Drug Treatments for Diabetes Mellitus


The goal of treatments for diabetes mellitus is glycemic control, that is the prevention of hyperglycemia. Chronic hyperglycemia leads to glycation, which is the non-enzymatic addition of sugars to proteins, as well as causing other chemical changes. Ultimately, the various chemical changes due to hyperglycemia are pathological for certain tissues and diabetic complications ensue. The major diabetic complications are listed below. We will discuss these in more detail in Conjoint 402 and 403 when we discuss neural, cardiovascular, and renal physiology.

    Cardiovascular Disease (heart attack, stroke, peripheral vascular disease)
    Nephropathy (kidney damage)
    Retinopathy (blindness)
    Peripheral Neuropathy (loss of sensation, autonomic dysfunction)
    Foot Ulcers (amputation)

Several large prospective studies have demonstrated that diabetic complications can be significantly reduced by intensive glycemic control. An unfortunate adverse effect of more intensive diabetic therapy is that it increases the risk for hypoglycemia.

Glycemic control can be determined through frequent monitoring of blood glucose, but in practice it is measured by measuring HbA1c, or the percentage of glycated hemoglobin. Hyperglycemia causes glycation of proteins, and hemoglobin is a convenient protein to examine since it can be obtained from a simple blood draw. HbA1c (expressed as a percentage) reflects the degree of glycemic control in the previous 4-8 weeks.  The American Diabetes Association recommends an HbA1c target of less than 7% for most diabetics.  (HbA1c is also now used as a tool for diagnosing diabetes mellitus; see Insulin Resistance).

Below are listed major drug treatments for diabetes mellitus that we have discussed in class.


Insulin

Insulin therapy is necessary for type 1 diabetics because they have an absolute insulin deficiency due to the autoimmune destruction of the pancreatic beta cells. Insulin therapy is also used in treating type 2 diabetes. As the disease advances, many type 2 diabetics will require insulin therapy, because the beta cells are damaged by hyperglycemia, and patients develop significant defects in insulin secretion.


Drugs that Increase Insulin Secretion

Sulfonylureas and Meglitinides

These drugs bind to and block the ATP-sensitive K+ channel on pancreatic beta cells, causing depolarization and increased insulin secretion (review Humoral Regulation). These drugs improve glycemic control, but patients taking them tend to gain weight. Sulfonylureas (glyburide, glimepiride) are older drugs and less expensive. A potential problem is that they can induce too much insulin secretion and hypoglycemia can result. The meglitinides (repaglinide, nateglinide) are newer drugs that are designed to avoid this problem. They have a shorter half-life, and are taken at mealtimes to enhance insulin secretion and prevent postprandial hyperglycemia.

Incretin-Based Therapies

Incretins are gastrointestinal hormones that increase insulin secretion (review Incretins). GLP-1 agonists are peptide drugs with a longer half-life than the native hormone because they are resistant to digestion by the protease DPP-4. DPP-4 inhibitors ("gliptins") prolong the action of native incretins.  DPP-4 inhibitors are less effective at lowering HbA1c than GLP-1 agonists, but an advantage is that they are oral drugs. 

GLP-1 agonists have the added benefit of inducing weight loss (several kilograms, depending upon the length of treatment). The mechanism is thought to be that GLP-1 delays stomach emptying into the small intestine, causing patients to eat less because they feel “full” sooner.


Insulin Sensitizers

These drugs improve insulin sensitivity, and thus work to counteract the key problem of type 2 diabetes: insulin resistance (review Insulin Resistance).

Metformin is one of the most widely prescribed drugs for type 2 diabetes, and is the first drug of choice used to treat newly diagnosed diabetes. It is also used to treat pre-diabetics (patients with impaired fasting glucose or impaired glucose tolerance) to delay or prevent the onset of type 2 diabetes.  Its mechanism of action is still being determined.  The main target of metformin appears to be the liver, where metformin inhibits gluconeogenesis.

Thiazolidinediones (TZD’s; pioglitazone, rosiglitazone) are agonists for a nuclear receptor known as PPAR-gamma. This receptor is expressed in adipocytes, but also in many other tissues.  Thiazolidinediones affect adipocyte gene expression, ultimately causing decreases in circulating fatty acids. They also affect adipocyte secretion of regulatory molecules: adipocytes secrete more adiponectin, which increases insulin sensitivity, and fewer adipokines that cause insulin resistance.

Unfortunately, there have been many safety concerns for the TZDs.  Between 2010 and 2013, access to rosiglitazone (trade name:  Avandia) was restricted due to concerns about an increased risk of heart attack. There are also safety concerns regarding pioglitazone (trade name:  Actos).  Both drugs cause weight gain and increased fluid retention, and increase the risk for heart failure.  Recent research has shown that it may be possible to develop PPAR-gamma receptor modulators.  The hope is to develop drugs that are insulin-sensitizing without causing adverse effects that increase the risk for cardiovascular disease.


Drugs that Decrease Glucagon Secretion

Glucagon is secreted by the alpha cells in the pancreatic islets of Langerhans. It is one of the postabsorptive state hormones, and functions to stimulate hepatic glucose production. Glucagon secretion can be higher than normal, particularly in type 1 diabetes mellitus. Reducing inappropriate glucagon secretion and hepatic glucose production helps to limit hyperglycemia. One type of drug in this category would be a GLP-1 agonist. The other is pramlintide, a synthetic analogue of the peptide hormone amylin, which is produced by the pancreatic beta cells (so amylin is also deficient in type 1 diabetes mellitus). Amylin inhibits glucagon secretion and also slows stomach emptying. Pramlintide is recommended as an adjunct to insulin therapy for type 1 and type 2 diabetics who are having difficulty with glycemic control.


Drugs that Decrease Glucose Reabsorption

SGLT2 inhibitors are drugs that decrease glucose reabsorption in the kidney (review Diabetes mellitus and polyuria). In trials, SGLT2 inhibitors have been shown to improve glycemic control and cause weight loss. SGLT2 inhibitors could become the next blockbuster drugs for treating diabetes mellitus. There are now 3 SGLT2 inhibitors (canagliflozin, dapaglifolozin, and empagliflozin) that are FDA-approved to treat type 2 diabetes mellitus.

A potential advantage of SGLT2 inhibitors is that they lower blood glucose through a mechanism that is independent of insulin, so they could be safely combined with other treatments.  However, there have been reports of ketoacidosis amongst users of SGLT2 inhibitors, and the FDA issued a warning about their use in May 2015.  Ketoacidosis is a serious condition that usually occurs in type 1 diabetics when insulin levels are too low.  Studies are ongoing to determine what other factors might contribute to the risk for ketoacidosis.   


Other drug characteristics

Above, the diabetes drugs are organized according to mechanism of action. The table below organizes the diabetes drugs according to different criteria that may also be useful in guiding treatment decisions.


Quick Quiz


Fill-in Answer Correct False Correct Answer
1. An adverse effect of intensive glycemic control in diabetes is an increased risk of _________.
2. Which of the following diabetes drugs tends to cause weight gain? [metformin, GLP-1 agonist, sulfonylurea, pramlintide]
3. Name the hormone secreted by the alpha cells that stimulates hepatic glucose production.
4. Name a hormone besides amylin that delays stomach emptying.
5. Name the type of insulin-sensitizing drug that is an agonist for PPAR-gamma.
6. Pramlintide is a drug that inhibits ________ secretion.
7. Name the insulin-sensitizing drug that is the most widely used.
8. What is measured to determine glycemic control?


(Spelling must be correct)




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