Diabetes Research: Groundbreaking

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Diabetes ResearchDiabetes Research is Groundbreaking!

American Diabetes Association Congress: Individualization at All Levels of Treatment

Patients should set glycemic targets based on individual characteristics and priorities as diabetes progresses.

New data and studies commentators say are “groundbreaking.”

The American Diabetes Association 2021 (ADA) Virtual Convention offered much. The target group were not only diabetologists but also care of people with type 2 diabetes.

Personalized goals for patients with type 1 diabetes

To date, national and international guidelines on type 1 diabetes are only based on evidence derived from type 2 studies. “Of course, we have guidelines for the management of people with type 1 diabetes, but this is mostly mixed up with broader recommendations that focus on type 2 diabetes,” stated Anne L. Peters, Keck School of Medicine, Los Angeles.

European and American diabetes societies have now joined forces to finally develop their “own” evidence-based recommendations for type 1 diabetes. The final version was presented at the EASD Congress at the end of September (see article below). There was already a foretaste at the ADA Congress.

What is the latest research on diabetes?

Individualization is the keyword at all levels. Diabetes starts with the glycemic target values. It should be set for each patient according to individual characteristics and priorities. But it can change as the disease progresses. HbA1c remains a vital parameter; and is complemented by other metrics such as pre-and postprandial blood glucose, time in range and glycemic variability. For most patients, an HbA1c target below 7% is adequate. “But any reduction in HbA1c is beneficial, even if the target cannot be reached,” emphasized Peters.

Insulin should mimic the physiological situation as best as possible and allow those affected a high degree of flexibility in everyday life, including concerning nutrition and physical activity, explained Sue Kirkman, University of Chicago. The consensus report recommends insulin pumps or multiple daily jabs, preferably with insulin analogues. Continuous glucose monitoring and closed-loop systems are rated even better, but they are unavailable everywhere and cause significantly higher costs.

With a separate chapter, the report acknowledges the high psychosocial and mental stress that type 1 diabetes poses to those affected, reported Frank J. Snoek, University of Amsterdam. “Emotional health is an important outcome of diabetes, and it requires a personal approach,” says the medical psychologist.

To support people with type 1 diabetes, physicians should specifically develop their professional skills to talk about problems with self-management and coping with emotional and social burdens.

Diabetic Nephropathy: KDIGO gives detailed recommendations

EASD and ADA address diabetic nephropathy as part of their recommendations for managing type 2 diabetes.

KDIGO (Kidney Disease: Improving Global Outcomes) has devoted its 120-page guideline to it — Almost anyway, because according to the focus of the international organization, the topic is not “kidney damage in diabetes” but “diabetes management in chronic kidney disease”. 

Diabetes ResearchThe KDIGO makes no distinction between type 1 and types 2 diabetes.

The guidelines agree on many core aspects, emphasized John B. Buse, University of North Carolina, Chapel Hill. The standard is that people with diabetic kidney damage should receive a RAS inhibitor, especially if they also have hypertension, as is often the case. The amount should be up to the maximum, and the blood pressure should be lowered to at least below 140/90 mmHg — if the patient can tolerate it, it can be lower. According to KDIGO, an increase in creatinine under RAS inhibitor can be tolerated if it does not exceed 30% in 4 weeks and there is no volume depletion.

Is There Diabetes Research?

Irrespective of the initial and current HbA1c value, antihyperglycemic pharmacotherapy now includes an SGLT2 inhibitor. It is an indispensable partner in addition to metformin as long as the eGFR is at least 30 ml/min. 

According to the unanimous opinion of the guideline authors, the best evidence of nephroprotection exists for gliflozine. Buse pointed out that the eGFR can drop at the beginning.

However, this is no reason to discontinue the SGLT2 inhibitor, as kidney performance stabilizes over the long term. If the patient does not tolerate the SGLT2 inhibitor or if there are contraindications, a GLP1 receptor agonist should preferably be prescribed for further blood sugar reduction. In the case of SGLT2 inhibitors such as GLP1-RA, active substances should be chosen whose cardio-renal benefit has been demonstrated in high-quality endpoint studies.

Top Antidiabetics in a head-to-head Comparison

Metformin was in place as first-line treatment, but it was unclear which antidiabetic would be best for second-line. It looked like when GRADE (Glycemia Reduction Approaches in Diabetes) was conceived in 2009 and launched in 2013. The industry-independent head-to-head study could serve as a model for a realistic study design. Unfortunately, the reality was not the case.

Is Triple the Optimum for Type 2 Diabetes?

According to Ralph A. DeFronzo, the University of Texas at San Antonio, there is a clear answer to the best treatment for type 2 diabetes.

-The triple combination of SGLT2 inhibitor, GLP-1 receptor antagonist (GLP1 RA) and pioglitazone

-No single antidiabetic has been able to combat all of the metabolic disorders that underlie type 2 diabetes

-The three active substances/active substance classes mentioned intervene in practically all central mechanisms of diabetes pathogenesis, explained De Fronzo.

How Likely is a Cure for Diabetes?

SGLT2 inhibitors slow down the increased glucose reabsorption in the kidney, improve beta cell function and increase glucose uptake in the muscles. 

GLP1-RAs complement this by increasing insulin secretion, slowing down glucagon secretion and exerting beneficial effects on liver and neurotransmitter function — key words: appetite and satiety. 

Thiazolidinediones such as pioglitazone are the only actual insulin sensitizers. Still, they have fallen into disrepute because of weight gain, especially since the positive effects on beta cell function, insulin sensitivity and HbA1c are more significant the more the patient gains weight. The triple combination with SGLT2 inhibitor and GLP1-RA can counterbalance the weight effect of pioglitazone. It does this without counteracting metabolic effects.

All three combination candidates reduce not only hyperglycemia-related microvascular complications but also provide cardiovascular protection, DeFronzo noted. 

The evidence for SGLT2 inhibitors and GLP1-RA is more solid than for pioglitazone, for which there are no studies with cardiovascular complications as the primary endpoint.

SGLT2 inhibitors reduce the risk- presumably primarily via haemodynamic effects — in addition to the known weight and blood pressure effects—the reduction in sympathetic tone and the increased availability of ketones as an energy source in the myocardium. 

In addition to reducing weight, blood pressure and lipids, GLP1-RA also has an anti-atherogenic, anti-inflammatory and anti-thrombotic effect. 

GLP-1 receptors are also found in the human heart, making direct myocardial effects likely, although what they look like is not entirely clear. Pioglitazone combines beneficial effects on inflammation, lipotoxicity, blood pressure and lipid profile.

Twincretin-based against diabetes and obesity

Stimulating two incretin receptors is likely to have a more substantial effect than a single agonist. It is the idea behind developing the GIP/GLP-1 receptor agonist Tirzepatide. 

In the phase 3 program SURPASS has demonstrated potent antidiabetic and weight-loss effects without increasing the risk of hypoglycemia.

The two incretins GLP-1 and GIP overlap and complement each other in their effects on the pancreas, gastrointestinal tract, adipose tissue and CNS, explained Daniel Drucker, University of Toronto. 

Tirzepatide can bind to the GLP1 and GIP receptors, providing a dual effect with a single molecule. The SURPASS program includes ten studies, 4 of which were presented at the ADA Congress. All showed an hba1c solid reduction of 2–2.5% and a drastic weight loss of about 12 kg within 40–52 weeks, as well as the usual incretin-associated gastrointestinal side effects with no significant surprises

The 40-week open-label study SURPASS-2, in which tirzepatide was compared with semaglutide, which has already been approved for the treatment of type 2 diabetes and also obesity in the USA. It has aroused the most significant interest. The comparison was not entirely fair, as semaglutide is given in higher amounts in obesity than in diabetes treatment and in SURPASS-2 (2.4 mg/week instead of 1 mg/week). At the start of the study, however, only the 1 mg was approved in the USA, explained study leader Juan Pablo Frías, National Research Institute, Los Angeles. One thousand eight hundred seventy-nine people who were stable on at least 1,500 mg/day of metformin as background were randomized.

Is there a true cure for diabetes?

In terms of HbA1c, the dual agonist performed significantly better than the GLP1-RA in all three amounts tested (5, 10 and 15 mg/week) (minus 2.09%–2.46% vs. 1.86%, p<0.001 ). Tirzepatide is superior in the anti-obesity effect, with weight losses of up to 12.4 kg in the 15 mg/week arm (6.2 kg with Semaglutide, p<0.001). 

However, more patients discontinued in the two study arms with higher amounts of tirzepatide than with semaglutide (12% and 13.2% vs 8.7%), primarily because of adverse effects.

For Drucker, these study results open “the next chapter in incretin-based therapies that will bring meaningful improvements in the health and quality of life of people with diabetes.” He was convinced that tolerability in everyday clinical practice would be better if doctors and patients could manage the amount given.


Diabetes mellitus is associated with obesity and insulin resistance. Therefore, this aims to lower the blood sugar level and reduce the patient’s body weight. Some active ingredients, thus, attack the so-called incretins. These postprandially released molecules regulate, among other things, how much glucagon and insulin release. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two such molecules.

GLP-1 inhibits glucagon release, promotes insulin release, delays gastric emptying, and inhibits hunger and thirst. GIP also stimulates glucose-dependent insulin secretion. It regulates glucagon release both in a hyperglycaemic phase and in a normal- or hypoglycaemic state.

The receptor of the GLP-1 molecule has, therefore long been the target structure of the GLP-1 receptor agonists. Combination agents of GIP and GLP-1 receptor agonists are now being explored. One such is tirzepatide.

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