Addition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial

doi:10.1016/j.amjmed.2003.07.023

The American Journal of Medicine

Volume 116, Issue 4, 15 February 2004, Pages 230-235

https://doi.org/10.1016/j.amjmed.2003.07.023 Get rights and content

Abstract

Purpose

To compare the efficacy of adding pioglitazone or bedtime isophane (NPH) insulin to maximal doses of metformin and an insulin secretagogue in patients with poor glucose control.

Methods

We conducted a nonblinded, open-label, randomized controlled trial involving 62 patients with type 2 diabetes and glycosylated hemoglobin (HbA_1C) levels >8.0%. Patients received either pioglitazone or bedtime NPH insulin in addition to their usual diabetes medication for 16 weeks. Outcome measurements of glycemic control, hypoglycemia, blood pressure, lipid levels, microalbuminuria, and quality of life were assessed at baseline and at 16 weeks.

Results

HbA_1C levels were lowered to a similar degree in each treatment arm (pioglitazone: –1.9% ± 1.5%; insulin: –2.3% ± 1.5%; P = 0.32), but hypoglycemia was less common among patients who received pioglitazone than those who received insulin (37% [11/30] vs. 68% [19/28], P = 0.02). Pioglitazone, but not insulin, resulted in an increase in high-density lipoprotein (HDL) cholesterol levels. Both treatments had similar effects on weight, other lipid values, blood pressure, and urine microalbumin levels.

Conclusion

Adding pioglitazone or bedtime insulin for 16 weeks improved glycemic control in type 2 diabetic patients with secondary oral agent failure. Pioglitazone was associated with less hypoglycemia and improved HDL cholesterol levels.

Section snippets

Methods

Eligible patients were recruited from the Vancouver Hospital Diabetes Centre between September 2001 and March 2002. Patients were 30 to 85 years old, had type 2 diabetes for more than 1 year, and were taking maximally tolerated doses of an insulin secretagogue and metformin. All had received diabetes education, were on a diabetic diet, and were performing home blood glucose monitoring. Their most recent HbA_1Cmeasurement was >8.0% while undergoing stable diabetes treatment for >12 weeks.

Results

Thirty-one patients were randomly assigned to each treatment arm. One patient was withdrawn from the pioglitazone group after 2 weeks because of noncompliance. In the insulin group, 2 patients voluntarily withdrew after randomization but before starting therapy, and 1 was withdrawn after 2 weeks because of noncompliance. Thirty pioglitazone and 28 insulin patients were left for analysis.

Patients in both treatment groups had similar baseline characteristics (Table 1). All patients were taking

Discussion

Despite evidence that tight glycemic control reduces complications in type 2 diabetes 1, 2, most patients do not have good control (12). One reason may be the progressive nature of type 2 diabetes, which is associated with worsening of metabolic control over time requiring an additional agent every 4 years to maintain optimal control (13). Another explanation is that type 2 diabetes is treated mainly in primary care environments, which are designed to manage acute illnesses rather than chronic

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Citation Excerpt :
Thus, 15 randomized controlled trials enrolling 2,860 patients with type 2 diabetes were included in analyses.12-14,19,21-27,30-33 Five of the 15 included studies (including 1,203 participants)13,19,21-23 compared rosiglitazone with placebo or active treatment and 10 (including 1,657 participants)12,14,24-27,30-33 compared pioglitazone with placebo or active treatment. Eight studies enrolled patients with either normo- or microalbuminuria at baseline,13,19,21-23,25,26,30 4 studies included patients with microalbuminuria,12,24,27,31 and 3 studies were carried out in patients with macroalbuminuria or proteinuria.14,32,33
Because of the major clinical and economic burden of diabetic nephropathy, new therapeutic tools to delay its progression are needed. Recent studies suggest that thiazolidinediones have renal benefits. We aimed to evaluate the effect of thiazolidinediones on urinary albumin and protein excretion in patients with diabetes mellitus.
Systematic review and meta-analysis by searching MEDLINE/PubMed, EMBASE, and Cochrane CENTRAL databases (1991 to September 2009).
Patients with diabetes mellitus.
Randomized controlled trials.
Thiazolidinediones (rosiglitazone and pioglitazone) compared with placebo or other antidiabetic agents.
Weighted (WMDs) and standardized mean differences (SMDs) for changes in urine albumin or protein excretion between the thiazolidinedione and control groups.
Of 171 originally identified articles, 15 studies (5 with rosiglitazone and 10 with pioglitazone) involving 2,860 patients were included in the analysis. In participants with baseline normo- or microalbuminuria, the WMD of proportional changes between the thiazolidinedione and control groups in urinary albumin excretion measured using time-specified collections was −64.8% (95% CI, −75.6 to −53.9) and the WMD of changes in albumin-creatinine ratio was −24.8% (95% CI, −39.6 to −10.0). Overall, in participants with normo- and microalbuminuria, thiazolidinedione treatment was associated with a significant decrease in urinary albumin excretion (SMD, −0.6 units of standard deviation [SD]; 95% CI, −0.8 to −0.4). Similarly, thiazolidinediones were associated with a significant decrease in urinary protein excretion in patients with proteinuria (SMD, −1.1 units of SD; 95% CI, −1.8 to −0.4).
Significant heterogeneity across included studies in several subgroup analyses; patient-level data not available.
Treatment with thiazolidinediones significantly decreases urinary albumin and protein excretion in patients with diabetes. This finding calls for clinical trials with hard renal outcomes to elucidate the potential benefits of thiazolidinediones on diabetic nephropathy.
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^☆: The study was funded in part by an investigator-initiated grant from Eli Lilly Canada. Eli Lilly had no role in the study design, collection, analysis, or interpretation of the data, or the decision to submit the manuscript for publication. Dr. Thompson has received speaker honoraria from Eli Lilly Canada.

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Clinical studyAddition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial☆

Abstract

Purpose

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Diabetes Res Clin Pract

Am J Med

Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Lancet

Standards of medical care for patients with diabetes mellitus

Diabetes Care

Glycemic control with diet, sulphonylurea, metformin or insulin in patients with type 2 diabetes. Progressive requirement for multiple therapies (UKPDS 49)

JAMA

Health care and health status and outcomes for patients with type 2 diabetes

Diabetes Care

Starting insulin therapy in patients with type 2 diabetes. Effectiveness, complications and resource utilization

JAMA

Thiazolidenedionesa new class of antidiabetic drugs

Diabet Med

The effect of a thiazolidenedione drug, troglitazone, on glycemia in patients with type 2 diabetes poorly controlled with sulphonylurea and metformin. A multicenter, randomized, double-blind, placebo-controlled trial. Troglitazone triple-therapy study group

Ann Intern Med

Rosiglitazone in combination with glimepiride plus metformin in type 2 diabetic patients

Diabetes Care

Hypoglycemia

Diabetes Care

Guidelines for encouraging psychological well-being. Report of a working group of the World Health Organization and International Diabetes Federation European Region St. Vincent Declaration action programme for diabetes

Diabet Med

Outcomes of patients with hypertension and non-insulin-dependent diabetes mellitus treated by different systems and specialties

JAMA

The UK Prospective Diabetes Studya review

Diabetes Care

Medical care for patients with diabetes. Epidemiologic aspects

Ann Intern Med

Clinical study
Addition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial☆