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Aim: Metformin therapy reduces microvascular complications in Type 2 diabetes; questions remain, however, regarding its impact on macrovascular events. This study examined metformin use in relation to risk of cardiovascular-related hospitalization and mortality., Methods: We conducted a retrospective cohort analysis, using Saskatchewan Health administrative databases to identify new users of oral antidiabetic drugs. Subject groups were defined by medication use during 1991-1999: sulphonylurea monotherapy, metformin monotherapy, or combination therapy. Deaths and non-fatal hospitalizations recorded during the study period were identified as cardiovascular-related from ICD-9 codes. The main outcome was a composite of first non-fatal hospitalization or death. Standard multivariate techniques, including propensity scores, were used to adjust for potential confounding. Multivariate Cox proportional hazard models were used to examine the relationship between metformin use and the composite endpoint., Results: Metformin monotherapy was associated with a lower risk of the composite endpoint (adjusted hazard ratio 0.81; 95% confidence interval 0.68, 0.97) compared with sulphonylurea monotherapy. Combination therapy with meformin and a sulphonylurea was associated with lower mortality, but had similar hospitalization rates, to sulphonylurea monotherapy., Conclusions: Metformin monotherapy was associated with a lower risk of cardiovascular-related morbidity and mortality, and combination metformin and sulphonylurea therapy was associated with a reduced risk of fatal cardiovascular events, when compared with sulphonylurea monotherapy.

Objective: The aim of this study was to examine the relationship between use of metformin and sulfonylurea and mortality in new users of these agents., Research Design and Methods: Saskatchewan Health databases were used to examine population-based mortality rates for new users of oral antidiabetic agents. Individuals with prescriptions for sulfonylurea or metformin in 1991-1996 and no use in the year prior were identified as new users. Prescription records were prospectively followed for 1-9 years; subjects with any insulin use were excluded. Causes of death were identified based on ICD-9 codes in an electronic vital statistics database. Multivariate logistic regression and survival analyses were used to assess the differences in mortality between drug cohorts, after adjusting for potential confounding variables., Results: The total study sample comprised 12,272 new users of oral antidiabetic agents; the average length of follow-up was 5.1 (SD 2.2) years. In subjects with at least 1 year of drug exposure and no insulin use, mortality rates were 750/3,033 (24.7%) for those receiving sulfonylurea monotherapy, 159/1,150 (13.8%) for those receiving metformin monotherapy, and 635/4,683 (13.6%) for those receiving combination therapy over an average 5.1 (SD 2.2) years of follow-up. The adjusted odds ratio (OR) for all-cause mortality for metformin monotherapy was 0.60 (95% CI 0.49-0.74) compared with sulfonylurea monotherapy. Sulfonylurea plus metformin combination therapy was also associated with reduced all-cause mortality (OR 0.66, 95% CI 0.58-0.75). Reduced cardiovascular-related mortality rates were also observed in metformin users compared with sulfonylurea monotherapy users., Conclusions: Metformin therapy, alone or in combination with sulfonylurea, was associated with reduced all-cause and cardiovascular mortality compared with sulfonylurea monotherapy among new users of these agents.

Objective: To review the best evidence-based literature on the insulin analogue, lispro insulin, and to provide guidelines for its use., Quality of Evidence: Using the MeSH terms, lispro and insulin analogues, we searched PubMed, Current Contents, MEDLINE, and EMBASE from January 1986 to July 1998 and selected 42 articles out of 97 for high quality and relevance to family medicine. Twenty-eight were randomized controlled trials, but only two studies were blinded because lispro and regular insulin have different optimal times of administration., Main Message: The new insulin analogue, lispro, produces a much more rapid, higher, and shorter-lasting peak level of insulin than regular human insulin, thus mimicking physiologic secretion of insulin more closely. This allows insulin administration just before or just after meals and means patients can manage with fewer snacks. Lispro controls postprandial blood glucose levels better and does not cause hypoglycemia. Although most older studies showed no change in glycosylated hemoglobin (HbA1c) levels, a few recent studies involving refinements, such as continuous subcutaneous insulin infusion or basal insulin to reduce preprandial glucose levels, have found small but significant improvements. Insulin lispro has also been used successfully in cases of insulin resistance and insulin allergy., Conclusions: Lispro is a useful addition for motivated diabetic patients who like to achieve better control of HbA1c without increased hypoglycemia and to match mealtime insulin injections with diet, exercise, and various lifestyles.

Objective: To review the available literature on the new insulin analogue insulin lispro and provide information on its efficacy, indications for use and contraindications., Data Sources: MEDLINE searches were made for articles published from 1966 to 1996 using the indexing term "lispro", "Humalog" and "insulin analogs"., Study Selection: About 30 studies and review articles were selected based on their relevance to the stated objective. These were critically appraised for the purpose of writing the review article so that it would be relevant to general practitioners, internists and nurse educators., Data Synthesis: The therapeutic challenge when treating diabetic patients is to bring the blood glucose level into as normal a range as possible, with minimal hypoglycemia and hyperinsulinemia. Insulin lispro has a much faster, higher and shorter-lasting peak serum insulin level than regular human insulin, thus mimicking physiologic secretion of insulin more closely. As a result, there is improvement in postprandial blood glucose levels and decreased episodes of hypoglycemia, with no change in the hemoglobin A1c (HgbA1c) level. The ability to inject insulin lispro immediately before the meal allows greater flexibility of lifestyle. Compared with regular insulin, insulin lispro is associated with a lower risk of hypoglycemia with exercise several hours after a meal. It is therefore most useful for the motivated, compliant diabetic patient who would like to achieve a better hypoglycemia-HgbA1c ratio as well as for patients desiring further flexibility with premeal insulin injections. Use of insulin lispro has been shown to improve HgbA1c levels in patients using insulin pumps. It is well tolerated, and therapy is often continued after studies are completed. Further study is needed to establish optimal basal regimens.