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Dr Jonathon Sullivan:
In Part 1 of this series we talked about the basics of type 2 diabetes. I included a bit of ancient history. You're welcome. And then we went on to discuss some of the pathophysiology. If you haven't already seen that episode I strongly suggest you go back and watch it now because that material will be essential for you to understand what's going on in this episode.

Dr Jonathon Sullivan:
And what exactly is going on in this episode? We're going to talk about modern medical approaches to Type 2 diabetes, specifically pharmacotherapies. And this isn't just intended for those of you who actually have diabetes, but for everyone. Because even if you don't have diabetes you almost certainly have a friend or a loved one or a coaching client who does and who has to take one or more of these medications. And even if you don't, well, knowledge is power. Or at least it's knowledge.

Dr Jonathon Sullivan:
Hi I'm Jonathan Sullivan and welcome back to Greysteel. Treatment of type 2 diabetes is properly based on an understanding of the pathophysiology of the disease in general and the patient's individual pathophysiology in particular. At the most basic level this means knowing that diabetes results from a deficiency in either insulin, insulin signalling, or both. That understanding paved the way for the first really effective pharmacotherapies.

Dr Jonathon Sullivan:
In the early 1920s work by Nobel laureate Frederick Banting and Dr Charles Best, building on discoveries and work by many others, resulted in the first clinically practical isolations of insulin from animals and the first successful treatment of insulin-dependent diabetics. In the 1940s, experiments designed to isolate new sulfonamide antibiotics resulted in the isolation of sulfonylureas and the demonstration that they reduced blood sugar in animals.

Dr Jonathon Sullivan:
By the time I went to med school in the late 1980s sulfonylureas were still the mainstay of treatment for Type 2 diabetes. And that was pretty much all we had. Insulin and sulphonylureas. Biguanides came into widespread use in the 90s and since then we've seen an explosion of available agents for the treatment of type 2 diabetes working on multiple pathophysiological targets. This variety has broad implications for therapy as we'll see later.

Dr Jonathon Sullivan:
We can't really talk a lot about individual agents - that would take way too long - but we can talk about the various classes of antidiabetic drugs and how they work. This will also help us to solidify our understanding of the pathophysiology we discussed in the previous episode. So let's get it done.

Dr Jonathon Sullivan:
Arguably the most important class of drugs for type 2 diabetes is the biguanides of which the primary example is metformin, the only one still use for diabetics in the United States. This drug was known for a long time, but was only cleared for use in the US in the early nineties, about the time I was beginning internship and residency. It completely transformed our treatment protocols for this disease. Metformin is taken orally and it works by increasing insulin- sensitivity and normalizing liver glucose metabolism.

Remember that in the state of insulin resistance the liver dumps glucose into the bloodstream, worsening hypoglycemia. Metformin improves insulin sensitivity and reduces hepatic glucose output. The improvement in insulin sensitivity with metformin is not completely understood, but is probably through several mechanisms including effects on mitochondria energy metabolism and also on glucose transporters. The net effect is to make you more sensitive to insulin.

Metformin is therefore not just a biguanide, but also a member of a larger class of drugs we can call "sensitizers." It is taken orally and overall it is safe, effective, and well-tolerated. Along with lifestyle change, the most important and powerful intervention for diabetes, tt forms the first-line therapy for pre-diabetics and diabetes.

Metformin can produce some gastrointestinal side effects and also the serious side effect of lactic acidosis. It should not be used in the setting of serious liver or kidney disease. A big plus of metformin is that it does not cause hypoglycemia or low blood sugar, a prime consideration for the development of any drug treatment strategy in diabetes.

Also in the sensitizer category are the drugs called thiazolidinediones, also called "glitazones" or just "TZDs." These include drugs like rosiglitazone, pioglitazone, and the now unavailable troglitazone which was withdrawn by the FDA in 2000 due to an unfortunate tendency to cause liver failure. These drugs are taken orally and they work by altering the expression of genes involved in glucose and fat metabolism. They therefore reduce insulin resistance and also improve serum lipid profiles. Although the impact of this last effect on vascular heart disease and stroke isn't entirely clear.

By increasing sensitivity to insulin thiazoladinediones reduce inappropriate liver glucose output, decrease the release of free fatty acids implicated in lipotoxicity, and they improve glucose uptake from the bloodstream into cells. Side effects include edema which can worsen heart failure. But it's important to note that TZDs do not have a direct effect on heart muscle tissue. Other side effects include anemia, osteoporosis, and pathological fractures. So these drugs are relatively contraindicated in patients with heart failure, liver disease, and osteoporosis.

Next, we come to a class of drugs called the "secretagogues." These are medications that tell the weary, overworked beta cells in your pancreas that they're just not working hard enough to overcome tissue insulin resistance and they need to make more insulin.

"And bid them make bricks without straw."

There are two main subclasses of secretagogues and they both work at the level of the beta cell by essentially poisoning the potassium transporter in the beta cell membrane which affects the voltage across the membrane which in turn allows calcium to rush into the beta cell which is the final signal for insulin release into the bloodstream. A lot of detail in this video to keep the nerds happy. Don't worry there won't be a test.

The first group of secretagogues is the sulfonylureas which include the drugs glipizide, gylburide, and glimeripide, among others. These drugs are veteran players in the war against diabetes and they're still used widely. They're taken orally and are often brought in when lifestyle and metformin aren't enough to control blood sugar in HBA1c. The big side effect is hypoglycemia. These drugs cause you to release more insulin and so they increase the risk that you'll drop your blood sugar. They can produce weight gain which is not great, especially in diabetes, and there is some data suggesting they can worsen the extent of heart damage in the setting of myocardial infarction, probably via their action on the potassium channels although that data is far from robust and doesn't implicate all the drugs in this class. The bigger problem with sulfonylureas is that unlike some other treatment approaches like biguanides and thiazolidinediones is that they don't seem to retard the rate of progression of diabete, the time to beta cell failure and the need for supplemental insulin.

In my opinion, there are theoretical reasons to be concerned that by flogging the overworked beta cells to make more insulin they might actually accelerate progression to beta cell failure and insulin dependence.

I'm compelled to point out that this is a speculative theoretical concern and there's no data yet that ramming speed actually hastens the progression of the disease. But these drugs don't slow it either. And in 2019 I think that mandates a careful re-evaluation of their role in diabetes management given the other options we have available now.

The other class of secretagogues is the meglitinides including repaglinide and nateglinide. These drugs work much the same as sulfonylureas although they exert their effect on a different region of the potassium transporter. They have a more rapid onset and a shorter duration of action. As such they can be used in patients who tend to get huge spikes in their sugar just after eating, but that's a sign of decreased beta cell function. And so again I think these drugs should be used carefully. They're taken orally and they have a side effect profile similar to sulfonylureas, particularly hypoglycemia. Which we hate.

Now we turn our attention to a class of drugs that I call the incretin-amylin-based therapies. Amylin, like insulin, is a short protein or a peptide secreted by the beta cells of the pancreas when we eat. It helps stop glucose production in the liver, slows down stomach emptying, and makes you feel full so you hopefully eat less. An injectable synthetic peptide called pramlintide is an amylin analogue very similar to amylin and it has the same effects. It can therefore help decrease the need for insulin in patients with advanced type 2 diabetes and promotes modest weight loss. Downsides? Well it can promote weight loss and too much of a good thing is not a good thing. It can also cause nausea and vomiting. The biggest drawback is that as a peptide it can't be taken orally. It has to be injected.

Now. When you eat your pancreas responds to an increase in blood sugar by releasing the insulin peptide - basic stuff - but at the same time your gut and your mouth also release peptides or short proteins called increase "incretins" like GLP-1 and GIP. These incretins further stimulate the pancreas to produce insulin. They are therefore natural secretegogues. Like synthetic amylin, the incretins promote fullness and satiety and decrease gastric emptying.

As in the case of amylin, we now have synthetic incretin analogs, short peptides called exenatide and liraglutide for use in type 2 diabetes. The synthetic incretin analogs exenatide and liraglutide mimic incretin action and therefore they promote insulin release, decrease glucagon-stimulated liver production of glucose, increase satiety, decrease appetite, promote weight loss, and possibly help prevent the hepatic steatosis or fatty liver seen in many diabetics. Again, these drugs are used by injection, particularly before meals, and they are considered first-line agents. They have a broad side effect profile including hypoglycemia, abdominal pain, nausea, vomiting, and weight loss. There have also been concerns about pancreatitis, a serious immune reaction called angioedema, and thyroid cancer. Yummy.

The incretins are very short acting because they're broken down by an enzyme dipeptidylpeptidase-4 or DPP-4. DPP-4 chews up incretins shortly after they're released, terminating their biological effect. So another way to enhance their effect is by giving a DPP-4 inhibitor, a medicine that blocks this enzyme and prevents it from chomping on the incretin. This decreases the rate of breakdown and prolongs the duration of incretin action.

DPP-4 inhibitors include sitagliptin, alogliptin, linagliptin, and other gliptins. The side effect profile is similar to the incretin analogs and also includes headache, heart failure, and joint pain. Concerns about increased risk of cancer remain unproven. But the big advantage is that DPP-4 inhibitors can be taken orally.

Now let's take a look at the SGLTT2 inhibitors or "glucosurics." You may recall from our first video in the series that even in ancient times it was recognised that diabetes causes excess urination or polyuria and that the urine was sweet hence the name diabetes mellitus. Sugary urine or glucosuria happens because the kidney can only reclaims so much glucose from filtered blood and rescue it from the urine. Once the blood sugar gets high enough, past the renal glucose threshold, the kidney starts to spill glucose. The glucosurics actually enhance this effect as a way to lower blood glucose. This category includes drugs like canagliflozin and dapagliflozin which are taken orally. They can be useful in combination with other medications and help to lower blood sugar and promote mild weight loss. They can contribute to hypoglycemia especially used with insulin or sulfonylureas and because they increase the amount of glucose in the urine they can contribute to urinary tract infections.

One last class of oral anti diabetic medications: the alpha-glucosidase inhibitors. They inhibit alpha-glucosidase.

Ok. You were probably expecting more than that inside the lining of the gut. There are alpha-glucosidase enzymes whose job it is to cut up carbohydrates into simple sugars that can be absorbed across the gut wall and into the bloodstream. Alpha-glucosidase inhibitors block this process and so diminish your gut absorption of carbohydrates. I don't think you need to be a brain surgeon to see how this could help control blood sugar. This class includes drugs like acarbosee and miglitol which are taken orally. Because these drugs leave more carbohydrate behind in the gut where bacteria can get at them and use them as food, common side effects include flatulence, diarrhea, and bloating. Hypoglycemia can also occur.

Finally there are insulins. When Type 2 diabetes can't be controlled with oral medications or progresses to the point of beta cell failure the patient needs insulin. Insulin therapy is properly tailored to the patient's individual pathophysiology and insulin comes in various preparations to accommodate different needs. Short- and long-acting insulins, rapid insulin, different delivery systems, and so on. A discussion of the fine art of tailoring insulin therapy to the individual needs of type 2 diabetic patients is beyond the scope of this video although we may discuss it in the future. If you want to learn more I strongly suggest that you watch this video - Can Exogenous Insulin Mimic Endogenous Insulin Action? - by Dr. Adi Mehta from the Department of Endocrinology at the Cleveland Clinic. (Link in the doobileedoo.)

And this goes for other anti-diabetic medications too. We're able to tailor therapy much more than we could 20 years ago. Most clinicians use either the American Diabetes Association guidelines or the algorithm put forward by the American Academy of Clinical Endocrinology both of which start with lifestyle modification and usually metformin. Again these guidelines are a bit beyond the scope of this video, but I've included them in the doobileedoo.

For now I'd like to wrap up with some important observations. First, we know more about type 2 diabetes and have more strategies for the medical treatment of type 2 diabetes than ever before. Good thing since we also have more diabetes than ever before. But this means we also have more questions than ever before because that's how science rolls and a lot of these questions revolve around the beta cell, the principle player in type 2 diabetes, because if we can preserve the beta cell we can slow or prevent or even reverse the progression of the disease. So what are the exact mechanisms of beta cell failure? What medications or combinations do the best job of preserving beta cell function and increasing the time needed for additional therapies or insulins? Should we still be using sulfonylureas? Should we be using sensitizers and insulins earlier in the course of the disease to give the poor beta cells a break and let them catch their breath? What biomarkers and biomarker signatures can we use to tailor therapies to individuals for best results and which therapies work best with specific types of lifestyle interventions to prevent or reverse loss of beta cell function? All of these questions and many more are under investigation right now.

For the moment if you have type 2 diabetes or pre-diabetes your job is to lose weight, exercise more, talk with your doctor, and keep taking your medicine. Discuss treatment strategies with your physician and consider consultation with a diabetes specialist or an endocrinologist to make sure your treatment is up to date. If you are an athlete of aging engaged in heavy training make sure your doctors know all about your exercise and nutritional regimens because these things matter and may play into medication selection and timing, especially when it comes to insulins, sulfonylureas, and other medications that can cause hypoglycemia. And above all educate yourself. Hopefully this video has helped you get started.

In the next video in this series we're going to talk about lifestyle medication for type 2 diabetes, the most powerful intervention available. Hope you'll join us then. Thanks for watching this episode of Greysteel.

Remember this information is for educational and infotainment purposes only and does not constitute advice for any particular person, patient, disease, or condition. If you have questions about your health you should work closely with your physician.

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