Summary: Key classes of antidiabetic drugsFeb. 1, 2018
*Source, lecture held by prof Clifford Bailey, Aston University in Birmingham, United Kingdom*
After diagnosis of diabetes, glucose control is not the only factor that needs consideration, as CV risk and co-morbidities also require attention. The aim of therapy for T2DM is to improve glycemic control to reduce microvascular risk, and to lower macrovascular risk, mostly by control of lipids and BP. In addition, co-morbidities such as obesity, depression, fatty liver, and microvascular complications like kidney, eye and neuropathic diseases should be managed.
Multiple causes contribute to the development of T2DM
Insulin resistance and inadequate insulin production and secretion, among other problems all contribute to development of T2DM (13). The liver produces too much glucose, while the muscle does not receive enough of that glucose due to its insulin resistance. Often, excess adipose tissue is seen, which contributes to the proinflammatory state. And, because more glucose is filtered through the kidney, the kidney tends to adapt by reabsorbing more glucose. On the other hand, there is inadequate insulin production and often also excess production of glucagon. Moreover, there are various defects associated with the incretin effect, the microbiome is altered and there are various autonomic changes in the control of glucose regulation (13). As the hyperglycemia in T2DM is the result of multiple factors, bringing the glucose level down to as close to normal levels as possible, requires multiple therapies. The first approach in the management of hyperglycemia in T2DM is lifestyle improvement, through diet, exercise, health education and weight control.
Metformin is generally the preferable first-line oral anti-glycemic agent. Metformin can counter the action of insulin resistance. Its actions are partly insulin-dependent, and partly insulin-independent. Metformin can reduce hepatic glucose production and has a modest effect in enhancing the uptake and oxidation of glucose in the muscle. It has an important effect on the intestine, to increase the anaerobic glucose metabolism and increase glucose turnover (13).
Advantages of metformin include that it does not cause weight gain and hypoglycemia. It tends to slightly lower basal insulin levels and it often improves the lipid profile and various vascular parameters. Metformin can cause some gastro-intestinal intolerance. When prescribing metformin, it is important to make sure that renal function is adequate. If eGFR falls below 60 mL/min/1.73m² a dose reduction should be considered, and treatment should be stopped when eGFR is below 30 mL/min/1.73m² (13).
Insulin secretion can be stimulated with sulfonylureas (SU) or meglitinides, of which the first ones are the longer acting ones, and the meglitinides the prandial insulin releasers. These agents stimulate insulin secretion by acting on the K+ ATP channel on the surface of the pancreatic β-cell. They induce weight gain and confer a risk of hypoglycemia (see table 4) (13).
Pioglitazone and other peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists mostly act on adipose tissue to increase adipogenesis and lipogenesis in peripheral adipose depots. In this process, by creating insulin-sensitive adipocytes, ectopic fat is taken away from other tissues. These agents increase insulin sensitivity and rebalance the glucose-fatty acid cycle. They reduce inflammation, and variable effects on lipids and reduction of some CV risk markers and events have been reported. Adipogenesis results in weight gain. The onset of action is slow, but there is no risk of hypoglycemia. Liver function should be checked, as well as NYHA risk. Fluid retention and edema can occur, and a risk of fractures and HF is associated with the use of PPAR-γ agonists (13).
Two types of incretins exist: the oral dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) and injectable glucagon-like peptide-1 receptor agonists (GLP-1RAs). GLP-1RAs not only enhance glucose-induced insulin secretion, but also suppress glucagon production and additionally they have neural effects to promote satiety and to delay gastric emptying. DPP-4 inhibitors prolong the life of endogenous GLP-1 to increase the incretin effect. Altogether, these effects reduce hyperglycemia (14, 15).
DPP-4 inhibitors are weight neutral, while the satiety that is promoted with GLP-1RAs is helpful in achieving weight loss. Both classes do not cause hypoglycemia. Potential CV benefits have been reported with DPP-4 inhibiting therapy and GLP-1RAs. Their use may, however, lead to pancreatitis and GLP-1RA treatment may also induce nausea (14, 15).
Alpha-glucosidase inhibitors like acarbose are able to slow down the digestion of complex carbohydrates in the intestine, which is another route to decreasing the post-prandial glucose excursion.
Alpha-glucosidase inhibitors should be taken in conjunction with a diet rich in complex carbohydrates. Their advantages include that they do not cause weight gain, nor hypoglycemia. They may lower triglyceride levels. They can, however, cause gastro-intestinal disease and flatulence (13).
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, act on the kidney. These glucosuric agents are able to suppress the reabsorption of glucose from the proximal tubule. About 70-90 grams of glucose can be excreted via the urine per day, which not only reduces hyperglycemia in an insulin-independent way, but also lowers weight through the loss of calories and it may create an osmotic diuresis, which may contribute to the BP-lowering effect of SGLT2 inhibition (16).
They do not cause hypoglycemia and have potential beneficial effects on major adverse cardiac events and possibly on the kidney, as illustrated by the effects on eGFR described above. The excreted glucose increases the risk of genital mycotic infections. Cases of diabetic ketoacidosis have been described when insulin was reduced too much. In case of pioglitazone, a risk of HF has been described, as a consequence of edema (16).
If glycemic control cannot be achieved with each or all of the agents mentioned above, insulin therapy can be given. Insulin affects many of the defects in T2DM; it lowers hepatic glucose production, increases glucose uptake in the muscle, lowers lipolysis from adipose tissue, enhances protein anabolism and affects growth and differentiation.
A disadvantage of using insulin is that it can induce hypoglycemia and that it causes weight gain. Insulin therapy should be correlated with diet and exercise, and requires monitoring of blood glucose. Various formulations (rapid or short-acting and intermediate or long-acting) and delivery devices exist (13, 15).
Thus, multiple treatment options should be employed to get the glucose level as close to normal as possible, and should be started as soon as possible in order to defer or prevent the development of microvascular complications and to contribute to the long term reduction in macrovascular complications.