Chapter 33: Antidiabetic Drugs – Insulins & Oral Agents

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Welcome back to the Deep Dive.

Okay, if you've ever felt a bit lost in the sea of anti -diabetic drugs, the big one IDs, SGLT2s, all those acronyms.

Well, you're definitely not alone.

It's a really complex area.

Right.

So our mission today is to try and cut through some of that complexity.

We're diving deep into the pharmacology, the anti -diabetic meds drawing from chapter 33 of Lilly's Pharmacology for Canadian healthcare practice.

And the goal isn't just listing drugs.

We want to build a solid framework, you know, understand the classes, how they work, and crucially, the safety stuff you absolutely need to know.

Exactly structure and safety.

But before we even talk drugs, we have to start with the basics, right?

What's normal?

Absolutely.

You can't understand the problem without knowing the baseline.

And fundamentally, diabetes isn't just high blood sugar.

That's a symptom.

Okay.

It's actually defined as a complex disorder.

It messes with how your body handles carbs, fats, and proteins.

It's systemic.

Gotcha.

So to understand that, we need to look at the pancreas first.

Precisely.

The pancreas, got that dual role, you know, exocrine for digestion,

enzymes and stuff.

But for us, it's the endocrine function that matters.

Hormones straight into the blood.

And the key players there are.

Insulin and glucagon.

Insulin from the beta cells, glucagon from the alpha cells.

They're in these little clusters called the islets of Langerhans.

And these hormones keep our blood sugar in that tight range.

Yeah.

What is it normally?

Usually between four and six millimole.

That's the goal for homeostasis.

They balance each other out.

So insulin, what's its main job?

What signal is it sending?

Insulin is basically the storage hormone for glucose.

It tells muscle and fat tissue, hey, take up this glucose.

Okay.

And it tells the liver, store this glucose as a glycogen.

It stops the body from losing valuable nutrients.

And when that process breaks down,

that's when we see those classic diabetes symptoms.

Exactly.

The three polys.

Polyuria peeing a lot because the kidneys are trying to dump excess sugar.

Polydipsia being incredibly thirsty because of the fluid loss.

And polyphagia, excessive hunger because the cells aren't getting the glucose energy they need, even though it's floating around in the blood.

Okay.

So when does it become an official diagnosis?

What are the numbers?

We look for hyperglycemia.

So a fasting plasma glucose of seven millibel or higher.

Right.

Or an A1C that's glycosylated hemoglobin of 6 .5 % or more.

And that A1C, that's the long -term picture, isn't it?

Like a three month average.

Exactly.

It shows the bigger picture of glucose control.

And bringing that A1C down is the main therapeutic goal.

What's the usual target we're aiming for in Canada?

Generally for most patients, the goal is an A1C less than 7%.

Getting there really cuts down the risk of those nasty microvascular complications like eye and kidney damage.

Okay.

So we know what normal is and we know the goal.

Now let's talk about the two main ways this system breaks.

Type 1 and type 2 diabetes.

They sound similar, but they're really different beasts.

Oh, completely different.

Night and day, really.

Type 1 makes up maybe 10 % of cases.

It's autoimmune.

Meaning the body attacks itself.

Yeah.

The immune system mistakenly destroys the pancreatic beta cells.

The result, an absolute lack of insulin.

They just can't make it anymore.

So treatment is insulin, period.

No other option.

For type 1, yes.

Their life depends on getting insulin from an external source, what we call exogenous insulin, right from diagnosis.

Okay.

Then there's type 2, that's the much more common one, right?

Around 90%.

Correct.

And it's a different story.

It usually starts with insulin resistance.

The body makes insulin, maybe even lots of it initially, but the cells don't respond properly.

The receptors are sluggish or fewer in number.

And this is heavily linked to lifestyle factors.

Very strongly linked to obesity, inactivity, what we call metabolic syndrome.

Over time, the pancreas can also get tired and its ability to secrete insulin decreases too.

So it becomes a problem of both resistance and a secretory defect later on.

This difference totally changes how you approach treatment then.

Absolutely.

For type 1, like we said, insulin right away.

For type 2, the first step is always aggressive lifestyle changes.

Diet, exercise, losing weight.

All of that.

You try that first.

If the A1C targets still aren't met, then you typically add an oral medication.

Metformin is usually the first choice.

And insulin for type 2 comes much later.

Generally, yes.

It's often reserved for later stages when those lifestyle changes in oral meds aren't enough, usually because the pancreas's insulin production has really declined.

Got it.

Before we jump into the specific drugs quickly, what about those really scary high sugar emergencies,

DKA and HHS?

Right.

Diabetic ketoacidosis, DKA, and hyperosmolar hyperglycemic state, HHS,

both are severe hyperglycemia.

How do they differ?

DKA is characterized by that lack of insulin forcing the body to burn fat for energy, producing ketones.

Ketones are acidic, hence the ketoacidosis.

You also get hyperglycemia and dehydration.

And HHS.

HHS involves extreme hyperglycemia and severe dehydration, but usually without significant ketone production or acidosis.

Historically, DKA was seen more in type 1 and HHS in type 2.

But that's blurring a bit now.

Yeah, we sometimes see DKA in type 2 now, especially in younger folks.

The presentations can sometimes overlap, so you need careful assessment.

One last group.

Gestational diabetes.

High sugar during pregnancy.

What's the go -to treatment?

Insulin is really the preferred drug therapy.

Most oral drugs just don't have enough solid safety data in pregnancy.

Even metformin.

I thought I heard.

There are some studies on metformin and an older drug, glabaride, but insulin is still generally considered the standard of care.

The good news is it often resolves after the baby is born.

But it does increase the risk for type 2 later in life for the mother, right?

It certainly does.

It's a significant risk factor.

Okay, let's move on to the drugs themselves.

Starting with insulin, since it's essential for and often needed for type 2 eventually.

You mentioned exogenous insulin.

What's critical for using these safely?

Timing.

Everything comes down to pharmacokinetics.

The onset, when it starts working, the peak, when it's strongest, and the duration, how long it lasts.

You have to know this for each type.

So let's break down the main families based on that timing.

What's the fastest?

That would be the rapid acting insulins.

Think Lispero, Aspart, Glycine.

Their onset is super quick, like 10 to 15 minutes.

Oh, 15 minutes.

Sounds like it could be risky if you don't eat.

Exactly.

That's the absolute crucial teaching point.

The patient must eat within 15 minutes of taking it.

If they don't, their blood sugar could plummet.

It's designed to mimic that natural insulin surge you get right when you start digesting a meal.

Okay, rapid acting, eat within 15 minutes.

What's next?

Short acting insulin, often called regular insulin.

Its onset is a bit slower, maybe 30 to 60 minutes.

And regular has a unique feature, doesn't it?

Yes.

It's the only insulin type that can be given intravenously, IV.

This makes it essential for tweeting emergencies like DKA in the hospital, where you need a continuous IV infusion.

Right, IVUs only for regular.

Okay, moving slower now.

Next up is intermediate acting insulin, NPH, neutral protamine hegedorn.

This one looks different.

How so?

It's cloudy or opaque.

All the others, rapid, short and long acting, are clear solutions.

NPH has a slower onset and longer duration than a regular, often used to cover insulin needs between meals or overnight.

It's frequently mixed in the same syringe with rapid or short acting insulin.

Cloudy NPH.

Got it.

And the longest duration.

Those are the long acting insulins, sometimes called basal insulins.

Examples are glargine and ditamir.

They're designed to provide a steady, low level insulin coverage over a full 24 hours, sometimes even longer.

Like a background insulin level.

Exactly, mimicking the pancreas's constant basal secretion.

And glargine has a really interesting property.

What's that?

Glargine is often described as peakless.

It forms little microprecipitates under the skin that release insulin very slowly and steadily.

No distinct peak.

And no peak means safer.

Generally, yes, especially regarding overnight hypoglycemia.

That steady release reduces the risk of blood sugar dropping too low while sleeping, which was a bigger concern with NPH.

Okay.

These different timings lead to different ways of dosing insulin.

Can you compare the main strategies?

Basal bolus versus sliding scale?

Sure.

Basal bolus therapy is really the gold standard now.

It tries to mimic a healthy pancreas as closely as possible.

How does it do that?

You use a long acting basal insulin once or twice a day to cover the body's background needs.

Then you use a rapid or short acting bolus insulin before meals to cover the carbs eaten and maybe add correction doses if the sugar is high before the meal.

Makes sense.

Mimicking nature.

So what was wrong with the older sliding scale method?

I still see it sometimes.

The big problem with sliding scale is that it's reactive.

You only give insulin after the blood sugar is already high.

Ah, plain ketchup.

Exactly.

It often leads to these big swings like a roller coaster of high and low blood sugars because it doesn't really address the underlying constant basal need for insulin.

That's why it's generally discouraged for routine management.

Good distinction.

Before we leave insulin, let's hammer home the safety.

You said timing is key.

What else?

Insulin is a high alert med, right?

Definitely a high alert medication.

Mistakes can have severe consequences.

Remember the visual rule.

Rapid, short and long acting are clear.

NPH is cloudy.

And mixing.

You mentioned mixing NPH with regular or rapid.

There's a specific way to do that.

And the order is critical to prevent contamination.

Think clear before cloudy.

You inject air into the cloudy NPH vial first, then inject air into the clear regular rapid vial, then you draw up the clear insulin, then you draw the cloudy NPH into the same syringe.

Why that specific order?

Air cloudy, air clear, draw clear, draw cloudy.

You absolutely must avoid getting any of the cloudy NPH into the clear vial.

NPH is modified, and mixing it into the clear vial could change the rapid or short acting insulin's onset and peak, which is dangerous.

Okay, clear before cloudy.

Got it.

Let's switch gears to the oral drugs used for type 2 diabetes.

Where do we usually start?

First line therapy for type 2, assuming no contraindications, is almost always a big one eyed.

And the main one is metformin.

It's been around a long time, but it's still a cornerstone.

How does metformin work?

What's its main action?

Its primary effect is reducing hepatic glucose production.

It tells the liver, hey, stop releasing so much stored glucose.

It also has a secondary effect of increasing the sensitivity of peripheral tissues to insulin.

So it's working on the liver's output, not forcing the pancreas to make more insulin.

Exactly.

And that's its major advantage, because it doesn't directly stimulate insulin secretion.

Less risk of hypoglycemia.

Much lower risk of causing hypoglycemia when used alone.

It also typically doesn't cause weight gain, unlike some other classes.

That safety profile is why it's first line.

But metformin isn't without risks.

There's a major warning related to kidneys, right?

A critical one.

Lactic acidosis.

It's rare, but potentially fatal.

Because of this risk, metformin is contraindicated in patients with significant kidney dysfunction.

The cutoff is usually a creatinine clearance below 30 mm.

Okay, check kidney function.

What else?

Something about contrast dye.

Yes.

Another huge safety point.

If a patient on metformin needs a radiology study that uses iodinated contracts media, like certain CT scans or angiograms.

You have to stop the metformin.

You have to hold the metformin before the procedure, and for at least 48 hours afterward, until kidney function is confirmed to be stable.

The contrast dye can potentially cause acute kidney injury.

And if that happens while metformin is in the system, the risk of die procedures.

Crucial.

Now, what about older drugs that do stimulate insulin?

The sulfonylureous.

Right.

Drugs like glycozide or glabaride.

These work directly on the pancreas, stimulating the beta cells to release more insulin.

So they require the pancreas to still have some function left.

Yes.

You need functioning beta cells for them to work.

And the direct consequence of forcing out more insulin is?

Higher risk of hypoglycemia and weight gain.

Exactly.

Those are the main side effects you watch for with sulfonylureous.

There's a similar class, but shorter acting, glinides.

Yes.

The glinides, like rapaglinide, they also stimulate insulin release, but have a much shorter duration of action.

How does that change how you use them?

Their main use is for controlling post -meal glucose spikes.

Because they're short acting, they must be taken with meals.

And importantly, if the patient skips a meal, they must skip the dose for that meal to avoid hypoglycemia.

Good for people with irregular eating schedules.

Okay, meal dependent.

Let's move to drugs that work on insulin resistance.

The thiazolidinidions or TZDs, like pioglitazone.

These are insulin sensitizers.

They make the body cells respond better to the insulin that's already there.

But they work slowly.

It can take several weeks or even months to see their full effect.

And TZDs have a significant warning too, related to the heart.

Yes, a major contraindication.

They can cause fluid retention, edema, and weight gain, which can worsen or precipitate heart failure.

So they're contraindicated in patients with a New York Heart Association class three or five heart failure.

Okay, watch for fluid retention, avoid and severe heart failure.

Got it.

What about some of the newer classes?

DPP -4 inhibitors.

Cytogliptin is one.

The DPP -4 inhibitors, or gliptins, their mechanism is kind of cool and indirect.

They work by inhibiting the enzyme DPP -4, which normally breaks down incretin hormones.

Incretins, what do they do?

Incretins are hormones released by your gut after you eat.

They naturally stimulate insulin synthesis and release, and they also decrease glucagon secretion, but only when blood glucose is high.

So by preserving these incretins, DPP -4 inhibitors help lower both fasting and post -meal glucose levels.

Interesting.

And they generally have a lower risk of hypoglycemia compared to sulfonylureous.

Yes, because their action is glucose dependent.

They enhance the body's natural response, rather than just forcing insulin out, regardless of the glucose level.

Okay.

Now, probably the newest major class of oral agents,

SGLT -2 inhibitors, kinagliflozin and pagliflozin.

These work totally differently, right, on the kidneys.

Completely different mechanism, yeah.

They inhibit the sodium glucose co -transporter II, or SGLT -2, protein in the kidney tubules.

And SGLT -2 normally pulls glucose back into the blood.

Right.

It reabsorbs glucose that's been filtered by the kidneys.

So by blocking it, these drugs cause excess glucose to be excreted in the urine.

You literally pee out sugar.

That sounds effective.

Are there other benefits?

Yes, a major one.

Several SGLT -2 inhibitors have shown significant cardiovascular benefits, reducing risks in patients with type 2 diabetes who already have cardiovascular disease.

So they're often recommended for that population now.

But making people pee out sugar must have some downsides, side effects.

It does.

Because there's sugar in the urine, there's an increased risk of genital yeast infections and urinary tract infections, UTIs.

Makes sense.

Also, because you're losing glucose and fluid, they can sometimes cause dehydration or volume depletion.

So you need to watch for that, especially in the elderly or those on diuretics.

Okay, kidney action, CV benefits, but watch for infections and dehydration.

Got it.

Are there injectable drugs besides insulin?

Yes, the incretin mimetics.

These are related to the DPP4 inhibitors we just talked about, but instead of preserving natural incretins, these drugs mimic them.

Examples are exenatide and liraglutide.

So they do similar things, boost insulin, lower glucagon.

Yes, but they often have stronger effects.

They also significantly slow down gastric emptying how fast food leaves your stomach.

Which would make you feel fuller.

Exactly.

It increases satiety, which often leads to weight loss, a significant benefit for many type 2 patients.

They're given by subcutaneous injection, like insulin.

Any common side effects with those?

Nausea and vomiting are quite common, especially when starting therapy, partly due to that slowed gastric emptying.

Okay.

So we've covered a lot of drugs that lower blood sugar.

Now the flip side,

what happens if blood sugar goes too low?

Hypoglycemia.

What's the danger zone?

Generally defined as plasma glucose below 4 millimolel.

It's the most common acute complication of insulin therapy and some oral meds like sulfonylureas.

What are the signs?

How would someone know?

Symptoms tend to progress.

Early on, you get neurogenic or autonomic symptoms.

Things like sweating, trembling, anxiety, palpitations, hunger.

Okay.

The body's initial alarm bells.

Right.

If it gets worse, you start seeing neuroglycopenic symptoms because the brain isn't getting enough glucose.

That can mean confusion, drysiness, weakness, dizziness, blurred vision, difficulty speaking, and in severe cases, seizures or unconsciousness.

Scary stuff.

How do you treat it if the person is conscious and can swallow?

The standard is the rule of 15.

Give 15 grams of a fast -acting carbohydrate.

Like what?

Glucose tablets are ideal because they're precisely measured, but you could also use about 34 cup of regular juice or non -diet soda or some hard candies.

Avoid chocolate or things with fat as fat slows glucose absorption.

Okay.

15 grams fast carbs.

Then what?

Wait 15 minutes, then recheck the blood glucose.

If it's still below 4 millimolel, repeat the 15 grams of carbs.

Once the sugar is back up, they should eat a more substantial snack or meal with protein and carbs to prevent it from dropping again.

And if the patient is unconscious or unable to swallow?

In a hospital setting, for example.

The quickest way is intravenous D50W that's 50 % dextrose in water.

It works almost immediately.

And if you don't have IV access, readily available.

Then glucagon injection is the alternative.

It can be given subcutaneously or intramuscularly.

Glucagon works by stimulating the liver to release stored glucose.

Is there a safety tip with glucagon?

Yes, a really important one.

Glucagon can often cause vomiting.

So if you're giving it to an unconscious person, you must roll them onto their side before you inject it.

This helps prevent aspiration if they do vomit.

Turn them on their side first.

Got it.

Got it.

Is there any specific drug that changes how you treat hypoglycemia?

Yes, one exception.

Patients taking alpha -glucosidase inhibitors.

Acarbose is the main one, need to know something specific.

Acarbose works by slowing the breakdown of complex carbohydrates in the gut.

So if someone on acarbose becomes hypoglycemic, giving them table sugar, sucrose, or starchy foods won't work quickly enough because the drug blocks their digestion.

So what should they use?

They need to use pure glucose, like glucose tablets or gel or potentially milk or honey, which contains simpler sugars that bypass the drug's action.

That's a key education point for those patients.

Good tip.

Okay, let's bring this all together.

Thinking about the nurse or practitioner giving these meds,

what are the absolute key nursing considerations?

Assessment is paramount.

Always, always check the patient's current status and their plasma glucose level before giving any anti -diabetic medication.

You need that baseline.

What else in assessment?

Compatibility.

Yes, especially with insulins.

Know which ones can and cannot be mixed.

Remember, Glargine, Lantus,

and Detamir, Levamir typically cannot be mixed with any other insulin in the same syringe due to their formulation, especially Glargine's low pH.

Okay, and during implementation, any technique reminders?

For insulin administration,

always gently roll the cloudy NTH vial between your palms to mix it.

Never shake it vigorously as that can damage the insulin protein.

Roll, don't shake.

And remember the mixing order.

Clear before cloudy if you're combining regular rapid with NPH.

Also, injection site rotation is crucial.

Why is rotating site so important?

To prevent lapodystrophy, that's either atrophy or hypertrophy of the subcutaneous fat.

These changes can really alter how consistently the insulin is absorbed.

The key is to rotate sites within one anatomical area, like different spots on the abdomen, for about a week before moving to a completely different area, like the thigh.

Okay, rotate within a region, then change regions.

What about oral agents?

Make sure the patient is actually eating or able to tolerate food, especially before giving drugs like sulfonylureas or glinides that can cause hypoglycemia.

And always be vigilant about those metformin contraindications, kidney function, and contrast dye procedures.

That requires active monitoring and communication.

And finally, patient education must be huge here.

Massive.

Patients need to understand their specific medication regimen, the timing, the doses, potential side effects like hypoglycemia.

They need meticulous foot care, checking their feet daily for any sores or problems, because diabetes can impair circulation and sensation.

What else?

Lifestyle things.

Absolutely.

Reinforce avoiding smoking, limiting alcohol, wearing medical alert jewelry indicating they have diabetes.

And, you know, acknowledge the practical challenges too, like the cost of testing supplies.

Those strips can be over a dollar each, which is a real barrier for some people.

That's a really important practical point.

Okay, let's try to wrap this up.

We've covered a ton of ground.

We really have.

From the basic difference between type 1, no insulin, and type 2, resistance, then deficiency, through the whole spectrum of insulin kinetics, the super -fast list bro needing food now versus the steady, peakless, glare gene providing background cover.

And the oral agents, like metformin working on the liver with low hypo -risk but that critical kidney contrast warning, versus the SGLT2s making you pee out sugar but offering heart benefits.

It all comes back to understanding how each drug works and critically, it's timing.

The onset, peak, duration matching that to meals and the patient's needs.

That pharmacokinetic knowledge isn't just academic, it's what allows for safe, effective, life -saving clinical practice.

So here's something to think about as we finish.

We're seeing more and more technology insulin pumps giving continuous infusions, continuous glucose monitors, tracking sugar 24 -7.

Diabetes management is shifting from just timed injections to managing these complex tech systems.

It really is a whole new layer.

Right.

So thinking about that trend, how much deeper does our understanding of pharmacokinetics and individual patient physiology need to become to really use these technologies safely and effectively?

To truly personalize care, especially for tricky populations like kids or maybe indigenous communities facing unique access challenges.

That's the million dollar question, isn't it?

Integrating that tech safely requires an even more profound grasp of how these drugs work second by second in that specific person.

It's the next frontier in truly individualized diabetes care.

Definitely food for thought.

Well, this has been an incredibly insightful deep dive into anti -diabetic pharmacology.

Thank you so much for breaking down such a complex topic so clearly.

My pleasure.

It's crucial information for anyone involved in diabetes care.