GLP-1 receptor antagonists suppress post-meal glucose excursions and are compatible with basal insulin; the combination addresses both FPG and PPG.
For nearly a decade since the introduction of the first basal analog insulin, glargine, the dictum in type 2 diabetes mellitus (T2DM) management has been “fix fasting first.” This is a valuable teaching and reflects on the importance of fixing a major defect in glucose control, the fasting blood glucose (FBG). However, emerging data and new, more simple-to-use therapies are raising the question of whether “fix fasting first” is the whole story. Where does “Control the post-meal glucose (PPG)” fit in? Or does it deserve consideration at all early in treatment?
Metformin, a biguanide, largely fixes the fasting glucose. By suppressing hepatic gluconeogenesis through sensitization to insulin action at the level of the liver (and to a lesser extent in the periphery, enhancing glucose disposal), metformin results in exposure to lower glycemic levels in the fasting overnight period. Since it is an oral therapy and does not cause hypoglycemia or weight gain, it is an excellent first agent for treatment of most patients.
As T2DM progresses, basal analog insulin (glargine or detemir) is frequently required, usually added to 1 or more oral agents, to reach a target FBG of 100 to 130 mg/dL. When used properly, basal insulins cause very little weight gain and have low risk of severe hypoglycemia. Newer oral antidiabetic agents, such as the DPP-4 inhibitors and SGLT-2 inhibitors, work in a complementary fashion with metformin and insulin and, again, do not cause hypoglycemia or weight gain.
But despite this healthy armamentarium to combat diabetes, barely 50% of patients reach and maintain the ADA goal A1C of <7%. So with so many great tools, why such a poor track record of control?
“To a man with a hammer, everything looks like a nail”
So said Mark Twain. Has FBG control been an attractive target because so many of our available tools impact it? There is no doubt that our current strategy to fix fasting first has enabled the control of countless patients with T2DM. But what about the roughly equal numbers of patients who have had their FBG fixed but are not at goal A1C? Are we using the right tools on them?
We know that when dosed properly, basal insulin is a lifesaving therapy. Experts in diabetes, however, have increasingly recognized the problem of “over basaling.” This occurs when we over-rely on basal insulin to force the A1C to goal levels (usually with some difficulty). This can result in weight gain, hypoglycemia, and often less than optimal control of blood sugar. “Over basaling” is essentially reliance on a therapy that largely impacts the FBG to correct a problem that is, in part, due to post-meal glucose excursions. It is like using a hammer to drive in a screw.
Several factors should draw our attention to the importance of early control of PPG. PPG excursions are the first manifestation of deteriorating glycemic control. Patients spend many more hours of their day in a post-prandial rather than in a fasting state. By the time diabetes can be diagnosed, there is usually a well-established elevation in both PPG and FBG. Why fix one in preference for the other? To me it makes more sense to fix both together.
While the data on the impact of PPG excursions on diabetic complications is controversial and somewhat limited, studies like the Honolulu Heart Study1 and the DECODE2 trial should give us cause to consider the possible benefit of controlling PPG excursions. In DECODE, for example, at any given FBS level, the complication rate was higher with higher PPG values.
So why have we been slow to treat PPG? I believe it is largely because of uncertainty about use of agents that can lower PPG exclusively, largely the mealtime, or prandial, insulins (ie, lispro, aspart, and glulysine). Primary care physicians do not have much experience with this tool. Practitioners are unsure of how to dose mealtime insulin. They are not sure how many doses per day are needed. There is real concern about causing hypoglycemia and weight gain, and about disrupting the patient’s lifestyle with mealtime injections. It is so much easier to just “fix fasting first.”
No wonder so many patients take so much basal insulin.
Wield a different hammer
New agents on the horizon may resolve some of these concerns. We are learning that the injectable GLP-1 RA therapies are not all alike. Some (such as exenatide weekly and liraglutide) seem to reduce glycemia overall without suppressing post-meal glucose spikes specifically. Others are decidedly more “prandial” in nature, significantly reducing post-meal glucose excursions primarily. The currently available prandial GLP-1 RA is exenatide BID, which does a superb job of suppressing glucose excursion after breakfast and dinner, when it is dosed. Also, now available in Europe is lixisenatide, a once-daily prandial GLP-1 RA that performs much like exenatide but with once-daily dosing and fewer adverse effects. This drug is currently under review by the FDA for approval in the United States.
Results from the GetGoal phase III3clinical trial program with lixisenatide plus glargine and an excellent study by John Buse4 and colleagues examining exenatide added to glargine show significant potential for the combination of a prandial GLP-1 RA and glargine to lower not only FBG, but also PPG excursions, improving A1C levels, getting more patients to goal A1C and doing so with no increase in hypoglycemia or weight gain. So it appears that PPG can be addressed with little or no increase in adverse events or risks.
I think we are looking at the horizon of a day when 2 tools are readily at our disposal to achieve 2 goals-at the same time. We have well-proven basal analog insulin to fix FBG and now prandial GLP-1 RAs that can be combined with basal analog insulin to improve FBG and PPG simultaneously. Fears of mealtime dose calculation are gone, since the prandial GLP-1 RAs are given in fixed doses. Concern about increased hypoglycemia is gone, since these agents have shown no propensity to cause low blood sugar levels. Dread is reduced about possible weight gain with the addition of mealtime therapy, since the prandial GLP-1 RAs are weight neutral or even lead to weight loss.
The prandial GLP-1 RAs are not adverse effect–free, to be sure. Questions are unanswered about the incretin class and causation of pancreatitis and pancreatic cancer (there is little signaling for such problems in clinical use of these drugs, however). There are reports of GI adverse effects, especially (lixisenatide less than exenatide). But many of these adverse effects subside with time.
Overall, the combination of a prandial GLP-1 RA, such as exenatide BID or lixisenatide QD, with basal analog insulin may at last allow us to address FBG and PPG together without undue complication, adverse effects, or difficulty of use. It just seems to make sense to “fix what’s broken” as opposed to just “fixing fasting first.” It seems only intuitive that addressing fasting and post-meal needs simultaneously makes sense to achieve goal A1C. I guess time will tell if my musings are correct.
1. Honolulu Heart Study Program
2. Hyvrinen M, Qiao Q, Tuomilehto J; DECODE Study Group. Hyperglycemia and stroke mortality: comparison between fasting and 2-h glucose criteria. Diabetes Care. 2009;32:348-354.
3. GetGoal Trials Series Summary
4. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154:103-112. doi:10.1059/0003-4819-154-2-201101180-00300.