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.

Obesity Surgery in Diabetes Mellitus: A Three Year Trial Shows High "Cure Rates." The Implications for Population Health

In case there is any doubt about the long-term efficacy of obesity surgery for diabetes, check out this three year study that was just published by the New England Journal of Medicine. 150 persons between the ages of 20 and 60 years with an A1c greater than the recommended target of 7% and a BMI greater than 27 were randomly assigned to either gastric bypass, sleeve gastrectomy or intensive medical therapy. 8 persons dropped out after being assigned to medical therapy and one patient had their surgery cancelled. Over the next 3 years, 4 persons were lost to follow up.

Of the remaining participants, two thirds were women and three quarters were white. The mean age was 48 years, the average BMI was a prodigious 36 and the mean A1c was a poor 9.3%, with an average duration of diabetes of just over 8 years. 

Of the 40 medical patients, 5% ended up with an A1c of 6%, versus 38% of the 48 bypass and 24% of the 49 sleeve patients.  The average weight loss was 4.3 kg in the medical patients vs. 26 and 21 kg in the bypass and sleeve patients. While only 2% of medically treated patients were able to stop their diabetes medications, 69% and 43% of the bypass and sleeve patients were able to do so. Only four patients in the surgery groups required additional surgery for the treatment of complications.  None died.

The Population Health Blog finds the results compelling enough to believe that the surgical option for obesity-related diabetes mellitus may be turning out to be a first line option.  The complication rate is acceptably low and the "cure" rate of up to 70% (if defined as not having to take medications) is likely to be welcomed by patients facing a lifetime of otherwise chronic illness.

Criticisms?

Critics may worry that any long-term economic benefits at a population-based level may be cancelled by the cost of surgery.  The PHB understands that, but doesn't believe that obesity surgery should be viewed through a "return-on-investment" lens.  Rather, the value assessment of "outcome" (in terms of diabetes and obesity cure) per unit of cost (dollars spent) is a as good as an investment compared to, say, coronary artery bypass grafting or a knee replacement.

Critics may also worry that obesity surgery is more of a symptom of an overfed society and that our national treasure would be better spent on understanding our dietary dysfunctions.  The Population Health Blog cannot disagree, but doubts that our national health spending can be wired so that every dollar spent on the promotion of nutritional wisdom will reduce the near-term health care cost crisis from diabetes.  We need to be prepared to invest in both.

Implications for Population Health

It appears to the PHB that this was a single site "efficacy" study involving an academic medical center.  We don't know if the low complication rate observed here is typical of other hospitals that offer obesity surgery.  In addition, this study did not examine the impact of the more popular approach of banding surgery.  That being said, this three year trial suggests that bariatric surgery should be offered in the suite of options for persons meeting the criteria above.

The good news is that shared decision making has already been evaluated in this setting.  While the majority of participants are more likely to chose conservative treatment, the point is that a 40-70% chance of cure over three years should be raised in the course of patient-centric coaching.  Population health vendors in the diabetes-obesity "space" should be prepared to engage patients on this treatment option and help them decide if surgery is the right choice for them.

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