The following outlines the options for treating patients without indicators of high risk or without existing atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF).
The goals are divided into two key areas:
Glucose management and maintenance or achievement of weight goals.
If the HbA1c is above the established target and there are no cardiovascular diseases, no risk of cardiovascular diseases, no chronic kidney disease, and no heart failure, the therapy should then be aligned with the primary goal that is individually tailored to the patient.
These goals are further divided into:
• Achieving the agreed-upon blood sugar target
• Avoidance of hypoglycemia
If there is no increased risk of atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure, the first step should be to set goals for blood sugar control and weight. For pharmacological treatment, metformin is suitable, and if this is insufficient, it can be combined, for example, with DPP-4 inhibitors. A combination with sulfonylureas is not recommended due to the risk of hypoglycemia and weight gain. Hypoglycemia must be avoided, especially in high-risk patients and older patients.
• If the primary goal is the avoidance of hypoglycemia, DPP-4 inhibitors can be used in combination with metformin. DPP-4 inhibitors are also recommended as first-line therapy if metformin is not tolerated. Due to their very good tolerability, they are particularly suitable for older patients. Older patients are at high risk for dementia due to severe hypoglycemia. However, DPP-4 inhibitors should not be combined with GLP-1 receptor antagonists.
• In overweight patients, GLP-1 receptor agonists or SGLT-2 inhibitors should be preferred. A combination of SGLT-2 inhibitors and GLP-1 receptor agonists is also possible.
• DPP-4 inhibitors can be combined with SGLT-2 inhibitors if the HbA1c target is not reached.
If the HbA1c target is not achieved with these combinations, the next step would be therapy with basal insulin while continuing the previous medication.
While sulfonylureas are cost-effective and some sulfonylureas do not increase cardiovascular risk, all studies have shown that sulfonylureas shorten the functional lifespan of beta cells for insulin production. Treatment with sulfonylureas only provides one to two additional years of improved blood sugar control, after which the patient’s condition worsens due to the loss of beta cell capacity. Therefore, we do not recommend sulfonylureas.
Type 2 diabetes is a progressive disease. With monotherapy, it is often only possible to achieve the HbA1c goals individually set with the patient for a limited period of a few years. It has been shown that an initial combination therapy of metformin with vildagliptin (a DPP-4 inhibitor) leads to a significantly slower deterioration of blood sugar control compared to sequential therapy, where treatment starts with metformin and escalates to additional therapies if monotherapy fails. This likely applies not only to vildagliptin but also to combination therapies with GLP-1 receptor agonists and SGLT2 inhibitors. If HbA1c is 1.5-2% above the desired target, combination therapy should be considered right from the start.
For patients without chronic kidney disease or cardiovascular disease, and without a higher risk for these conditions, the goal is blood sugar control and weight management.
In overweight/obesity, treatment with GLP-1 receptor agonists with proven efficacy for weight loss is the main focus.
If blood sugar control is the main focus of treatment, metformin or other substances, including combination therapy, should be used, as these have been proven to lower blood sugar and achieve blood sugar targets. Substances should be chosen without the risk of hypoglycemia.
Insulin also lowers blood sugar very effectively but is associated with the risk of hypoglycemia.
If HbA1c is not within target range in overweight patients or in cases of inadequate blood sugar reduction, other barriers that cause elevated blood sugar levels should be identified.
Important measures include:
Self-management of diabetes
Training in blood sugar self-monitoring or continuous glucose monitoring (CGM)
Identifying social factors affecting health
Pharmacologic-Approaches-to-Glycemic-Treatment Fig 9.3
Intermediately effective are the DPP-4 inhibitors.
DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-1 inhibitors, and thiazolidinediones lower blood sugar without causing hypoglycemia.
The incretin effect was described in the previous section (treatment of patients
with indicators…).
• Incretins stimulate the beta cells of the pancreas to release insulin.
• Incretins inhibit the formation of glucagon in the alpha cells of the pancreas (glucagon releases glucose from the liver).
• Incretins delay gastric emptying, resulting in a longer feeling of fullness, which leads to reduced food intake.
The effect of incretins is limited by the enzyme dipeptidyl-peptidase-4 (DPP-4), which breaks down GLP-1 within minutes.
GLP-1 is a peptide made of 30 amino acids (peptide = organic compound made from amino acids).
When the enzyme DPP-4 is inhibited, GLP-1 is broken down more slowly. This prolongs and enhances the effect of the body’s own GLP-1. Therefore, there is the potential to develop medications that inhibit the DPP-4 enzyme, known as DPP-4 inhibitors.
With DPP-4 inhibitors (gliptins), HbA1c can be reduced by about 0.8 to 1 percent. In combination with metformin, DPP-4 inhibitors support weight loss (approximately 1 kg). Hypoglycemia does not occur. Therefore, these medications are also suitable for older patients, for whom it is especially important to avoid hypoglycemia.
Europa (EMA)
USA (FDA)
Indien (CDSCO/DCGI)
Gliptine gibt es auch in Fixkombinationen
Europa (EMA)
USA (FDA)
Indien (CDSCO/DCGI)
The patent protection for DPP-4 inhibitors has expired, so they are now available as generics. The effectiveness of the generics does not differ from the original preparations.
For most approved DPP-4 inhibitors, large endpoint studies are available. The studies showed no increased risk for the endpoints of heart attack, stroke, or cardiovascular death. In the study with saxagliptin, there was an increase in hospital admissions due to heart failure. The reason for this in this particular study is unclear, as no worsening of heart failure occurred in all other studies. Therefore, the guidelines do not recommend the use of saxagliptin in patients with heart failure. The side effects of DPP-4 inhibitors are at the level of the comparator groups that received placebo. The studies showed no increased risk of pancreatitis or pancreatic cancer.
If the individual HbA1c target is not achieved with the combination of metformin and one of the above substances, a combination of three medications from the substances listed above may be considered. However, it does not make sense to combine DPP-4 inhibitors with GLP-1 receptor agonists.
Glitazones (Thiazolidinediones (TZD)) in Type 2 Diabetes
Pioglitazone (Actos®) is also referred to as an “insulin sensitizer.” Pioglitazone does not increase insulin production but instead makes the cells more sensitive to the available (both endogenous and injected) insulin. It reduces “insulin resistance” and thus the body’s insulin requirements. As a result, blood sugar levels drop—both fasting and postprandial. The reduction in HbA1c is approximately 1%. A large study showed that pioglitazone does not increase the risk of heart attack, stroke, or cardiovascular death. Pioglitazone can be combined with all other blood sugar-lowering substances. It can also be used in patients with kidney insufficiency. Disadvantages include slight weight gain and the potential to worsen existing heart failure. In postmenopausal women, the fracture rate is also higher, and there is suspicion that it may increase the risk of bladder cancer.
In a large UK database study involving over 90,000 patients, the mortality of sulfonylureas was compared with metformin and pioglitazone over a follow-up period from 1990 to 2005 (I. Tzoulaki et al., BMJ 2009, 339:b4731). In patients treated with sulfonylureas, mortality was approximately 40% higher compared to those treated with metformin. Despite the possibly increased risk of bladder cancer, the mortality risk in the pioglitazone-treated group was reduced by 40% compared to metformin.
The guidelines focus on the essential problem faced by most patients with type 2 diabetes: overweight or obesity.
First, a realistic assessment must be made of what is achievable for an individual patient. However, this assessment must also be adjusted to the new possibilities. In the past, apart from the usual measures such as lifestyle changes, dietary therapy, and an intensified structured weight reduction program, we had no means to achieve significant weight loss. These measures proved ineffective for the vast majority of overweight and obese patients. As a result, many doctors have given up on addressing the fundamental problem of weight with their patients. With GLP-1 receptor agonists, SGLT-2 inhibitors, and bariatric surgery now available, effective therapeutic options have emerged, enabling significant weight reduction in almost all patients.
• Very effective medications: Semaglutide and Tirzepatide
• Effective medications: Dulaglutide, Liraglutide
Intermediately effective medications include GLP-1 receptor agonists (not listed above) and SGLT-2 inhibitors.
Weight-neutral medications include DPP-4 inhibitors and metformin. In some studies, a small weight reduction of 1 to 2 kg has been observed with the combination of DPP-4 inhibitors and metformin.
In overweight patients—therefore, almost all patients with type 2 diabetes—sulfonylureas or insulin should preferably not be used, as they are associated with significant weight gain.
Unfortunately, sulfonylureas still have a very high prescription rate. The primary reason for their use is cost. Sulfonylureas are inexpensive, and as a result, the risks of weight gain and hypoglycemia (which can be fatal in some cases) are often accepted.
Sulfonylureas (SU) in Type 2 Diabetes
Sulfonylureas act on the beta cells and lead to insulin secretion.
Mechanism of Action of Sulfonylureas:
This image was created using artificial intelligence.
Mechanism of Action of Sulfonylureas:
The available sulfonylureas include:
Notes by region:
Glinides
Europe (EMA)
USA (FDA)
India (CDSCO/DCGI)
In summary:
Glinides also stimulate insulin release from the beta cells. They are sometimes referred to as sulfonylurea analogs.
Sulfonylureas lower blood sugar and HbA1c only for a short duration. This was first shown in the large UKPDS study using Glibenclamide (see the figure below) and has been confirmed in all longer-term studies. After a maximum of two years, HbA1c returns to baseline levels, and blood sugar levels begin to rise again.
In several large comparative studies between Metformin and sulfonylureas, it was shown that patients treated with sulfonylureas had to start a second diabetes medication earlier than patients treated with Metformin. Because sulfonylureas stimulate the release of insulin from the beta cells, treatment with sulfonylureas leads to an earlier exhaustion of the remaining beta cells. Sulfonylureas also have the disadvantage of causing weight gain (see figure). Furthermore, sulfonylureas are suspected of increasing the risk of heart attack and stroke by 20-30%. Gliclazide and Repaglinide do not increase the risk of heart attack or stroke, likely due to their shorter duration of action. Sulfonylureas can also lead to hypoglycemia. Particularly, patients with liver and kidney insufficiency are at risk. Hypoglycemia caused by sulfonylureas is life-threatening and always requires hospitalization with monitoring over several days. Due to their low cost, sulfonylureas are still prescribed very frequently. However, because of the dangerous side effects mentioned above, it is ethically increasingly difficult to justify their use in treatment.
Cost-effective are also Thiazolidinediones.
Pioglitazone is widely used worldwide but should not be used in patients with heart failure. Rosiglitazone and Troglitazone are no longer prescribed due to side effects.
Acarbose in Type 2 Diabetes
Acarbose is no longer included in the latest recommendations for glucose-lowering therapy in Type 2 diabetes. Acarbose has a minimal effect on lowering blood sugar. Approximately half of patients must discontinue treatment due to bloating. In a large study (UKPDS) over two years, the HbA1c reduction was 0.2%. Therefore, it is rarely useful to use Acarbose as an add-on to Metformin or as monotherapy.
Acarbose is still approved in many EU countries (e.g., as Glucobay®). It is also FDA-approved (Precose®), but rarely prescribed nowadays. It plays practically no role in modern US guidelines (only mentioned briefly).
India:
Acarbose is still commonly used, also in combination with Metformin or other antidiabetic medications. It is primarily prescribed for diabetes patients with significant postprandial blood sugar spikes. Numerous generics and fixed-dose combinations are available (e.g., Acarbose + Metformin, Acarbose + Voglibose in some preparations).
Asia (e.g., China, Japan):
In these regions, Acarbose still has a higher status due to the clinical relevance of postprandial hyperglycemia in Asian populations.
In China, Acarbose is even one of the most commonly prescribed oral antidiabetic drugs.