Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study.

OBJECTIVE: Metformin was approved by the Food and Drug Administration in 1995 subject to the conduct of a randomized trial to evaluate the risk of lactic acidosis or other serious adverse events (SAEs) with this agent, under usual care conditions. RESEARCH DESIGN AND METHODS: The Comparative Outcomes Study of Metformin Intervention versus Conventional (COSMIC) Approach Study was a randomized, open-label, active-comparator, parallel-group, 1-year trial in type 2 diabetic patients suboptimally controlled on diet or sulfonylurea. Patients received metformin (n = 7,227) or other usual care treatments (n = 1,505). The primary end point was the incidence of SAEs, death, and hospitalization. RESULTS: SAEs occurred in 10.3% (95% CI 9.6-11.1%) of the metformin group and in 11.0% (9.5-12.7%) of the usual care group (P = 0.431). Lactic acidosis did not occur. All-cause mortality (1.1% [0.9-1.4%] vs. 1.3% [0.8-2.0%], P = 0.596) and hospitalization (9.4% [8.8-10.1%] vs. 10.4% [8.9-12.1%], P = 0.229) were similar between groups. CONCLUSIONS: The incidence of SAEs was similar between groups. Lactic acidosis was not observed. Metformin may be safely prescribed for type 2 diabetes if contraindications and warnings are respected. This study demonstrates the utility of large, simple trials for risk evaluation of treatments for common diseases.

Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study.

OBJECTIVE: Metformin, a biguanide antihyperglycemic medication, lowers blood glucose in patients with type 2 diabetes with minimal risk of hypoglycemia. Most common side effects include diarrhea, nausea and vomiting. Extended-release metformin (Glucophage XR)*, a once-daily tablet using the patented GelShield Diffusion System release mechanism, may be better tolerated than immediate-release metformin (Glucophage). This retrospective chart review examined the overall gastrointestinal (GI) tolerability of both formulations. RESEARCH DESIGN AND METHODS: Patient charts were reviewed and data were collected from October 2001 to May 2002. Adult patients with type 2 diabetes started on extended-release metformin (metformin-XR) or switched from immediate-release metformin to metformin-XR within the previous 2 years were eligible for inclusion in the metformin-XR cohort. Patients started on immediate-release metformin within the previous 2 years were eligible for inclusion in the immediate-release metformin cohort. Previous experience of GI side effects while taking immediate-release metformin did not prevent inclusion in either cohort, though patients with significant underlying GI disease or moderate to severe hepatic or renal impairment were excluded. GI tolerability was assessed during the first year of treatment with immediate-release metformin or metformin-XR. Primary endpoints were overall GI tolerability and frequency of diarrhea during the first year of treatment. RESULTS: A total of 471 patients' charts were reviewed and data were collected from four diabetes clinics; 310 (metformin-XR) and 158 (immediate-release metformin) eligible patients were included. Patients were, on average, 56 years old, and overweight (mean body mass index 33 kg/m2). The majority of patients were Caucasian (50%), Hispanic (24%) or Black (19%). Mean daily doses were 1258 mg (range 500-2500 mg) for metformin-XR and 1282 mg (range 500-2550 mg) for immediate-release metformin. About 25% of the metformin-XR cohort had been switched from immediate-release metformin due to a history of GI adverse events (AE). Despite this, the frequency of any GI AE was similar between metformin-XR and immediate release metformin (11.94 vs. 11.39%, p = 0.86). The incidence of individual GI AE also did not differ significantly between cohorts. In a cohort of 205 patients started on immediate-release metformin and switched to metformin-XR, the frequency of any GI AE was 26.34% (while taking immediate release metformin; n = 205) vs. 11.71% (after switching to metformin-XR; n = 205) (p = 0.0006) and the frequency of diarrhea was 18.05% (while taking immediate-release metformin) vs. 8.29% (after switching to metformin-XR) (p = 0.0084). CONCLUSIONS: In this retrospective chart review, patients switched from immediate-release metformin to metformin-XR experienced fewer GI side effects on comparable doses of the extended-release metformin.

A Comparison of the Cough Profile of Fosinopril and Enalapril in Hypertensive Patients with a History of ACE Inhibitor-Associated Cough.

OBJECTIVE: Cough frequency and severity with fosinopril and enalapril were assessed in hypertensive patients with previous angiotensin-converting enzyme inhibitor (ACEI)-associated cough. DESIGN: Prospective, multicenter, randomized, 8-week double-blind treatment. PATIENTS: One hundred seventy-nine patients (mild-to-moderate hypertension, nonsmokers, mean age 58 years; 55% females; 72% Caucasian, 6% black, 19% Hispanic) were studied. Patients with other cough etiologies, significant co-morbidity, or confounding medications were excluded. INTERVENTIONS: Patients were randomized to fosinopril 10 mg (n = 85) or enalapril 5 mg (n = 94) once daily. Dosage could be doubled for blood pressure control after 4 weeks. Outcome measurements: The primary end point was all-cough frequency based on patient daily diary ratings; a cumulative cough frequency score was calculated. Secondary end points included cough severity, nonproductive cough frequency, night awakenings, cough time of day, and spontaneously reported cough. RESULTS: Fosinopril and enalapril demonstrated similar blood pressure control. Significant cough profile differences were observed in favor of fosinopril: all-cough frequency was 40.6 plus minus 3.8 (mean plus minus SE) versus 52.8 plus minus 3.6 (p = 0.02); nonproductive cough frequency was 26.7 plus minus 3.5 versus 40.3 plus minus 3.4 (p less-than-or-equal 0.01); and cough time of day was 49.2 plus minus 5.2 versus 66.0 plus minus 5.0 (p = 0.02), for fosinopril and enalapril, respectively. Subgroup analysis revealed all-cough frequency was 33.5 plus minus 6.3 versus 56.6 plus minus 5.3 (p = 0.006) for fosinopril and enalapril, respectively, in patients who previously had cough on one of these two ACEI (predominantly enalapril). Ten (12%) fosinopril and 25 (27%) enelapril patients spontaneously reported cough (p = 0.01). CONCLUSIONS: Hypertensive patients with previous ACEI-associated cough reported less frequent cough with fosinopril compared to enalapril, based on cumulative patient diary scores and spontaneously reported cough. This difference was most apparent in the subgroup of patients who previously experienced cough associated with enalapril therapy. Patients with prior ACEI-associated cough may experience less frequent with fosinopril.