OBJECTIVE -To determine the efficacy and safety of rosiglitazone (RSG) when added to insulin in the treatment of type 2 diabetic patients who are inadequately controlled on insulin monotherapy. RESEARCH DESIGN AND METHODS-After 8 weeks of insulin standardization and placebo (PBO) run-in, 319 type 2 diabetic patients with mean baseline HbA 1c Ն7.5% (8.9 Ϯ 1.1 to 9.1 Ϯ 1.3) on twice-daily insulin therapy (total daily dose Ն30 U) were randomized to 26 weeks of additional treatment with RSG (4 or 8 mg daily) or PBO. Insulin dose could be downtitrated only for safety reasons. The primary end point was reduction of HbA 1c from baseline.RESULTS -RSG 4 and 8 mg daily significantly improved glycemic control, which was unchanged on PBO. By intent-to-treat analysis, treatment with RSG 8 mg plus insulin resulted in a mean reduction from baseline in HbA 1c of 1.2% (P Ͻ 0.0001), despite a 12% mean reduction of insulin dosage. Over 50% of subjects treated daily with RSG 8 mg plus insulin had a reduction of HbA 1c Ն1.0%. Neither total:HDL cholesterol nor LDL:HDL cholesterol ratios significantly changed with RSG treatment. Serious adverse events did not differ among groups.CONCLUSIONS -The addition of RSG to insulin treatment results in significant improvement in glycemic control and is generally well tolerated. Diabetes Care 24:1226 -1232, 2001T ype 2 diabetes is a common and serious disorder that accounts for Ͼ$100 billion in annual health care expenditures in the U.S. alone (1), mostly because of chronic complications associated with the condition. It is characterized by an impaired sensitivity of target tissues to insulin and impaired insulin secretion by pancreatic ␤-cells, which leads to hyperglycemia and, over time, to microvascular and macrovascular complications (2-6). Results of the U.K. Prospective Diabetes Study (UKPDS) have shown that improvement of glycemic control reduces these complications and that progressive ␤-cell failure usually leads to the need for combination therapy to maintain glycemic control (7-10). The UKPDS demonstrated that even insulin-treated patients were unable to sustain adequate glycemic control.The insulin-sensitizing effects of the thiazolidinedione (TZD) class of oral antidiabetic agents may alter the natural history of type 2 diabetes. By improving insulin sensitivity at the level of the target tissues, including adipose and muscle tissues, TZDs enhance the effectiveness of both endogenous and exogenous insulin (11), thereby improving glycemic control and perhaps slowing the decline of ␤-cell function. Rosiglitazone (RSG) is a potent TZD that binds to the peroxisome proliferator-activated receptor-␥ and improves insulin action in isolated tissues (11), ␤-cell function in animals (12,13) and humans (14), and glycemic control in patients with type 2 diabetes (15,16).This article reports the results of the efficacy and safety of RSG added to previously ineffective insulin monotherapy in patients with type 2 diabetes who participated in a multicenter randomized double-blind trial. The aim of ...

This study evaluated the efficacy and safety of rosiglitazone monotherapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone [2 or 4 mg twice daily (bd)] or placebo for 26 weeks. The primary end point was change in hemoglobin A 1c ; other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lipids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A 1c relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations relative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased significantly. Homeostasis model assessment estimates indicate that rosiglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved ␤-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no increase in adverse events with rosiglitazone. In the short-term, rosiglitazone is an insulin sensitizer that is effective and safe as monotherapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions. (J Clin Endocrinol Metab 86: 280 -288, 2001) I NSULIN RESISTANCE contributes to the pathophysiology of several major chronic diseases. Insulin resistance precedes the development of type 2 diabetes mellitus and contributes to the hyperglycemic state in about 80 -85% of patients with this disorder (1, 2). In addition, evidence suggests that insulin resistance and hyperinsulinemia are also associated with other disease states, such as polycystic ovarian syndrome, an insulin-resistant state that leads to hyperinsulinemia, thus stimulating excessive ovarian androgen production in genetically susceptible individuals (3, 4). Insulin resistance and hyperinsulinemia have also been associated with increased risks of atherosclerosis and hyperten-

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A total of 52 weeks of therapy with RSG (4 mg b.i.d.) did not adversely affect cardiac structure or function in patients with type 2 diabetes and produced significant and sustained reductions in hyperglycemia. Decreases in ambulatory diastolic blood pressure with RSG were superior to those with GLB.

The principle of replacing prandial insulin lispro with a once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) for type 2 diabetes inadequately controlled on a multiple daily insulin injections regimen was tested with albiglutide. RESEARCH DESIGN AND METHODS In this treat-to-target study, basal plus prandial insulin was optimized over 4 weeks before participants were randomized (1:1) to albiglutide plus optimized basal insulin glargine and lispro (dose reduced by 50% at randomization; subsequently, lispro injections were fully discontinued 4 weeks later) (n 5 402) or to continued optimized lispro plus optimized glargine (n 5 412). RESULTS Mean 6 SD HbA 1c at baseline, 7.8 6 0.6% (61 6 7 mmol/mol) in the albiglutide 1 glargine group and 7.7 6 0.6% (60 6 7 mmol/mol) in the lispro 1 glargine group, was reduced at week 26 to 6.7 6 0.8% (49 6 8 mmol/mol) and 6.6 6 0.8% (48 6 8 mmol/mol), respectively (least squares [LS] difference 0.06% [95% CI 20.05 to 0.17]; noninferiority P < 0.0001). In the albiglutide 1 glargine group, 218 participants (54%) replaced all prandial insulin without reintroducing lispro up to week 26. Total daily prandial insulin dose was similar at baseline but was lower by 62 units/day (95% CI 265.9 to 257.8; P < 0.0001) at week 26 in the albiglutide 1 glargine group, and the total number of weekly injections was also reduced from 29 to 13 per week. Less severe/documented symptomatic hypoglycemia (57.2% vs. 75.0%) occurred in the albiglutide 1 glargine group with meaningful weight differences (LS mean 6 SE 22.0 6 0.2 vs. 12.4 6 0.2 kg; P < 0.0001) vs. lispro 1 glargine. Gastrointestinal adverse events were higher with albiglutide 1 glargine (26% vs. 13%). CONCLUSIONS A once-weekly GLP-1RA was able to substitute for prandial insulin in 54% of people, substantially reducing the number of prandial insulin injections; glycemic control improved, with the added benefits of weight loss and less hypoglycemia in the GLP-1RA arm. Replacing prandial insulin with a weekly GLP-1RA can simplify basal plus prandial insulin treatments and achieve better outcomes in type 2 diabetes.

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<b>Objective: </b>The principle of replacing prandial insulin lispro with a once-weekly GLP-1 receptor agonist (GLP-1RA) in type 2 diabetes inadequately controlled on a multiple daily insulin injections regimen was tested with albiglutide. <p> </p> <p><b>Research Design and Methods</b>: In this treat-to-target study, basal+prandial insulin was optimized over 4 weeks before participants were randomized (1:1) to albiglutide plus optimized basal insulin glargine and lispro (dose reduced by 50% at randomization; subsequently lispro injections were fully discontinued 4 weeks later) (n=402), or to continued optimized lispro plus optimized glargine (n=412).</p> <p> </p> <p><b>Results<a>:</a></b> <a>Mean±SD HbA_1c at baseline, 7.8±0.6% (61±7 mmol/mol) in the albiglutide+glargine group and 7.7±0.6% (60±7 mmol/mol) in the lispro+glargine group, were reduced at week 26 to 6.7±0.8% (49±8 mmol/mol) and 6.6±0.8% (48±8 mmol/mol); respectively (LS difference 0.06% [95% CI, −0.05 to 0.17]; noninferiority <i>P</i><0.0001)</a>. In the albiglutide+glargine group, 218 participants (54%) replaced all prandial insulin without reintroducing lispro up to week 26. Total daily prandial insulin dose was similar at baseline but was lower by 62U/day (95% CI −65.9 to −57.8; <i>P</i><0.0001) at week 26 in the albiglutide+glargine group <a></a> and the total number of weekly injections was also reduced from 29 to 13 per week. Less severe/documented symptomatic hypoglycemia (57.2% vs. 75.0%) occurred in the albiglutide+glargine group with meaningful weight differences (LS mean±SE: −2.0±0.2 vs. +2.4±0.2 kg; <i>P</i><0.0001) vs. lispro+glargine. Gastrointestinal adverse events were higher with albiglutide+glargine (26% vs. 13%). </p> <p> </p> <p><b>Conclusions<a>:</a></b> A once-weekly GLP-1RA was able to substitute for prandial insulin in 54% of people, substantially reducing the number of prandial insulin injections; glycemic control improved, with the added benefits of weight loss and less hypoglycemia in the GLP1RA arm. Replacing prandial insulin with a weekly GLP-1RA can simplify basal+prandial insulin treatments and achieve better outcomes in type 2 diabetes. </p>

The glycemic efficacy of weekly Albi 50 mg to replace prandial insulin lispro (Lis) was evaluated in T2DM inadequately controlled on a multiple daily insulin regimen (≥3 injections/day). Basal/bolus insulin was optimized during a 4 week run-in phase before randomization to: 1) Albi + optimized insulin glargine (Gla), with prandial Lis subsequently discontinued by week 4 (n = 402) or 2) optimized Lis + optimized Gla (n = 412). At 26 week, the LS mean ± SE change from baseline in HbA1c was −1.04 ± 0.04 vs. −1.10 ± 0.04% (treatment difference 0.[95% CI, −0.05, 0.17]%; non-inferiority p &lt;0.0001) (Table). In the Albi + Gla group, 218 subjects (54%) replaced all prandial insulin without reintroducing Lis through to 26 week, resulting in a total daily insulin dose reduction of 61 U. Mean number of injections was reduced from 29 to 13 (mean change ± SD: −16 ± 8) per week. GI adverse events were higher in the Albi group (26% vs. 13%). Albi + Gla was favorable for severe or documented symptomatic hypoglycemia (n: 230 [57%] vs. 309 [75%]) and weight change (LS mean ± SE: −2.0 ± 0.2 vs. +2.4 ± 0.2 kg; p&lt;0.0001) vs. Lis + Gla. In conclusion, Albi meaningfully improved glucose control; prandial insulin was stopped in 54% of participants, allowing substantial reductions in insulin dose and number of injections, less hypoglycemia, and body weight loss. Disclosure J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. A.J. Nino: Employee; Self; GlaxoSmithKline plc.. Stock/Shareholder; Self; GlaxoSmithKline plc. J. Soffer: Employee; Self; GlaxoSmithKline plc.. Other Relationship; Self; GlaxoSmithKline plc.. J.M. Mallory: None. L.M. Erskine: Employee; Self; GlaxoSmithKline plc.. Stock/Shareholder; Self; GlaxoSmithKline plc. A. Acusta: Employee; Self; GlaxoSmithKline plc. J.F. Dole: Employee; Self; GlaxoSmithKline plc. M. Carr: Employee; Self; GlaxoSmithKline plc. P. Home: Consultant; Self; AstraZeneca. Other Relationship; Self; Biocon, Boehringer Ingelheim GmbH. Research Support; Self; GlaxoSmithKline plc.. Consultant; Self; Hanmi Pharmaceutical. Other Relationship; Self; Janssen Research & Development. Consultant; Self; Janssen Research & Development, Merck & Co., Inc.. Other Relationship; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; AntriaBio, Inc., Earlysign, Roche Diabetes Care Health and Digital Solutions. Research Support; Self; Sanofi. Consultant; Self; Sanofi.