Insulin for Persons Already on Metformin: A Population Health Perspective

As most population health providers know, diabetes guidelines tend to focus on shorter-term or "intermediate" outcomes, such as average blood sugar levels or A1c levels.  That's because these short-term measures are surrogates for "long term" outcomes, such as blindness and kidney disease.

Two inconvenient facts have complicated the focus on intermediate outcomes:  

1) Once a threshold has been achieved, lower short-term blood glucose control doesn't necessarily lead to better long term outcomes;

2) The side effects of drugs - that otherwise work quite well at achieving short-term blood glucose control - may outweigh any long-term advantages. 

And now a just-published research study from JAMA raises the possibility that insulin has additional long-term side-effects.

According to diabetes mellitus treatment guidelines from organizations like the American Diabetes Association, the first medication option for Type 2 diabetes should be metformin.  If that doesn't work, the ADA suggests that there are several options for a second drug, including one of several sulfonylureas (glyburide, glipizide or glimepiride) or insulin. 

Sulfonylureas are pills, but have a reputation for not leading to the same level of diabetes control as insulin.  Unfortunately, while it's a more potent means of blood glucose control, insulin has to be injected.

Further details on the methodology are below.* Basically, Veterans Affairs electronic records were "mined" to find thousands of persons with diabetes who were using metformin and then had to start either insulin or a sulfonylurea.  Propensity scoring was then used to create two otherwise similar cohorts of patients and neutralize the impact of the diabetes control and disease burden.

2436 patients on metformin and insulin were compared to 12,180 patients on metformin and a sulfonylurea. 

After a median of 50 months of observation, the risk of a heart atttack, stroke or death from all causes was 43 per 1000 person-years in the insulin group vs. 33 in the sulfonylurea group.  That difference was statistically significant.  When deaths alone were examined, there was likewise an increased number in the insulin group (34 per 1000 person years) vs. the sulfonylurea group (23 per 100 person years).

The Population Health Blog's take:

This study raises the possibility that, among persons with diabetes on metformin, insulin is associated with an increased absolute risk of about 1 per 100 person years (10 per thousand person years, or one person out of a hundred persons followed for one year) of heart attack, stroke or death vs. the sulfonylurea pill.  Yikes.

Before we ban insulin in this population, however, the PHB is reminded that this was an observational study.  As an accompanying editorial points out, propensity scoring is not perfect and other unmeasured and confounding factors in the population could be biasing the results.  Short of a randomized clinical trial, there are other databases that could be mined the same way.  That includes those of the population health vendors, who also have a stake in risk stratification and long-term follow-up.

In the course of coaching persons with diabetes on metformin who are considering insulin, the additional risk of heart attack, stroke or death should be raised.  While the study above isn't perfect, the possibility is something that health care consumers need to weigh.

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*Methodology:

Veterans 18 years and older who.....

1) were followed for at least two years with provider visits every 6 months,

 2) who had been placed on metformin and regularly used it between 2001 and 2008,

3) had one year of records prior to the first prescription for metformin and

4) were not on dialysis or in hospice

Once a vet filled a prescription for either insulin (long acting, premixed or short/long acting) or a sulfonylurea (glyburide, glipizide or glimepiride) and continued it for 6 months, their records became eligible for the study.  Patient records were excluded if there was no follow-up for six months, if the meformin was stopped for 3 months or a third diabetic drug was prescribed.

52% (approximately 92,000) of the 178,000 vets on metformin did not use another medicine.  Most were men (95%) and white (70%).  2948 were started on insulin and 39,990 started a sulfonylurea. The persons placed on insulin had, on average, worse diabetes control (A1c 8.5% vs. 7.5%) and a higher disease burden.