Will Insulin Treatment Disappear in Type 2 Diabetes?

 Whether "insulin-free type 2 diabetes" is either "coming" or "nonsense" was the topic of a debate at the recent European Association for the Study of Diabetes 2022 Annual Meeting.

Bruce H.R. Wolffenbuttel, MD, PhD, argued the "nonsense" view, given the heterogeneity and progressive nature of type 2 diabetes, while Apostolos Tsapas, MD, PhD, expressed confidence that newer approaches will eventually render insulin treatment unnecessary for people with type 2 diabetes.

According to Wolffenbuttel, insulin will always be necessary for some patients with type 2 diabetes because the condition is "characterized by both increased insulin resistance and reduced insulin secretion, but reduced insulin secretion is a basic feature in many, has a strong genetic background, and further decreases over time."

But Tsapas argued that one of the strongest arguments in favor of abandoning insulin in type 2 diabetes is the recent shift away from glucose-lowering to cardiovascular outcomes as the main focus of treatment.

Insulin Secretion Decreases Over Time

Wolffenbuttel cited several studies demonstrating the fact that insulin will always be needed in type 2 diabetes, including the landmark United Kingdom Prospective Diabetes Study (UKPDS), in which insulin secretion was already reduced by 50% at the time of diagnosis.

And he emphasized that the condition is heterogeneous. In one study that separated out the roughly 6% of individuals with autoimmune diabetes (type 1 diabetes) or other rare subtypes, about 10% of those with World Health Organization-defined type 2 diabetes were insulinopenic, with high insulin sensitivity and low beta-cell function, while another 61% were "classical," with low insulin sensitivity and low beta-cell function. Just 27% were hyperinsulinemic and tended to be severely obese.

And in another study that identified five phenotypic subgroups of diabetes, by 5 to 6 years, insulin treatment was required by some among all five clusters, including by 5% to 8% of those with insulin-resistant and obesity-related subtypes.

"Among those with obesity there is a subgroup who are insulin deficient at onset and need insulin replacement rather soon. So, it's a false conclusion to say that everyone with type 2 diabetes who is obese is insulin sufficient," said Wolffenbuttel, professor of endocrinology and metabolism at the University of Groningen, The Netherlands,

Indeed, another recent study identified forms of type 2 diabetes in which at least 30 genes were associated with low insulin secretion and lower body mass index compared to those with genes associated with insulin resistance and obesity. "It's very logical that these people will need insulin replacement therapy early in the course of their disease," he commented.

However, he said, those with severe insulin resistance may be able to postpone their need for insulin. This was done using a very low-calorie diet in one study, the UK (Diabetes Remission Clinical Trial (DiRECT) trial.

And the use of newer glucose-lowering drugs, particularly glucagon-like peptide-1 (GLP-1) agonists, can accomplish this as well through weight loss, Wolffenbuttel observed.

"When we start treatment, we want weight reduction as much as possible, but still, at this moment, we don't know the natural course during treatment. It may well be that certain patients need insulin right away while others will respond to GLP-1 agonists with a reduction in body weight and improvement in glycemic control and can postpone insulin treatment for a long period of time," he said.

Of course, given that insulin is associated with weight gain and hypoglycemia, he advised: "Be as restrictive with insulin as possible, and if people need insulin treatment, continue to use all measures, like lifestyle, like regular exercise, to minimize the amount of insulin people need to achieve optimal glycemic control...Limiting weight increase is essential."

Other Therapies Will Bypass the Need for Exogenous Insulin 

Tsapas began by summarizing data regarding the major drawbacks of insulin therapy, namely weight gain and hypoglycemia, and results showing that other agents, GLP-1 agonists, in particular, are associated with weight loss and not with hypoglycemia, compared to insulin. This was confirmed in several meta-analyses, including one from Tsapas' group published in May 2021.

And in the Treating to Target in Type 2 Diabetes (4-T) trial, for example, insulin therapy was associated with weight gain regardless of regimen (basal alone, basal-bolus, or split-mixed).  

Weight loss, in turn, can lead to type 2 diabetes remission, as in the DiRECT study, which used meal replacements, noted Tsapas who is professor of medicine and diabetes at Aristotle University of Thessaloniki, Greece.

Numerous studies have also linked insulin therapy to hypoglycemia in type 2 diabetes, including the Outcome Reduction With an Initial Glargine Intervention (ORIGIN) trial, while GLP-1 agonists are associated with far less hypoglycemia with equivalent or improved effect on glycemic control.

"I think it's obvious that, irrespective of the trial, the use of a GLP-1 agonist is associated with at least as good reduction of A1c as with insulin," Tsapas commented.

And the Qatar study showed the benefit of triple therapy using the GLP-1 agonist exenatide plus pioglitazone versus basal-bolus insulin in patients with long-standing type 2 diabetes insufficiently controlled with metformin plus a sulfonylurea.

"The non-insulin group achieved more durable glycemic control…Non-insulin was more efficacious than insulin," he noted.

"We're experiencing a paradigm shift where we're living in an outcomes rather than glucose-centered universe where the cardiovascular outcomes are much more important," he added.

He pointed to the well-described cardiovascular outcomes trials of GLP-1 agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors as evidence that these agents are strongly associated with cardiovascular benefit, to a far greater degree than insulin.

The evolution of type 2 diabetes management guidance from the American Diabetes Association (ADA) and EASD has reflected the diminishing role of insulin therapy from a solid second-line after metformin, when the first ADA/EASD consensus statement came out in 2006, to the most recent one, discussed at the current meeting, in which it's placed further down in the treatment algorithm.

Tsapas also listed several emerging treatments that could even further diminish the role of insulin in type 2 diabetes, including verapamil, metabolic endoscopy procedures such as Orbera and EndoBarrier, bariatric surgery, and even stem cell-derived islet cell transplants.

"Insulin-free treatment is coming...because insulin treatment has clinically important disadvantages compared to other glucose-lowering medications, and these days, we're living in a cardiovascular outcomes universe," Tsapas reiterated.

Further, he said that insulin "is not the most cost-effective option. It's not the most efficacious option...and efficacious non-insulin therapies exist or are being developed that bypass the need for exogenous insulin."

Tsapas has reported being an advisor to and/or researcher for Boehringer Ingelheim, Novo Nordisk, and Eli Lilly. Wolffenbuttel has reported being a researcher, consultant, advisor, and/or speaker for JDRF, Diabetes Fonds NL, Novo Nordisk, Roche, Sanofi, AstraZeneca, Boehringer Ingelheim, Ascensia, Ancora Health, and Nuevo Care.

The debate took place September 22 at the EASD 2022 Annual Meeting.

https://www.medscape.com/viewarticle/981561