Metformin and Insulin vs. Insulin Alone for Type 2 Diabetes
Metformin and Insulin vs. Insulin Alone for Type 2 Diabetes
Objectives To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes.
Design Systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.
Data sources The Cochrane Library, Medline, Embase, Science Citation Index Expanded, Latin American Caribbean Health Sciences Literature, and Cumulative Index to Nursing and Allied Health Literature until March 2011. We also searched abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes Congresses, contacted relevant trial authors and pharmaceutical companies, hand searched reference lists of included trials, and searched the US Food and Drug Administration website.
Review methods Two authors independently screened titles and abstracts for randomised clinical trials comparing metformin and insulin versus insulin alone (with or without placebo) in patients with type 2 diabetes, older than 18 years, and with an intervention period of at least 12 weeks. We included trials irrespective of language, publication status, predefined outcomes, antidiabetic interventions used before randomisation, and reported outcomes.
Results We included 26 randomised trials with 2286 participants, of which 23 trials with 2117 participants could provide data. All trials had high risk of bias. Data were sparse for outcomes relevant to patients. Metformin and insulin versus insulin alone did not significantly affect all cause mortality (relative risk 1.30, 95% confidence interval 0.57 to 2.99) or cardiovascular mortality (1.70, 0.35 to 8.30). Trial sequential analyses showed that more trials were needed before reliable conclusions could be drawn regarding these outcomes. In a fixed effect model, but not in a random effects model, severe hypoglycaemia was significantly more frequent with metformin and insulin than with insulin alone (2.83, 1.17 to 6.86). In a random effects model, metformin and insulin resulted in reduced HbA1c, weight gain, and insulin dose, compared with insulin alone; trial sequential analyses showed sufficient evidence for a HbA1c reduction of 0.5%, lower weight gain of 1 kg, and lower insulin dose of 5 U/day.
Conclusions There was no evidence or even a trend towards improved all cause mortality or cardiovascular mortality with metformin and insulin, compared with insulin alone in type 2 diabetes. Data were limited by the severe lack of data reported by trials for patient relevant outcomes and by poor bias control.
Metformin is a glucose lowering drug that, among other mechanisms, is supposed to work by enhancing insulin action mainly in the liver. Metformin is often recommended as the first line drug in patients with type 2 diabetes. Because of disease progression, a substantial proportion of these patients eventually end up on insulin, at which point doctors are recommended to continue metformin use. The rationale behind this combination mainly relates to suggested beneficial metabolic effects, such as reduced blood glucose and body weight.
The United Kingdom Prospective Diabetes Study suggested a beneficial effect of metformin monotherapy, compared with conventional (diet) treatment, on cardiovascular disease and mortality after about 10 years in overweight patients with type 2 diabetes. These findings were partly supported by the Hyperinsulinemia: the Outcome of its Metabolic Effects (HOME) trial comparing combined metformin and insulin versus insulin alone. However, other trials have suggested that metformin combined with sulphonylurea (that is, insulin secretagogues) versus sulphonylurea alone could increase mortality. Thus, the effect of metformin combined with other glucose lowering drugs such as insulin providing regimens on patient relevant outcomes might differ from its effects during monotherapy.
Whether oral glucose lowering drugs should be continued when initiating insulin remains unclear. An insulin sparing effect has been observed when using oral glucose lowering drugs with insulin. However, the progressive nature of type 2 diabetes with its decline in endogenous insulin secretion could result in patients with advanced disease more closely resembling type 1 diabetes, in which adjunct treatment with, for example, metformin, has not proven to improve glycaemic control. Thus, despite international recommendations to use metformin in combination with insulin in patients with type 2 diabetes and therefore the possible widespread use of this treatment regimen worldwide, insufficient and contradictory data exist in the literature to justify this policy.
Previous meta-analyses of glucose lowering drugs have included trials of insulin in combination with various glucose lowering compounds such as metformin, but have not addressed the specific effect of metformin and insulin in this respect. In the light of these considerations and the growing number of patients with type 2 diabetes receiving insulin worldwide, we compared the benefits and harms of metformin and insulin versus insulin alone in randomised clinical trials.
Abstract and Introduction
Abstract
Objectives To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes.
Design Systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.
Data sources The Cochrane Library, Medline, Embase, Science Citation Index Expanded, Latin American Caribbean Health Sciences Literature, and Cumulative Index to Nursing and Allied Health Literature until March 2011. We also searched abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes Congresses, contacted relevant trial authors and pharmaceutical companies, hand searched reference lists of included trials, and searched the US Food and Drug Administration website.
Review methods Two authors independently screened titles and abstracts for randomised clinical trials comparing metformin and insulin versus insulin alone (with or without placebo) in patients with type 2 diabetes, older than 18 years, and with an intervention period of at least 12 weeks. We included trials irrespective of language, publication status, predefined outcomes, antidiabetic interventions used before randomisation, and reported outcomes.
Results We included 26 randomised trials with 2286 participants, of which 23 trials with 2117 participants could provide data. All trials had high risk of bias. Data were sparse for outcomes relevant to patients. Metformin and insulin versus insulin alone did not significantly affect all cause mortality (relative risk 1.30, 95% confidence interval 0.57 to 2.99) or cardiovascular mortality (1.70, 0.35 to 8.30). Trial sequential analyses showed that more trials were needed before reliable conclusions could be drawn regarding these outcomes. In a fixed effect model, but not in a random effects model, severe hypoglycaemia was significantly more frequent with metformin and insulin than with insulin alone (2.83, 1.17 to 6.86). In a random effects model, metformin and insulin resulted in reduced HbA1c, weight gain, and insulin dose, compared with insulin alone; trial sequential analyses showed sufficient evidence for a HbA1c reduction of 0.5%, lower weight gain of 1 kg, and lower insulin dose of 5 U/day.
Conclusions There was no evidence or even a trend towards improved all cause mortality or cardiovascular mortality with metformin and insulin, compared with insulin alone in type 2 diabetes. Data were limited by the severe lack of data reported by trials for patient relevant outcomes and by poor bias control.
Introduction
Metformin is a glucose lowering drug that, among other mechanisms, is supposed to work by enhancing insulin action mainly in the liver. Metformin is often recommended as the first line drug in patients with type 2 diabetes. Because of disease progression, a substantial proportion of these patients eventually end up on insulin, at which point doctors are recommended to continue metformin use. The rationale behind this combination mainly relates to suggested beneficial metabolic effects, such as reduced blood glucose and body weight.
The United Kingdom Prospective Diabetes Study suggested a beneficial effect of metformin monotherapy, compared with conventional (diet) treatment, on cardiovascular disease and mortality after about 10 years in overweight patients with type 2 diabetes. These findings were partly supported by the Hyperinsulinemia: the Outcome of its Metabolic Effects (HOME) trial comparing combined metformin and insulin versus insulin alone. However, other trials have suggested that metformin combined with sulphonylurea (that is, insulin secretagogues) versus sulphonylurea alone could increase mortality. Thus, the effect of metformin combined with other glucose lowering drugs such as insulin providing regimens on patient relevant outcomes might differ from its effects during monotherapy.
Whether oral glucose lowering drugs should be continued when initiating insulin remains unclear. An insulin sparing effect has been observed when using oral glucose lowering drugs with insulin. However, the progressive nature of type 2 diabetes with its decline in endogenous insulin secretion could result in patients with advanced disease more closely resembling type 1 diabetes, in which adjunct treatment with, for example, metformin, has not proven to improve glycaemic control. Thus, despite international recommendations to use metformin in combination with insulin in patients with type 2 diabetes and therefore the possible widespread use of this treatment regimen worldwide, insufficient and contradictory data exist in the literature to justify this policy.
Previous meta-analyses of glucose lowering drugs have included trials of insulin in combination with various glucose lowering compounds such as metformin, but have not addressed the specific effect of metformin and insulin in this respect. In the light of these considerations and the growing number of patients with type 2 diabetes receiving insulin worldwide, we compared the benefits and harms of metformin and insulin versus insulin alone in randomised clinical trials.
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