MANAGEMENT OF TYPE 2 DIABETES- THE PLACE OF DIPEPTIDYL PEPTIDASE IV (DPP-4) INHIBITORS

“I am 51-year-old man. I have had diabetes for the past 10 years. I have been on Metformin all along. I take it 1g in the morning and another 1g in the evening (that is 12 hourly after food). Recently my health care provider has added another agent to my regime called Sitagliptin. I am taking 100mg daily. According to my health care provider it is for better control of my blood sugar. Kindly throw more light on the issue”. The enquirer has what is termed Type 2 diabetes. I referred to a material from Frontiers in Endocrinology 19 June 2019. The author is Baptist Gallwitz titled “Clinical Use of DPP-4 Inhibitors”.

The regulation of insulin secretion is important to maintain euglycaemia (normal blood glucose). In type 2 diabetes, a deterioration of insulin secretion and the development of peripheral insulin resistance lead to the development of hyperglycaemia (high blood glucose). Insulin is physiologically constantly secreted to a small extent during the fasting state in order to enhance glucose uptake by the peripheral tissues. After a meal, insulin secretion is stimulated quickly and considerably in order to maintain plasma glucose concentrations within a narrow physiological range. The post-prandial (after food/meal) stimulation of insulin is not only promoted by the post-prandial rise in glucose concentrations, but also by the gastrointestinal hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). These two hormones stimulate insulin secretion by the beta cells of the pancreas under hyperglycemic conditions and contribute to about70% of the post-prandial insulin secretion. They are called incretin hormones to highlight their important physiological action in stimulating post-prandial insulin secretion. “Incretin” is actually derived from intestinal secretion of insulin. The trigger for the beta cells of the pancreas to secrete insulin actually originate from the gut. The so-called incretin effect describes the phenomenon that orally ingested glucose leads to a much higher insulin response than intravenously administered glucose.

In type 2 diabetes, the incretin effect is diminished while at the same time, post-prandial insulin secretion is deteriorating. A pharmacological elevation of GLP-1 is able to restore insulin secretion in type 2 diabetes. Since the GLP-1 dependent stimulation of insulin secretion is only present under hyperglycaemic conditions, there is a very low intrinsic risk of hypoglycaemia and thus the growing use of incretin mimetics as antidiabetic agents. GLP-1 has another beneficial effect in type 2 diabetes that contributes to maintaining euglycaemia. In type 2 diabetes glucagon secretion is excessively stimulated and glucagon stimulates hepatic (liver) glucose production. Insulin and glucagon work in tandem but with opposing effects-while insulin decreases blood glucose (sugar), glucagon increases blood glucose (sugar). Because of the diminished incretin effect in Type 2 diabetes, glucagon interprets this as glucose lack and therefore stimulates hepatic glucose production. GLP-1 inhibits glucagon secretion under hyperglycaemic conditions and thereby improves glycaemia. GLP-1 is a peptide hormone with a short plasma half-life of a few minutes. The short biological half-life is due to a rapid enzymatic degradation of GLP-1 (and GIP also) by the enzyme dipeptidyl peptidase IV (DPP-4). A therapeutic intervention is therefore to inhibit the degradation of the enzyme dipeptidyl peptidase IV (DPP-4) and prolong the incretin effect in insulin stimulation. Thus DPP-4 can be inhibited by orally active small molecules called the DPP-4 inhibitors. An example is the Sitagliptin given to the enquirer.

The administration of DPP-4 inhibitors leads to a 2-3-fold elevation of endogenous GLP-1 concentration. The DPP-4 inhibition contributes to a normalization of glycaemia in type 2 diabetes. DPP-4 inhibitors have become firmly established class of oral antidiabetic agents for the treatment of type 2 diabetes. Sitagliptin was the first agent introduced in 2006. Others are Vildagliptin, Saxagliptin, Linagliptin, Allogliptin. DPP-4 inhibitors are implemented into the treatment algorithms of type 2 diabetes in many national and international guidelines.

It should be noted that the various DPP-4 inhibitors do not form a homogenous class of molecules. They show different interactions with the active site of the enzyme molecule. As a result, there are three different classes of DPP-4 inhibitors.  Class 1 comprises of saxagliptin and vildagliptin. Class 2 include Alogliptin and linagliptin. Class 3 include Sitagliptin, Anagliptin, Gemigliptin, and Teneligliptin. DPP-4 inhibitors are orally active, rapidly absorbed, and suitable for once daily or twice daily administration, leading to a DPP-4 inhibition of 70–90% over 24 h. Except for linagliptin, they are eliminated renally after little metabolization.

DPP-4 inhibitors are widely used in the management of type 2 diabetes. The clinically most relevant and important action of DPP-4 inhibitors is the endogenous elevation of the incretin hormone concentration of GLP-1 that consecutively leads to a glucose-dependent stimulation of insulin secretion and an inhibition of glucagon secretion. The insulinotropic effect of DPP-4 inhibitors explains why this class of agents is replacing the use of sulfonylureas as insulin releasing agents. The risk of hypoglycaemia (low blood sugar) is very low as compared to sulfonylureas. Furthermore, DPP-4 inhibitors are body weight neutral, whereas sulfonylurea therapy is associated with body weight gain. All DPP-4 inhibitors can be given in a standard dose without the need for dose titrations.

Type 2 Diabetes mellitus (T2D) is the most common form of diabetes and one of the most common chronic diseases, and its prevalence is raising worldwide [1]. T2D is characterized by a sustained hyperglycaemia due to the persistent damage in insulin secretion by pancreatic β-cell dysfunction and by insulin resistance at the peripheral tissues [1]. However, administration of glucose-lowering medications is insufficient to maintain glycaemic control in many patients and changes in life-style, such as physical exercise and nutrition, both with lowest adverse side effects, are presumed to be the most promising approaches to prevent or delay the onset of T2D. Accordingly identification of dietary components as potential antidiabetic agents has become an essential subject in the current research.

Polyphenol-rich cocoa has a role to play in the management of diabetes. Deterioration of functional β-cell mass is observed during type 2 diabetes and this critically affects to the maintenance of normoglycaemia. Polyphenol-rich cocoa  protect β-cells against death-inducing damaging factors, enhance glucose stimulated insulin secretion and induce β-cell replication. Polyphenol-rich cocoa improves glucose homeostasis by slowing carbohydrate digestion and absorption in the gut. Polyphenol-rich cocoa improves insulin sensitivity by regulating glucose transport and insulin signaling proteins in insulin-sensitive tissues (liver, adipose tissue, and skeletal muscle) and preventing in these tissues oxidative and inflammatory damage associated with diabetes. The daily/regular consumption of polyphenol-rich cocoa constitutes a natural and economic approach to prevent or contribute to the treatment of Type 2 diabetes.

DR. EDWARD O. AMPORFUL

CHIEF PHARMACIST

COCOA CLINIC