Miscellaneous hypoglycemics

Definitions & Key takeaways

Hypoglycemics are used to treat type II diabetes mellitus. They include drugs like sulfonylureas, biguanides, meglitinides, alpha-glucosidase inhibitors, and thiazolidinediones. Each type of medication works in a different way to lower blood sugar levels.

For example, sulfonylureas and meglitinides are secretagogues, meaning they stimulate the pancreas to produce more insulin. Biguanides inhibit production of new glucose from the liver. Alpha-glucosidase inhibitors prevent starch from being broken down into glucose in the gastrointestinal system, whereas thiazolidinediones make tissues more sensitive to insulin.

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Introduction0:00–1:35

Hypoglycemics are used to treat high blood sugar, a condition commonly known as diabetes mellitus. As a quick review, Type 1 diabetes mellitus, which most commonly affects children and adolescents, arises when certain cells of the pancreas known as beta cells are unable to produce enough insulin to maintain normal blood glucose levels.
This is in contrast to Type 2 diabetes mellitus where the body is able to produce insulin, but the tissues don’t respond as well to it, or in other words, these individuals are insulin resistant.Many hypoglycemics, like sulfonylureas, promote the release of insulin from the beta cells of the pancreas and therefore are known as insulin secretagogues.
In this video, however, we’ll be focusing specifically on the use of non-secretagogues in the treatment of Type 2 diabetes.
These medications include multiple classes of medications such as biguanides, thiazolidinediones, alpha glucosidase inhibitors, amylin analogues, and sodium glucose transporter 2 inhibitors.
It’s important to note, however, that diet and exercise should always be the first step in managing diabetes before initiating medications, and should generally be continued while on medication as well.
There are two classes of medications that increase insulin sensitivity and decrease the production of new glucose and they include biguanides and thiazolidinediones.

Biguanides1:35–4:03

Let's start with the biguanides. Biguanides are the first line of therapy for the treatment of type 2 diabetes.
There is one main medication in the biguanide class and that is metFORMIN. It's main mechanism of action is to decrease the production of new glucose from the liver, or to inhibit hepatic gluconeogenesis.
Although the exact mechanism remains unknown, it’s believed that metFORMIN does this by increasing the activity of a liver enzyme known as AMP-dependent protein kinase (or AMPK).
AMPK has many complex functions, namely it plays a role in insulin signaling, as well as helping to regulate the metabolism of glucose and lipids.
Activated AMPK inhibits certain genes that promote gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase.
Thus, via AMPK activation, metFORMIN results in the reduction of gluconeogenesis. In addition, activation of AMPK causes the glucose transporter protein GLUT4, stored within adipose and muscle tissue, to embed into the plasma membrane, allowing glucose to enter.
Thus, metFORMIN increases insulin sensitivity in these tissues and promotes peripheral glucose uptake, and this reduces the overall levels of glucose in the blood.
A third mechanism of action of metFORMIN is that it decreases the intestinal absorption of glucose, and again, causes less glucose to enter the bloodstream.
MetFORMIN also reduces plasma glucagon levels, which is a hormone that stimulates glycogenolysis in the liver. Glycogenolysis is the breakdown of glycogen molecules into glucose, therefore, less glycogen means less glucose in the blood.
As a result, metFORMIN lowers fasting and postprandial, or post-meal, glucose levels; but it’s important to note that metFORMIN is not associated with hypoglycemia!
Finally, besides diabetes type II, this medication can be used to treat polycystic ovarian syndrome, or short PCOS, and antipsychotic-induced weight gain in individuals with schizophrenia or schizoaffective disorder.The most common side effects of metFORMIN are gastrointestinal disturbances such as diarrhea, nausea, vomiting, and abdominal cramps.
It is also associated with weight loss, and therefore metFORMIN is particularly useful in overweight or obese diabetic patients.

Thiazolidinediones4:03–6:39

Furthermore, long-term use of metFORMIN is linked to vitamin B12 deficiency, therefore these individuals should consider B12 supplementation.
Although rare, one of the most well-known side effects of metFORMIN is lactic acidosis. Typically, lactate is taken up by the liver and utilized in the process of hepatic gluconeogenesis.
However, since metFORMIN inhibits gluconeogenesis, the lactate builds up in the blood. In healthy individuals this excess lactate usually does not become problematic because the kidneys are able to excrete it in the urine.
In patients with renal dysfunction, however, the kidneys are unable to clear the excess lactate and it can lead to acidosis.
Thus, metFORMIN is contraindicated in patients with renal impairment. In addition, since it can cause lactic acidosis, metformin is also contraindicated in individuals with liver impairment, alcoholism, and conditions that are associated with tissue anoxia and increased lactic acid production, such as heart failure, respiratory failure, or shock.
Metformin treatment must be stopped before the administration of intravenous iodinated contrast medium, which is just like metformin, excreted by the kidneys.
Therefore, iodinated contrast can reduce metformin’s elimination and cause lactic acidosis!The next group of medications is the thiazolidinediones, sometimes just referred to as glitazones.
The two main medications in this class are rosiglitazone and pioglitazone. Similar to the biguanides, thiazolidinediones are insulin sensitizers, meaning they make peripheral tissues more sensitive to the insulin that the body has already produced.
But, in contrast to metFORMIN, these medications have a slow onset of action, meaning they might require several weeks to develop their therapeutic effect.
They work as agonists at a receptor known as the peroxisome proliferator activated receptor gamma, or PPAR gamma. Normally, this receptor is activated when ligands such as free fatty acids bind to it, after which, it binds to DNA and another receptor known as a retinoid X receptor.
This complex is then able to regulate the transcription of genes involved in glucose and lipid metabolism. In particular, it increases insulin sensitivity in adipose, liver, and skeletal muscle.

Alpha glucosidase inhibitors6:39–7:31

The medications rosiglitazone and pioglitazone are synthetic ligands that can bind to PPAR gamma receptors in the same way as the natural ligands, which leads to increased insulin sensitivity.
In fact, these medications have been shown to increase insulin sensitivity or glucose uptake in peripheral tissues by 30-50%.
In addition, thiazolidinediones increase adiponectin levels, which is a hormone that inhibits hepatic gluconeogenesis; and stimulates glucose uptake by skeletal muscles, consequently decreasing blood glucose levels.
As a result, just like metFORMIN, these medications lower fasting and postprandial glucose levels.Furthermore, the thiazolidinediones also increase the synthesis of proteins involved in lipid metabolism.

Synthetic amylin analogues7:31–8:20

The end result is a decrease in triglycerides, and increase in both high density lipoprotein or HDL and low density lipoprotein or LDL.
LDL is sometimes called "bad cholesterol" because it can lead to atherosclerosis, or plaque buildup in blood vessels, which can ultimately lead to weight gain and cardiovascular disease.
In terms of side effects, when used as monotherapy, these medications are rarely associated with hypoglycemia. But, it’s important to note that they can cause fluid retention and edema, which can further increase the risk of heart failure; therefore, they are contraindicated in individuals with NYHA class III or IV heart failure.
Next, thiazolidinediones are associated with weight gain and increased risk of osteopenia and fractures. There is also some concern that these medications can increase the risk of hepatitis and liver failure, and therefore liver enzymes must be monitored closely, particularly during the first few months of initiating therapy.

SGLT2 inhibitors8:20–8:57

Rosiglitazone in particular has been shown to increase the risk of certain cardiovascular events such as myocardial infarction and stroke, while pioglitazone can increase the risk of bladder cancer.
Now the next two classes of medications, the alpha glucosidase inhibitors and amylin analogues act directly upon the GI tract by delaying the breakdown of food and its excretion from the body.

Memory palace8:57–12:20

Lets look at the alpha-glucosidase inhibitors, which includes the medications acarbose and miglitol. Alpha glucosidase is an enzyme that is found in the brush border of the intestines and it breaks down oligosaccharides and disaccharides into simpler monosaccharide units, like glucose, which is eventually absorbed through the lining of the intestine and into the blood.
Alpha glucosidase inhibitors prevent this process and reduce intestinal glucose absorption; thus they should be taken just before meals.
This ultimately lowers postprandial glucose levels; but in contrast to the previous two groups, these medications lack an effect on fasting glucose!
Now, as far as the side effects go, the undigested carbohydrates remain within the colon and are digested by intestinal bacteria.
This results in increased bacterial fermentation and gastrointestinal disturbances like gas, bloating, and diarrhea. Therefore, if individuals on alpha-glucosidase inhibitors experience hypoglycemia, they should not be treated with sucrose since it will promote gastrointestinal side effects; instead, they should be treated with dextrose whose absorption is not inhibited.
Finally, alpha-glucosidase inhibitors are contraindicated in individuals with intestinal conditions, such as inflammatory bowel disease.Now that we’ve discussed alpha glucosidase inhibitors, let’s now move onto a minor class of medications known as synthetic amylin analogues, which includes the medication pramlintide.
Amylin is a hormone that is secreted alongside insulin from the beta cells of the pancreas. Amylin, and its synthetic analogue, pramlintide, lower blood glucose by delaying gastric emptying, inhibiting glucagon secretion, and improving satiety.
Unlike the other medications discussed thus far, pramlintide is an injectable medication, not an oral one. Also unlike other medications discussed, pramlintide is most commonly used in combination with insulin and it can be used in both Type 1 and Type 2 diabetes.
Side effects associated with pramlintide include nausea and an increased risk of hypoglycemia when used with insulin. Finally, the main contraindication for pramlintide is gastroparesis, a condition in which the stomach can't empty food properly.The last group of miscellaneous medications we’ll discuss are the SGLT2 inhibitors, which include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.
In proximal convoluted tubules in the kidney, there’s a transporter known as the sodium glucose-like transporter 2 or SGLT2 and it accounts for 90% of all renal glucose absorption.
When this transporter is inhibited by SGLT2 inhibitors the kidney is unable to reabsorb glucose. Instead, it causes glycosuria and the glucose is excreted out into the urine.
The SGLT2 inhibitors have been known to cause various genital infections such as vulvovaginal candidiasis and urinary tract infections, but they are also associated with side effects such as weight loss, polyuria, and dehydration.
Moreover, dehydration is followed by a reduction in intravascular volume and subsequent hypotension. Also, SGLT2 inhibitors can cause hyperkalemia and ketoacidosis.
In terms of contraindications, these medications are contraindicated in individuals with recurrent urinary tract infections, such as in individuals with anomalies of the urinary tract; and in individuals with renal impairment.
Moreover, since they can cause acute kidney injury, it’s important to note that before and after initiating therapy you should monitor serum creatinine.Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts!
So let’s set the scene in an apartment. Someone is shouting insults outside, which represents insulin.
So the medications that increase insulin sensitivity will go right by the window. Next, we have a dining table in the middle of the room and this will be where we put the medications that act on the GI tract.
Finally, there’s a urinal on one side of the wall where we’ll put medications that increase renal glucose excretion. By the window, we have the foreman of a construction site for metFORMIN.

Review12:20–13:07

He’s standing in front of a guitar amp with the letter K on it to help you remember it activates AMPK. Behind him is a bushel of sugarcanes to help you remember it inhibits gluconeogenesis.
Next, let’s put a sensitive little girl crying on top of the sugarcane. She’s crying because of the man shouting insults to remind you of the increased insulin sensitivity.
Next let’s have the two inhibitory mechanisms in a cage next to the sugarcane. First is a sponge shaped like the stomach to represent decreased glucose absorption in the GI tract.

Mind map13:07–13:14

Then there’s an empty sugar bowl where the sugar,