Type 2 diabetes: Medications

There are various classes of active antidiabetic substances with different modes of action:

• Some drugs stimulate the production of insulin (sulfonylureas and glinides) and can therefore cause low blood sugar (hypoglycemia).
• Others increase the efficacy of the body's own insulin and have less risk of causing low blood sugar levels (metformin and glitazones).
• Or they enable the needs-required production of insulin for as long as blood sugar levels are elevated (DPP-4 inhibitors (gliptine) and GLP-1 receptor agonists (glutide)).
• There are others that increase the amount of sugar (glucose) released from the kidneys (SGLT-2 inhibitors (gliflozine)).
• Or they may delay the breakdown of carbohydrates in the intestinal tract, meaning that they are absorbed more slowly into the blood stream (alpha-glucosidase inhibitors).

Biguanide

This drug class includes substances like metformin

Metformin is a biguanide that continues to be recommended in the type 2 diabetes guidelines as a first-choice drug for cases with no increased risk of cardiovascular disease. The active substance reduces the release of sugar (glucose) from the liver and increases the insulin sensitivity in the cells. It can also promote a drop in LDL cholesterol levels and reduce appetite (according to studies with limited evidence). Metformin does not directly influence the release of insulin, meaning that monotherapy with metformin has a low-risk of resulting in low blood sugar levels (hypoglycemia). The substance can be combined with other antidiabetics and insulin.

The available endpoint studies point to metformin reducing the incidence of diabetes-associated cardiovascular disease as well as overall mortality rates (according to studies with limited evidence).

It is very common for patients to suffer gastrointestinal problems such as nausea, loss of appetite, stomach pains, vomiting, and diarrhea in the initial stages of treatment using metformin. There can also be changes in the way different tastes are perceived. This is why therapy begins using low a dosage, which is then increased gradually. The use of metformin is limited especially in the case of renal insufficiency. During therapy with metformin, the renal function must be assessed every 3 to 6 months. Metformin use should be discontinued if the estimated glomerular filtration rate (eGFR) is below 30 ml/min, according to the practice recommendation Therapy of Type 2 Diabetes (2020) from the German Diabetes Society.

Alpha-glucosidase inhibitors

This drug class includes substances such as acarbose and miglitol

Alpha-glucosidase inhibitors are taken at mealtimes and help delay the breakdown of carbohydrates by inhibiting the intestinal enzymes responsible for splitting carbohydrates into simple sugars. The sugar (glucose) is then absorbed more slowly into the bloodstream, reducing the elevated blood sugar levels, especially after meals (postprandial hyperglycemia). However, they have a limited effect on blood sugar levels and are now rarely used in the treatment of diabetes.

When administered as a monotherapy, alpha-glucosidase inhibitors do not cause low blood sugar or result in weight gain. The typical side effects include flatulence, gastrointestinal problems, and diarrhea. An increase in liver enzyme levels may also occur. A gradual dosage increase during the initial stage of therapy with alpha-glucosidase inhibitors can help limit any gastrointestinal problems.

Glitazones/Thiazolidinediones

This drug class includes substances like pioglitazone

Glitazones (e.g., thiazolidinediones such as pioglitazone) improve the insulin sensitivity of fatty tissue, the liver, and muscles. and correspondingly glucose uptake, while reducing both the fasting and post-meal blood sugar levels.

Typical side effects associated with this drug class include an increase in fatty tissue, upper respiratory tract infections, water retention, and visual impairments (usually in the early stages of the therapy as a result of blood sugar level fluctuations), and an elevated risk of osteoporosis and bone fractures. Due to the side effects, glitazones are used only in exceptional cases in the treatment of type 2 diabetes.

The available endpoint studies point to a potential risk reduction for the onset of cardiovascular disease related to pioglitazone (according to studies with limited evidence).

Sulfonylureas

This drug class includes substances such as glibenclamide, glimepiride, gliclazide and gliquidone

Sulfonylureas work by stimulating the release of insulin from the pancreas. Because this effect is triggered regardless of the current blood sugar level, the risk of low blood sugar is increased. The drop in blood sugar can be further exacerbated due to interactions with numerous other types of medications (for example, aspirin, and other painkillers, and anti-clotting agents).

All previous endpoint studies state that sulfonylureas can prevent diabetes-induced complications affecting the eyes (retinopathy), kidneys (nephropathy), nerves (neuropathy), and feet (diabetic foot syndrome) (according to studies with limited  evidence).

When used over an extended period of time, the effectiveness of sulfonylureas in the treatment of type 2 diabetes begins to decrease, and there is normally weight gain during therapy using sulfonylureas. Other typical side effects include gastrointestinal problems.

Glinides

This drug class includes substances such as repaglinide and nateglinide

Similar to sulfonylureas, glinides also increase the body's production and release of insulin in the pancreas regardless of the current blood sugar level. In contrast to sulfonylureas, they are fast acting with the effects lasting only a short time. This means that the risk of low blood sugar still exists but is greatly reduced. Glinides are taken before mealtimes and can help reduce blood sugar increases caused by food intake. For people who eat at irregular intervals, thanks to the short duration of their effects compared with sulfonylureas, they can be applied with more flexibility.

Glinides - similar to sulfonylureas - can also lead to weight gain and gastrointestinal problems, such as stomach pain, nausea, and diarrhea.

Due to the lack of evidence regarding their therapeutic benefit, glinides are nowadays used only in justified and exceptional situations in the treatment of type 2 diabetes.

DPP-4 inhibitors (Gliptine)

This drug class includes substances such as saxagliptin, sitagliptin, vildagliptin, and linagliptin

DPP-4 (dipeptidyl peptidase-4) inhibitors (gliptins) inhibit the DPP-4 enzyme in the blood. This means that certain intestinal hormones responsible for insulin release are broken down more slowly in the blood. The post-meal blood sugar level is reduced but the fasting level is not. They also reduce the production of sugar in the liver. Monotherapy is associated with a low risk of low blood sugar levels. Furthermore, neither weight gain nor reduced effectiveness associated with long-term use have been reported. The available endpoint studies have not yet been able to demonstrate whether they can prevent diabetes-associated accompanying illnesses and complications.

DPP-4 inhibitors can be taken in combination with other antidiabetics and fixed-dose combinations (for example, metformin and sitagliptin in one tablet) are available.

Examples of typical side effects include upper respiratory tract and urinary tract infections, gastrointestinal problems, symptoms of exhaustion, skin rashes, headaches, dizziness, and inflammation of the paranasal sinuses, gastrointestinal tract, and/or pancreas.

SGLT-2 inhibitors (Glifozines)

This drug class includes substances such as dapagliflozin, empagliflozin, ertugliflozin and canagliflozin

SGLT-2 (sodium dependent glucose co-transporter 2) inhibitors (glifozines) reduce blood sugar levels by blocking the SGLT-2 enzyme in the kidney. Without this enzyme, less sugar (glucose) is transferred from the kidneys back into the bloodstream and more glucose is excreted in the urine via the kidneys. The blood sugar level drops.

This excretion of excess calories results in weight loss. Blood pressure can also drop. Several endpoint studies have shown that some SGLT-2 medications positively influence the progression of kidney diseases (nephropathy) and heart failure and help prevent early death as well as reducing the risk of heart attacks and death in type 2 diabetes patients with preexisting cardiovascular conditions (moderate to high level of evidence).

When administered as a monotherapy, SGLT-2 inhibitors do not increase the risk of low blood sugar. Potential side effects include urinary tract and genital infections, fluid loss, skin rashes, and itching, dizziness, constipation and/or nausea, increased thirst and/or urinary urgency, as well as diabetic ketoacidosis.

GLP-1 receptor agonists

This drug class includes dulaglutide, exenatide, liraglutide, semaglutide, lixisenatide and albiglutide

GLP-1 stands for glucagon-like peptide-1 and refers to a protein that belongs to the gastrointestinal group of hormones. GLP-1 is released as a reaction to food intake and is involved in the control of the sugar metabolism: It promotes the release of insulin from the pancreas while simultaneously inhibiting the hormone glucagon - which has the opposite effect to insulin. GLP-1 receptor agonists (glutides) simulate the effects of the gastrointestinal hormone GLP-1. They also cause an early onset of the sensation of being full and result in weight loss.

In contrast to the above-listed drug classes, the majority of GLP-1 receptor agonists still have to be injected subcutaneously, i.e., into the subcutaneous fatty tissue. Patient can self-inject 1 or 2 times daily or once a week. The active substance semaglutide in tablet form was approved in Europe in April 2020.

In particular, these substances result in weight loss. Current endpoint studies show that some GLP-1 receptor agonists also reduce the risk of cardiovascular and kidney disease (nephropathy) as well as reducing the premature mortality rate – especially in persons with preexisting heart disease (moderate to high evidence level).

Gastrointestinal problems, such as nausea and a feeling of fullness, are common and often subside as therapy continues. Typical side effects include skin rashes, headaches, dizziness, fatigue, inflammation of the nose, throat and/or gallbladder, elevated enzyme levels, increased heart rate and/or arrhythmia.