Metformin and Insulin Combo Cuts Mortality in Type 2 Diabetes

Alexander M Castellino, PhD

May 16, 2016

A new retrospective study indicates that, in type 2 diabetes, treatment with insulin is safer when it is used together with metformin.

In the research, recently published in PLoS One, a team from Cardiff University, Wales, showed that patients on insulin and metformin were at a significant 40% reduced risk for death and a significant 25% reduced risk for major adverse cardiac events (MACE) compared with those treated with only insulin. However, the combination was not significant in reducing cancer.

"If at all possible, patients with type 2 diabetes initiated on insulin should also be given metformin," senior author Craig Currie, PhD, professor of applied pharmacoepidemiology, Cardiff University, Wales, told Medscape Medical News.

Asked to comment, Jason Baker, MD, assistant professor in clinical medicine and attending endocrinologist at Weill Cornell Medicine, New York, told Medscape Medical News: "These results from a retrospective analysis are not surprising and support what we already know. It is reassuring and a reminder that insulin alone may not be appropriate for some of our patients."

Dr Baker has been in endocrinology practice for 15 years, has type 1 diabetes himself, and treats patients with type 1 as well as type 2 diabetes.

The Cardiff Study

The Cardiff researchers used the Clinical Practice Research Datalink, which collects longitudinal data from 660 participating primary-care practices in the United Kingdom.

Intensive management of patients with type 2 diabetes often involves using insulin alone or in combination with other glycemic medications.

Data were collected from January 2000 to January 2013 for patients with a diagnosis of type 2 diabetes, those with prescriptions written for at least two classes of glucose-lowering medications besides insulin, or those with a diagnosis of type 2 diabetes and a prescription for glucose-lowering medications besides insulin.

Patients were excluded for secondary diabetes, an insulin dose of more than 4 units/kg/day, no recorded weight, and history of large-vessel disease or cancer.

Primary outcome measure was all-cause mortality; secondary end points included incident MACE (myocardial infarction or stroke) and incident cancer (excluding nonmelanoma skin cancer).

Due to an imbalance in baseline characteristics, an analysis was also undertaken in patients with matching propensity scores.

First Study to Account for Insulin Exposure, Matched by Propensity Score

Of 12,020 patients with type 2 diabetes who progressed to insulin alone or in combination with metformin, 5536 were prescribed insulin and metformin and 6484 were prescribed insulin alone. Patients were followed for a median of 2.5 years.

Baseline characteristics showed that patients treated with insulin and metformin were younger (median, 61 years vs 67 years for insulin alone; P < .001) and had a higher mean body mass index (31.2 kg/m2 vs 28.2 kg/m2 for insulin alone; P < .001) and lower median serum creatinine levels (83.0 vs 95.0 µmol/L for insulin alone; P < .001); and that fewer patients on the combination therapy had a history of large-vessel disease (14% vs 27%; P < .001) and cancer (8% vs 12%; P < .001).

The researchers note these differences in baseline characteristics and observed: "[The] population of people receiving insulin in combination with metformin may be healthier than the monotherapy group."

Also figuring into the mix is the fact that metformin is contraindicated in patients with severe renal impairment. In their discussion, the researchers note that "28% of patients in the insulin-monotherapy group had a prior history of renal disease vs 18% in the insulin-plus-metformin group."

With patients prescribed insulin alone used as a referent group, the hazard ratio (HR) for all-cause mortality for the combination of insulin and metformin was 0.60; this trend persisted for many of the subgroups analyzed, including by gender, age, Charlson comorbidity index, baseline HbA1c, BMI, and duration of diabetes. For patients matched by propensity score, the trend persisted (HR, 0.62).

Patients prescribed insulin and metformin were also at a reduced risk for MACE (HR, 0.75) compared with those on insulin alone. For subgroup analysis, the data mirrored those seen for all-cause mortality.

However, significance was not documented for MACE for an analysis of patients matched by propensity scores.

In patients receiving insulin alone, the researchers noted that those prescribed high-dose insulin were at a 28% increased risk for all-cause mortality compared with those receiving low-dose insulin; the risk for MACE was not significantly reduced for the low-dose group.

Dr Currie and colleagues note, "To our knowledge, this is the first study to account for insulin exposure and to match the cohorts by propensity score."

Implications for Practice: Trend to Using Insulin With Metformin

"While this research indicates the potential benefits of using insulin in combination with metformin, we hope it will persuade investigators to undertake randomized studies to corroborate these results," Dr Currie told Medscape Medical News.

There has already been a trend toward a decreasing use of insulin monotherapy over the past decade, he and his colleagues point out.

They note that in the United Kingdom, the rate of insulin use has increased more than sixfold between 1991 and 2010. While insulin was used mainly as monotherapy in 1991, in 2010, 42% of patients were prescribed insulin in combination with metformin, with insulin monotherapy use decreasing to 37% of patients.

And based on information from the Centers for Disease Control and Prevention (CDC), in the United States, the percentage of patients with diabetes who were prescribed insulin only decreased from 26% in 1997 to 17.8% in 2011 and the percentage for those prescribed insulin and pills increased from 9.1% to 13%.

However, the number of patients taking medications for diabetes more than doubled during the same time period — from 8.4 million in 1997 to 17.7 million in 2011.

"It is a tragedy that we are still asking questions about commonly used drugs," Dr Currie said. "These risks and benefits should not be emerging decades after the drugs have been introduced," he stressed.

However, the treatment goals for patients with type 2 diabetes have also changed since the 1990s.

In a "Guidance for Industry" document, the US Food and Drug Administration (FDA) noted that in the past century treatment focused on reducing the risk of diabetic complications such as retinopathy, nephropathy, and neuropathy.

Whereas in the past decade, type 2 diabetes has been recognized as a cardiovascular risk equivalent by major organizations, including the American Heart Association, the American Diabetes Association (Circulation. 2015;132:691-718), and the European Society of Cardiology (Eur Heart J. 2013;34:3035-3087).

That's why in 2008, the FDA mandated that all new agents need to demonstrate that "therapy [for type 2 diabetes] will not result in an unacceptable increase in cardiovascular risk."

Endocrinologists Aware of Protection Offered by Metformin

Dr Baker explained that endocrinologists are aware of the protection offered by metformin. "In my own practice, less than 1% of type 2 diabetes patients are on insulin alone," he said.

He explained that there is a "style to treating diabetes."

Some physicians veer toward early use of insulin. And in the primary-care setting — which is where a lot of type 2 diabetes is treated — when patients are not adequately controlled, other medications are often withdrawn when insulin therapy is initiated, he pointed out.

In the setting of type 1 diabetes, less is known. With only insulin and pramlintide (Symlin, AstraZeneca) officially approved in this setting, the options are fewer, Dr Baker indicated.

In appropriate settings, metformin is sometimes prescribed off-label to type 1 diabetes patients, he told Medscape Medical News. These situations arise when glycemic control is not adequate or when a patient is overweight or is not controlled on high-dose insulin.

"This study is a reminder that it is important to individualize diabetes care for better control and risk reduction," Dr Baker said.

The authors report no relevant financial relationships. Dr Baker is a consultant for Sanofi and a speaker for Boehringer Ingelheim, Lilly, and Insulet.

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PLoS One. Published online May 6, 2016. Article

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