Beyond Glycemic Control and Weight Reduction: Benefits of Dual Agonists for GIP and GLP-1

Key Takeaways:

• Reducing weight in patients with type 2 diabetes decreases the risk for complications of excess weight and other comorbidities and the need for medications to treat them.
• Updated ADA/EASD recommendations emphasize putting the patient at the center of the therapy selection decision-making process and considering both their comorbidities and their priorities.
• The ADA/EASD recommend that—with the exception of patients with cardiovascular disease and chronic kidney disease—tirzepatide now can be used whenever a GLP-1 is indicated in the treatment of type 2 diabetes, particularly for those in whom A1C and weight reduction are the primary targets.

Role of Incretins in Management of Glucose Homeostasis
Incretin hormones have several actions that help control glucose levels, especially in the postprandial period. Of most importance, via stimulation of insulin secretion, incretins are responsible for approximately 75% of the insulin that is secreted in the postprandial period. Until this year, we had the dipeptidyl peptidase-4 inhibitors, which show modest increases in incretin hormones and a modest reduction in A1C, and the more potent glucagon-like peptide-1 (GLP-1) receptor agonists, which until recently were the most effective incretins for lowering A1C and weight. Glucose-dependent insulinotropic polypeptide (GIP) is another incretin, and in normal individuals, GIP is responsible for approximately 45% of postprandial insulin secretion.

Tirzepatide
The dual incretin coagonist tirzepatide is a single peptide that activates both the GLP-1 receptor and the GIP receptor, with resultant synergistic effects on insulin secretion and glycemic control. Studies with tirzepatide showed reductions in A1C of 2.3% to 2.6% when added to background orals and/or insulin, which was significantly greater compared with insulin and a GLP-1 receptor agonist. Although the mechanism for its impact on weight loss is not completely understood, the weight reduction seen with tirzepatide in the SURPASS studies also was significantly greater than any of the comparators, which included semaglutide (1 mg). There also were significant improvements in multiple cardiovascular risk factors, including blood pressure, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, as well as a 25% reduction in triglycerides and a reduction in inflammatory markers. We have not seen the results of the cardiovascular outcome trial yet, but it is fully enrolled, and we expect to hear those results when enough events have been reported.

The SURPASS-2 Study
In the past, most of the antihyperglycemic medications studied in clinical trials showed a reduction in A1C of 0.6% to 1.5%, and approximately 50% of patients achieved their A1C goal of <7.0%. In the open-label phase III SURPASS-2 study, the 3 doses of tirzepatide were compared with semaglutide 1 mg. The mean A1C levels were 0.6% lower with the highest dose of tirzepatide, and that A1C reduction was approximately 2.4%. Impressively, 92% of participants reached an A1C <7.0%, and 50% reached an A1C of <5.7%, which is a level that is considered normal. Semaglutide did well, with approximately 80% of patients reaching their A1C target—but again, we are entering an era of using these powerful medications where we can assume that most of our patients will be able to achieve an A1C of <7.0% and 50% may be able to normalize their glucose levels.

In general, we know that only approximately 50% of our patients with type 2 diabetes (T2D) are reaching their glycemic targets, and because more than 80% of these patients have excess weight or obesity, I think we need to have more effective treatments for lowering glucose and improving weight.

Long-term Benefits From the UKPDS
These results with tirzepatide are particularly exciting, given what we now know about the downstream effects of early glucose control. The importance of glycemic management for prevention of complications of diabetes has long been known but has now been emphasized with the 44-year follow-up data of the landmark United Kingdom Prospective Diabetes Study (UKPDS), presented at the 2022 European Association for the Study of Diabetes (EASD) Annual Meeting. Professor Holman and colleagues demonstrated an ongoing legacy effect of 10 years of more intensive glycemic control, followed by 34 years, at which point patients’ A1Cs tended to equilibrate. The important aspect of this study is that the first 10 years of the intervention have an impact 30 years later, and they were able to show a 15% reduction in myocardial infarction and a 26% reduction in microvascular complications. Of interest, both the all-cause mortality and the reduction in myocardial infarction were even greater in the metformin subgroup, with a 31% reduction in myocardial infarction and a 25% reduction in all-cause mortality, and this was despite there being less impact on glycemia. The patients receiving metformin had higher blood sugar, with greater impact on measures of myocardial infarction and all-cause mortality, but there was no significant difference in microvascular complications.

The investigators surmise that a drug-related benefit beyond glycemic control, such as reduction in inflammation, might help lower the risk of macrovascular complications and give additive benefit. I think this is important as we talk about these other agents that have beneficial effects on weight, and the GLP-1 receptor agonists also have a beneficial effect on myocardial infarction over a much shorter period of time. Based on this study, I think these medications have the potential for giving us ongoing benefits over the years.

Weight-Loss Benefits: The LookAHEAD Study
In addition to glucose management, we know that weight loss carries its own benefits for patients with T2D. The primary endpoint of showing a benefit of weight reduction on cardiovascular outcomes was not met in the multicenter, randomized LookAHEAD study (N = 5145), which was designed to examine the long-term effects of lifestyle interventions on patients with T2D and overweight. However, the importance of weight reduction was demonstrated by several important outcomes, including a higher rate of remission from diabetes, lower rates of neuropathy and kidney problems, improvement in depression, improvement in physical quality of life, decreased risks for development of frailty, and improvement in sleep apnea, urinary incontinence, nonalcoholic fatty liver disease, and disability and mobility. There also was an improvement in brain volume and a reduction in healthcare use and costs. I think these findings—in addition to what we know weight loss can do to cardiovascular risk factors—are important considerations, because many of our patients have most, if not all, of those comorbidities to go along with their diabetes and weight issues.

In the LookAHEAD study, it is important to mention that a subanalysis demonstrated a 21% reduction in cardiovascular events among patients who were able to lose more than 10% of their body weight. Therefore, when we see the impact that tirzepatide has on weight, we would surmise that weight loss alone should benefit a person’s cardiovascular outcome, perhaps over a longer time period than is typically done in a clinical trial. With a 10% or greater weight loss, we see progressive improvement in sleep apnea and a decrease in fibrosis when a patient has nonalcoholic steatohepatitis.

These data emphasize the importance of considering the benefits of weight loss on the multiple comorbidities of excess weight in our patients with diabetes, so we should consider this benefit when we select therapies for our patients with T2D and overweight.

Updated Recommendations From the ADA/EASD
I would like to recommend that you read the newest American Diabetes Association (ADA)/EASD treatment recommendations for antihyperglycemic therapy and T2D, which emphasize the considerations discussed above.

It is highly recommended that we put the patient at the center of the decision-making process and consider their comorbidities and priorities (eg, weight loss, avoidance of hypoglycemia, or avoidance of injections) when helping select therapies.

The recommendations continue to suggest that we consider cardiovascular disease, chronic kidney disease, and heart failure as an initial first step in determining treatment and apply evidence-based therapies that show improvement in these areas. However, in the absence of these compelling indications, you should consider A1C and weight. The recommendations elevate consideration of the patient’s weight and of selecting medications that have beneficial effects on weight.

It is recommended that therapies be selected that are most effective for your given goal. The authors present the ranking of the highest to the lowest efficacy for A1C and then separately for weight. Of interest, both tirzepatide and semaglutide were highlighted as the most effective not only for A1C lowering, but also for weight reduction.

The recommendations for selecting agents with the most powerful reduction in A1C also were related to the potential for durability for good glucose control. This gets back to the UKPDS data suggesting that if we can keep blood sugar controlled longer, the patient’s treatment will be simplified, limiting the need for additional medications and likely giving them additional long-term health benefits.

Because the cardiovascular outcome trial for tirzepatide has not been reported, we cannot consider tirzepatide as a substitute for GLP-1 receptor agonists in our patients with cardiovascular or chronic renal disease, but it will be interesting to see those results when they become available.

Final Thoughts
We have understood the importance of tight glycemic control for a long time. With the consideration for weight becoming more of a priority, many of us are emphasizing the importance of weight for the overall health of our patients with diabetes.

Incretin therapies are the most effective at both A1C reduction and weight reduction, and the dual agonist tirzepatide has even greater impact than a GLP-1 receptor agonist alone on these measures. With the exception of patients with cardiovascular disease and chronic kidney disease, tirzepatide can now be used whenever a GLP-1 receptor agonist is indicated in the treatment recommendations.

Your Thoughts?
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