Will Afrezza Replace Orals In Insulin Therapy?

Will Afrezza Replace Orals In Insulin Therapy?

By Robert Sacher


Oral drugs have dangerous side effects for diabetes patients.

Early insulin therapy may help avoid worsening effects of high blood glucose.

New study shows Afrezza is a superior delivery system for insulin.

MannKind Corporation, a biotechnology development company, along with their marketing partner, Sanofi, are in the early stage of market development of the world’s only inhaled insulin, Afrezza. Afrezza has removed the pain of injection and replaced it with an inhaler so successful in its design that the Afrezza inhaler could revolutionize the way blood sugar is controlled in the diabetic community, particularly with T2 diabetics who are currently non compliant or living with orals that may have long term destructive effects on a diabetic pancreas.

A recent study published on August 7th, 2015, shows Afrezza to be a valuable new approach in a direct comparison with oral medications. In the MannKind funded study, published at Diabetes Care, the authors state,

“Type 2 diabetic patients, poorly controlled with oral agents, may benefit from adding Afrezza, an inhaled Technosphere human insulin, at mealtimes… type 2 diabetic patients, with HbA1c between 7.5% and 10.0% and on Metformin or two or more oral antidiabetic agents, were randomly assigned to add either Afrezza or inhaled Technosphere placebo to their existing treatment regimen at mealtimes.”


compared to placebo, Afrezza significantly reduced HbA1c... Additionally, more patients using Afrezza at mealtimes achieved an HbA1c of 7.0% or lower compared to those in the placebo group…The investigators concluded that the results of this study suggest prandial Afrezza is a “viable option for those who require initiation of insulin but are reluctant to accept injectable therapy.”

According to a paper entitled, Starting Insulin Treatment In Type 2 Diabetes, published at Australian Prescriber Independent Review,

Almost all patients with Type 2 diabetes will eventually fail to respond adequately to oral hypoglycemic drugs and will require insulin therapy… A more common problem is when and how to commence insulin in patients with Type 2 diabetes who are in secondary failure. The term secondary failure refers to the ‘failure’ of oral hypoglycemic drugs to maintain glycemic control.”


“The United Kingdom Prospective Diabetes Study clearly showed that most people with type 2 diabetes will experience progressive pancreatic β cell dysfunction, despite excellent control. The secondary failure rate in this study was 44% after six years of diabetes. Since the time of the UKPDS, targets for glycemic control have become increasingly stringent so secondary failure of oral hypoglycemic drugs now occurs much sooner and is almost invariable.”

What’s wrong with the orals?

Let’s face it. When patients find out that they have diabetes, the last thing anyone would want to hear is that you will have to inject yourself over 2,000 times per year for the rest of your life. If you hope to live another twenty five years, that would be more than 50,000 injections throughout your remaining days. You can only imagine what your stomach will look like after that many years, fifty thousand needles.

Pharmaceutical companies have developed drugs which can be taken orally that can delay that day when a diabetic patient will pick up their first syringe or injection needle pen. But, what do those orals do to your internal organs? Here’s a comprehensive list and what some studies have discovered.

Let’s take a look.

Sulfonylureas are the first type of drugs many endocrinologists will prescribe for Type 2 diabetics. They work by stimulating the pancreas into making more insulin. You may know these drugs by their names, tolazamide, tolbutamide, or chlorpropamide. Or, you may know them by their brand names, Tolinase or Diabinese. There is also glyburide, glipizide, and glimepiride, newer and more powerful sulfonylurea pills. These you may know as the brand names, Glynase, Micronaase, Diabeta, or Glucotrol.

Sulfonylureas basically do one job, they stimulate your pancreas into making more insulin. However, according to a paper published in Diabetes Self Management,

“Unfortunately, sulfonylureas do not always succeed in controlling diabetes. With sulfonylurea therapy, some 10% to 20% of people will immediately fail to control their blood glucose levels adequately on the highest recommended dose (a situation called “primary failure”). Sulfonylureas themselves tend to overwork the pancreas until it eventually “burns out” and is unable to secrete an adequate amount of insulin, so roughly 5% to 10% of people who initially respond to sulfonylurea therapy will subsequently fail each year, a situation called secondary failure.

Statistically, you may have a one in five chance of having sulfonylureas not work for you right out of the gate but the idea that this class of drugs will eventually destroy your pancreas is a much more dangerous scenario. And, there is another unpleasant side effect. Once you start using this class of drug, you can expect to gain weight, something exactly the opposite of what a T2 diabetic needs since most T2s are already overweight. In addition, according to a statement at webmd.com, studies suggest that sulfonylureas only lower A1C by 1% to 2%.

Last, some sulfonylureas will cause skin rash and increased risk of sunburn. And, according to the Joslin Diabetes Center, the most common side effect of sulfonylurea drugs is hypoglycemia, the condition of having low blood sugar which can result in loss of consciousness, seizures, and death if not properly recognized and addressed.

What about Repaglinide?

Repaglinide, aka Prandin, is in a class of drugs called meglitinides. It works by stimulating insulin producing cells within the pancreas, tends to work faster and lasts for a shorter time period than sulfonylureas. However, weight gain is associated with its use, as is joint pain and diarrhea. Repaglinide can also cause hypoglycemia and according to NHS choices, a UK website, Repaglinide should not be used when you plan to drive your car or operate machinery.

And there’s a very long list of medicines that may interact with Repaglinide including the sulfonylureas, beta blockers (for cardiac arrhythmias, myocardial infarction, and hypertension), ACE inhibitors (for hypertension and congestive heart failure), anabolic steroids (for chronic wasting conditions such as cancer or AIDS), oral contraceptives, and several other classes of medications.

According to a paper regarding Repaglinide published at care.diabetes.org,

“The most frequently reported adverse events were upper respiratory tract infections and headaches..Symptoms of hypoglycemia were reported in 10% (15 of 151) of patients with normal renal function and in 15% (20 of 130) of those with renal impairment.”
However, and possibly most important, the report stated,

Glycemic control on repaglinide at the end of the treatment period was generally similar to that at baseline. No significant differences were observed between the different renal function groups with regard to the effect of repaglinide on HbA1cand FBG.
Tsulfonylureas only lower A1C by 1% to 2%. Therefore, Repaglinide does not do any better at lowering A1C than sulfonylureas.

What about Acarbose?

Acarbose, aka Precose, is a starch blocker, a class of drugs called alpha-glucosidase inhibitors. This drug will block a particular enzyme whose job is to break down carbohydrate in the intestines and thereby decreasing the rise of blood glucose after food consumption. While Acarbose can be used with other diabetes orals, because the absorption of carbohydrate is slowed, hypoglycemia can occur. And, according to a statement at diabetes self management.com,

“…these drugs slow the absorption of certain carbohydrates (including orange juice and white sugar), these sources will not work immediately to treat an episode of hypoglycemia…One of the biggest drawbacks to the alpha-glucosidase inhibitors is their side effects. Because they affect carbohydrate absorption in the small intestine, they can cause bloating, nausea, diarrhea, and flatulence.”

What about Pioglitazone or Rosiglitazone?

These two drugs, aka Actos and Avandia, are in the class of drugs know as thiazolidinediones and are sometimes called “glitazones.” These drugs work by making your body use its insulin more effectively by lowering glucose production in your liver. The first version of this drug was withdrawn, back in 2000, because it was shown to cause liver toxicity and death. Anyone taking a drug in this class is encouraged to take regular liver function tests in order to monitor toxicity levels.

And there’s always Sitagliptin, we know currently heavily advertised as Januvia and saxagliptin, aka Onglyza. There’s Iraglutid, heavily advertised as Victoza, and Exenatide, aka Byetta. These drugs delay your stomach from emptying therby suppressing your appetite. This class of drugs are called dipeptidyl peptidase-4 (DPP-4) inhibitors. They are supposed to work in conjunction with diet and exercise.

And, there’s Metformin.

In a class of drugs called biguanides, Metformin, aka Glucophage, lowers blood glucose without increasing insulin secretion, thereby it seems to be able to avoid destroying your pancreas. Ironically, the reason why it works is not known. Biguanides have been around since the 1920s, went out of fashion after the mass production of insulin, and came back into use in the 1950s.

Metformin is generic and inexpensive. There are side effects and around 1 in 3 users report having diarrhea. But, more important, Metformin can cause lactic acidosis, a condition caused by too much acid in your body. Abdominable pain and vomiting are symptomatic of this condition. And when Metformin is combined with other orals and/or insulin, hypoglycemia is another possible side effect. However, Metformin does seem to lower A1C results by about an extra 1% over other orals. If you do not suffer from any side effects, Metformin may be the best choice out of all groups of oral medications.

What is the advantage of Afrezza?

Doctor Howard Zisser, Director of Research and Technology, Sansum Diabetes Research Institute, in association with the Juvenile Diabetes Association and the College Of Engineering at the University of California at Santa Barbara [UCSB], states in a published video report in regard to their findings about Afrezza as used in their development of the world’s first artificial pancreas,

The advantage of inhaled insulin is that it gets in right away. It works very quickly... It will act when you want it to and by the time the meal is over, that insulin should be going away so you don’t have to worry about having low blood sugar a couple of hours after the meal. The purpose of this study was to use inhaled insulin to get better post prandial glucose control. The post prandial exposure is approximately half that of when [the patient] used inhaled insulin as opposed to when [the patient] does not use inhaled insulin. We’re very encouraged by these results as it brings [the patient’s] glucose level closer to normal.”

Dr. Korhan Raif, of The Quincy Medical Group, Illinois, states,

“I think it’s really going to help with compliance. I think the other thing is you are probably going to have a little less weight gain, you’re going to have a little less hypoglycemia, and people are going to end up in the E.R. a little bit less… Inhaled insulin is very rapid. You inhale it, you eat your meal and by the time you’re done with your meal, the insulin is out of your system so its less likely that you’ll have a low blood sugar episode”.

Dr. Supneet Saluja, Endocrinology, Mercy Medical Center, Baltimore, in a televised report, states,

If you have [insulin] in an inhaled form, the phobia for needles goes away. The device itself is really easy to use...”

Robert Gabbay, Chief Medical Officer of the Joslin Diabetes Center, states,

Inhalable insulin is a new way to deliver insulin… It gets absorbed really quickly into the body. The lungs, where the [inhaled] insulin ends up, has a lot of blood flow to it and quickly gets into the bloodstream… Some people with Type 2 diabetes may only need [this] mealtime insulin. Their body may make the rest of their insulin needs…Inhalable insulin is a new option for the treatment of diabetes. It’s exciting… ”

The reason why orals exist is because T2 diabetics do not want to inject insulin but not one of the orals can do what insulin can do for a diabetic. The orals are simply methods of working around the problem of a diabetic’s body not using insulin properly. But, none of the orals can properly address the main issue; insulin resistance. And, if they do, they may burn out a diabetic’s pancreas. And, that’s a lot like going from the frying pan into the fire.

Doctors prescribe orals because they believe that the T2 diabetic patient is better off on the orals than living without insulin. And until Afrezza, that logic made a lot of sense. If the patient would not inject, then provide the patient with the next best thing.

But, Afrezza may put an end to that paradigm. Afrezza is inhaled and may be more likely to be used because of that fact.

Early adopters, anecdotally, are reporting that they are lowering their A1C levels to prediabetic and normal ranges. A sampling of recent statements from a growing number of Afrezza users support the idea that Afrezza is a superior insulin therapy:

Laura Kronen: “My life has transformed since taking it. It’s truly amazing.”

Eric Fenar: “Afrezza allows me to live my life w/o high sugars. No unexplained lows hours after a meal”

Gustavo Basualdo: “This might be hard for non T1s to grasp but being able to change my routine with no extra effort or impact on BG is huge.”

Brian Lynch: “Afrezza is the real deal. Diabetics who want to embrace their lives, try and stay on it.”

Crusader 30: “Supper 109, 132, 118. Afrezza is all I expected…”

Afrezza Spiro: “BG numbers keep getting better. Afrezza in total control. It’s really that simple. Afrezza gives you insulin when you need it.”

Hillard Saveth: “…Went from 8.1 to 6.8, eating the same.”

Charles R. Lacy: “I still can’t [get] over how fast it works. The speed in which it works is incredible.”

Accepting that most early adopters are posting excellent A1C results on Afrezza, anecdotally, it is important to remember that these results will eventually have to be proven in a new Sanofi study. Sanofi will at some point need to address the issue of Afrezza having only received a non inferior determination at the conclusion of the FDA designed trials. And, there is still a question regarding any potential issues regarding inhaling insulin through the lungs which will need to be addressed in an eventual long term study.

However, starting patients on Afrezza when the T2 A1C level is still within a low diabetic range could keep cellular damage to a minimum. Afrezza can be used in conjunction with a nightime insulin if a basal is required. And, Afrezza can also be used in combination with Metformin if the patient is comfortable on that particular oral.

In a paper entitled, Clinical Evidence For The Earlier Initiation Of Insulin Therapy In Type 2 Diabetes, Dr. David R. Owens, states,

“The natural history of type 2 diabetes mellitus (T2DM) is a relentless progression of β-cell failure and dysregulation of β-cell function with increasing metabolic derangement. Insulin remains the only glucose-lowering therapy that is efficacious throughout this continuum. However, the timing of introduction and the choice of insulin therapy remain contentious because of the heterogeneity of T2DM and the well-recognized behavioral and therapeutic challenges associated with this mode of therapy…

Independent of its effects on glycemic control, insulin possesses anti-inflammatory and antioxidant properties that may help protect against endothelial dysfunction and damage resulting in vascular disease. Insulin therapy and the achievement of good glycemic control earlier in T2DM provide long-term protection to end organs via “metabolic memory” regardless of subsequent treatments and degree of glycemic control. This is evidenced from long-term observations continuing from trials such as the United Kingdom Prospective Diabetes Study. As such, early initiation of insulin therapy may not only help to avoid the effects of prolonged glycemic burden, but may also positively alter the course of disease progression.

So, will Afrezza replace orals in insulin therapy? Let’s wait and see.

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