An African-American Man with Type 2 Diabetes and Obesity

• Diagnosis 5 years ago, with an A1C of 6.7%
• Initially able to control his diabetes with exercise and improvement to his diet
• A1c of 7.8% 2 years following diagnosis
• Started on glipizide ER, 5 mg daily
• Glipizide ER increased 3 months later to 10 mg daily
• A1c of 8.4% 2 years later (4 years following diagnosis) with weight gain of 15 pounds
• Metformin added to glipizide ER regimen, started at 500 mg to minimize gastrointestinal (GI) effects
• Metformin titrated up to 1000 mg twice daily
• Mr. Slayton has now been on the glipizide ER plus metformin regimen for 1 year.
• In addition to diabetes, he has a 20-year history of dyslipidemia and an 18-year history of hypertension.
• Mr. Slayton works as a high school English teacher and is married with 3 grown children. His father had type 2 diabetes and died of cardiovascular disease (CVD) at age 57 his mother is currently treated for hypertension but is otherwise healthy. When Mr. Slayton was first diagnosed, he played golf regularly. He was forced to stop due to chronic back pain, and has not found another exercise activity he enjoys.
  He and his wife met with a dietitian once when he was first diagnosed, but he has not had any recent diabetes education. He states that his wife made some dietary changes at home after his diagnosis, but they still eat out for many meals and have slipped back into familiar eating patterns.
• Mr. Slayton is concerned that he will need to start on insulin. Although he is not fearful of injections, he has read that insulin may lead to weight gain -- he does not want to gain more weight because he is afraid it may worsen his back pain and increase his CVD risk.  

Which pharmacologic therapy options for type 2 diabetes would best meet Mr. Slayton's goal of improving his glycemic control without causing weight gain?

1.       Thiazolidinedione (TZD)

2.       Dipeptidyl peptidase-4 (DPP-4) inhibitor

3.       Glucagon-like peptide-1 (GLP-1) receptor agonist

5.       Either a DPP-4 inhibitor or a GLP-1 receptor agonist

Either a DPP-4 inhibitor or a GLP-1 receptor agonist could be considered as a treatment option for Mr. Slayton to bring his glycemic control closer to goal.

DPP-4 inhibitors act to enhance endogenous GLP-1, an incretin hormone, by decreasing its inactivation by the DPP-4 enzyme, thereby elevating active GLP-1 levels. 

 GLP-1 receptor agonists mimic the physiologic actions of the incretin hormone GLP-1.

Either a DPP-4 inhibitor or a GLP-1 receptor agonist could be considered as a treatment option for Mr. Slayton to reduce his glycemic control closer to goal.

• be weight neutral, with little to no effect on body weight
• have a low incidence of hypoglycemia and other side
• improve both fasting and postprandial hyperglycemia

Although Mr. Slayton has not been checking postprandial glucose levels, his fasting glucose average of 155 mg/dL is relatively low when compared to his A1C of 8.1%. This is in line with the results of a study by Monnier, et al, which showed that when the A1C is <8.4%, the relative contribution of postprandial glucose elevations to overall diurnal hyperglycemia is greater than the contribution from fasting glucose. Thus, Mr. Slayton may benefit from a medication that is effective at treating postprandial glucose elevations. 

Benefits of a DPP-4 inhibitor include an oral formulation, once-a-day dosing, and a low incidence of side effects -- but the medication is not available in generic form and is therefore more expensive than some other medications available to treat type 2 diabetes.

DPP-4 inhibitors are included as a part of the American College of Endocrinology (ACE)/AACE Roadmap to maximize therapy for patients with an A1C between 6.5% and 8.5%.

Either a DPP-4 inhibitor or a GLP-1 receptor agonist could be considered as a treatment option for Mr. Slayton to reduce his glycemic control closer to goal.

• decrease appetite
• reduce body weight (a long-term observational study by Klonoff, et al. showed progressive weight loss
• reduce both fasting and postprandial glucose elevations
• have a low rate of hypoglycemia
• improve some CVD risk factors, such as hypertension and dyslipidemia

GLP-1 agonists are not approved as monotherapy but can be given as combination therapy with a TZD, a sulfonylurea, or metformin, or as add-on therapy for patients taking a combination of a sulfonylurea and metformin, or metformin and a TZD. Liraglutide requires once-daily injection. 

Although GLP-1 agonists have a relatively high frequency of GI side effects such as nausea, these effects are mild-to-moderate in intensity and only ~5% of patients stop using it for that reason. GI side effects are reduced by initiating the medication at a low dose and titrating it up slowly. 

Either a DPP-4 inhibitor or a GLP-1 receptor agonist could be considered as a treatment option for Mr. Slayton to reduce his glycemic control closer to goal.

TZD - Although a TZD (such as pioglitazone or rosiglitazone) would likely improve Mr. Slayton's glycemic control, a common side effect is weight gain. A TZD in combination with metformin may not result in marked weight gain, but this medication class may not be the best choice for Mr. Slayton since weight loss is one of his primary goals.

Insulin – Although insulin would be very effective at improving Mr. Slayton's glycemic control, it may promote weight gain. This medication would not be the best treatment option for him at this time considering his goal of weight loss.

Based on Mr. Slayton's initial presentation and laboratory values what treatment options would you recommend to treat his hyperglycemia and minimize weight gain?

1.       Discontinue glipizide ER, continue metformin 1000 mg twice daily, and add basal insulin once daily

2.       Continue metformin 1000 mg twice daily, decrease glipizide ER to 5 mg daily and add a GLP-1 agonist

3.       Continue metformin 1000 mg twice daily and glipizide ER 10 mg daily and add sitagliptin 100 mg daily

4.       Either answer "2" or "3" would be appropriate

Question 2 Explanation:

Two treatment options (a GLP-1 agonist or a DPP4 inhibitor) are equally appropriate as add-on therapy to this patient's current glipizide ER and metformin medications.

The addition of either a GLP-1 receptor agonist or a DPP-4 inhibitor would be acceptable treatment options for Mr. Slayton to meet his goal of improved glycemic control without weight gain. Mr. Slayton and his physician can decide which treatment option is best after discussing the pros and cons of each medication regimen.

Metformin - Continuing metformin is a good decision for Mr. Slayton since he is tolerating it well, it is inexpensive, and the medication generally has a neutral effect on body weight. 

Glipizide ER - Mr. Slayton did have a weight gain of 15 pounds in the first 2 years after starting glipizide ER but he has not gained additional weight since starting metformin a year ago. He can continue on glipizide ER with the addition of sitagliptin or exenatide, but a dose reduction is generally recommended when exenatide is added to a sulfonylurea, due to an increased risk of hypoglycemia reported in clinical testing. 

Two treatment options (a GLP-1 agonist or a DPP4 inhibitor) are equally appropriate as add-on therapy to this patient's current glipizide ER and metformin medications.

Rationale for the treatment option not recommended at this time

Insulin - Although continuing Mr. Slayton on metformin is a good decision, since he is tolerating it well and the medication generally has a neutral effect on body weight, adding insulin could lead to weight gain. Mr. Slayton might also benefit from a medication that is more effective on postprandial glucose elevations than basal insulin.