice daily (bid) + either low (500 mg) or high (1000 mg) dose metformin bid. Four monotherapy arms received linagliptin 5 mg once daily, metformin 500 mg or 1000 mg bid or placebo. Patients with haemoglobin A1c (HbA1c) ≥11.0% were not eligible for randomization and received open‐label linagliptin + high‐dose metformin. Results: The placebo‐corrected mean (95% confidence interval) change in HbA1c from baseline (8.7%) to week 24 was ?1.7% (?2.0, ?1.4) for linagliptin + high‐dose metformin, ?1.3% (?1.6, ?1.1) for linagliptin + low‐dose metformin, ?1.2% (?1.5, ?0.9) for high‐dose metformin, ?0.8% (?1.0, ?0.5) for low‐dose metformin and ?0.6 (?0.9, ?0.3) for linagliptin (all p < 0.0001). In the open‐label arm, the mean change in HbA1c from baseline (11.8%) was ?3.7%. Hypoglycaemia occurred at a similar low rate with linagliptin + metformin (1.7%) as with metformin alone (2.4%). Adverse event rates were comparable across treatment arms. No clinically significant changes in body weight were noted. Conclusions: Initial combination therapy with linagliptin plus metformin was superior to metformin monotherapy in improving glycaemic control, with a similar safety and tolerability profile, no weight gain and a low risk of hypoglycaemia.     

A randomized, controlled trial comparing insulin lispro with human soluble insulin in patients with Type 1 diabetes on intensified insulin therapy. The UK Trial Group.

AIMS: Despite considerable experience with insulin lispro, few blinded comparisons with soluble insulin are available. This study compared insulin lispro with human soluble insulin in patients with Type 1 diabetes mellitus on multiple injection therapy who inject shortly before meals. METHODS: Glucose control, frequency of hypoglycaemia and patient preference were examined in the course of a prospective, randomized, double-blind, crossover comparison, with a 6-week run-in period and 12 weeks on each therapy. Ninety-three patients took part, all on multiple daily doses of insulin, with soluble insulin before meals and NPH (isophane) insulin at night. The main outcome measures were self-monitored blood glucose profiles, glycated haemoglobin, frequency of hypoglycaemic episodes, patient satisfaction and well-being and patient preference. RESULTS: Blood glucose levels were significantly lower after breakfast and lunch, but higher before breakfast, lunch and supper, in patients taking insulin lispro. Levels of HbA(1c) were 7.4 +/- 1.1% on Humulin S and 7.5 +/- 1.1% on insulin lispro (P = 0.807). The overall frequency of symptomatic hypoglycaemia did not differ, but patients on insulin lispro were less likely to experience hypoglycaemia between midnight and 6 a.m., and more likely to experience episodes from 6 a.m. to midday. Questionnaires completed by 84/87 patients at the end of the study showed that 43 (51%) were able to identify each insulin correctly, nine (11%) were incorrect, and 32 (38%) were unable to tell the insulins apart. No significant preference emerged: 35 (42%) opted for insulin lispro, 24 (29%) opted for Humulin S, while the remainder had no clear preference. CONCLUSIONS: Substitution of insulin lispro for soluble insulin in a multiple injection regimen improved post-prandial glucose control at the expense of an increase in fasting and pre-prandial glucose levels. Patients who already injected shortly before meals expressed no clear preference for the fast-acting analogue, and did not improve their overall control as a result of using it. Nocturnal hypoglycaemia was however, less frequent on insulin lispro, and may emerge as a robust indication for its use.     

Efficacy and safety of linagliptin as add-on therapy to insulin in Chinese patients with type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled trial

This 24-week, double-blind, placebo-controlled, phase III trial evaluated the efficacy and safety of linagliptin in 206 Chinese patients with inadequately controlled (glycated haemoglobin [HbA1c] 7.5%–10.0%) type 2 diabetes mellitus (T2DM) receiving insulin (basal or premixed) ± metformin. Patients were randomized (1:1) to receive linagliptin 5 mg/d or placebo. The decrease from baseline in HbA1c (primary endpoint) was greater with linagliptin than with placebo (−0.61% vs. −0.20%, adjusted mean difference −0.40%; P = 0.0016). Linagliptin demonstrated significantly greater improvement in 2-hour postprandial glucose (−1.77 mmol/L [−31.95 mg/dL]; P < 0.001), and a numerical reduction in fasting plasma glucose (−0.34 mmol/L [−6.2 mg/dL]; P = 0.2241) versus placebo. Proportionally more patients on linagliptin achieved a HbA1c reduction of ≥0.5% versus those on placebo (odds ratio 2.293, P < 0.01). Adverse events in both groups were similar, with no new safety findings or clinically relevant changes in body weight. Among investigator-defined hypoglycaemic events (linagliptin: 17.3%; placebo: 12.7%; odds ratio 1.48, P = 0.337), none were severe. In Chinese patients with T2DM, linagliptin add-on to insulin improved glycaemic control and was well tolerated, without increased risk of hypoglycaemia or weight gain.