Category Archives: Drugs for Diabetes

Type 2 Diabetes: Significant Health Benefits From Drugs Without Hypoglycemia

Insulin isn’t yellow

A recent study looked at the health benefits of type 2 diabetes drugs, comparing drugs that can cause hypoglycemia and those that don’t. The very first sentence of the abstract didn’t give me much hope for what followed. That sentence was: “Different guidelines provide similar, but not identical, therapeutic targets for HbA1c in type 2 diabetes. These targets can also depend from the different pharmacological strategies adopted for intensifying glycemic control.” Did you catch the misprint?

This meta-analysis of 13 clinical trials was looking for differences in various health outcomes over the course of at least two years, comparing successful intensive management to standard care or placebo. Successful intensive management was defined as at least a 0.5% (6 mmol/mol) improvement in hemoglobin A1c (HgbA1c) level. “Intensification” of drug therapy is usually applied to a patient who is not at goal HgbA1c level. Undoubtedly, the benefits of intensification will be greater for those at HgbA1c of 10% than for those at 7.5%. BTW, few large clinical trials include patients over 75 years of age.

For my U.S. readers, note that other countries often specify HgbA1c values as mmol/mol instead of %. And blood sugars are not our usual mg/dl, but instead reported as mmol/l. HbA1c of 7% equals 53 mmol/mol, which would indicate and average blood sugar of 154 mg/dl or 8.6 mmol/l. As another example, HbA1c of 6.5% is 48 mmol/mol, reflecting average blood sugar of 140 mg/dl or 7.8 mmol/l. Are you thoroughly confused yet?

In the general population, lowest levels of mortality are seen at HgbA1c’s around 5 to 5.5% (31 to 36.6 mmol/mol). The average healthy non-diabetic adult hemoglobin A1c is 5% (31 mmol/mol) and translates into an average blood sugar of 100 mg/dl (5.56 mmol/l). This will vary a bit from lab to lab. Most healthy non-diabetics would be under 5.7% (38.8 mmol/mol). In December, 2009, the American Diabetes Association established a hemoglobin A1c criterion for the diagnosis of diabetes: 6.5% (47.5 mmol/mol) or higher. Diagnosis of prediabetes involves hemoglobin A1c in the range of 5.7 to 6.4% (38.8 to 46.5 mmol/mol). 

Some expert panels recommend aiming for HgbA1c under 7% (53 mmol/mol), others recommend under 6.5% (48 mmol/mol). A major point of debate between the two guideline goals, is that the lower you set the goal, the greater the risk of drug-induced hypoglycemia, which can be lethal. In the early 1980s, the only drugs we had for diabetes were insulin, sulfonylureas, and metformin. Two of those three can can cause hypoglycemia. Now, a majority of our type 2 diabetes drugs don’t cause hypoglycemia.

“Try this for your vertigo”

The Italian researchers did this meta-analysis as part of their effort to produce diabetes drug treatment guidelines for the Italian population. On to the study at hand…

What Did the Researchers Find?

Improved glycemic (blood sugar) control by intensive attention reduced the major cardiovascular event rate by 10% and reduced renal adverse events by 25% but did not affect overall mortality or eye complications.

Intensified therapy with hypoglycemia-inducing drugs did not reduce overall mortality.

Drugs without potential for causing hypoglycemia were linked to lower risk of major cardiovascular events, kidney adverse events, and overall mortality, for HgbA1c under 7% (53 mmol/mol).

In conclusion, the results of this meta-analysis of RCTs show that in people with T2DM the improvement of glycemic control with drugs not inducing hypoglycemia is associated with a reduction in the risk of long-term chronic vascular complications (major adverse cardiac events and renal adverse events) and all-cause mortality, at least for HbA1c levels above 7%. The reduction of HbA1c below that threshold could have some favorable effects, but there is no available direct evidence in this respect. When the reduction of HbA1c is achieved with drugs inducing hypoglycemia, a progressive reduction of complications and an increase in the risk of severe hypoglycemia is observed. Therefore, the choice of the most adequate HbA1c target for each patient with T2DM should be made considering an appropriate risk/benefit ratio.

Full text in Nutrition, Metabolism & Cardiovascular Diseases.

I think the researchers were particularly glad to find that intensification of drug therapy can reduce risk of heart attack, stroke, kidney complications, and death; all this without the risk of hypoglycemia that comes with drugs like insulin and sulfonylureas. The lack of a mortality benefit from hypoglycemia-inducing drugs may also be important. The benefits of intensive drug therapy (or lack thereof) depend somewhat on the particular complication you’re trying to avoid, and on baseline HgbA1c. Drug therapy is complicated! I expect these researchers would recommend a treatment HgbA1c goal of <7% rather than <6.5%.

Steve Parker, M.D.

PS: Reduce your need for diabetes drugs by losing excess weight, exercising, and eating low-carb.

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Dr Edelman on Hypoglycemia Unawareness & Glucagon

Diabetes Daily has in important interview with Dr Steven Edelman on hypoglycemia (particularly in type 1 diabetes) and the need for injectable glucacon to treat it. This could easily apply also to type 2 diabetes that’s treated with insulin or other drugs that can cause hypoglycemia. Folks with type 1 diabetes seem to be more prone to hypoglycemia unawareness. That is, the blood sugar is dangerously low, but not recognized or treated promptly, potentially resulting death. Dr Edelman notes that dangerous hypoglycemia has been significantly reduced by the use of continuous glucose monitoring (CGM).

Note that CGM measure glucose levels in the the fluid in between the cells of subcutaneous tissue (AKA interstitial fluid). Your familiar fingerstick glucose is measuring capillary fluid levels. Capillaries are tiny blood vessels at the end of arteries. After going through the capillaries, blood enters veins for the return trip to the lung and heart. Glucose levels in the interstitial fluid and capillaries may not be the same as in the large arteries delivering glucose to the brain. Most CGM devices will provide the user with an alert when the glucose level drops too low, so that remedial action can be taken.

An excerpt from Diabetes Daily:

What are some ways that the CGM can most effectively help avoid hypos?

Well, one of the things I do in clinic is to really check where people set their upper and lower alerts. I had a patient yesterday in clinic who has had type 1 for 60 years. Her A1C is unbelievable, but she does have hypo unawareness and her lower alert was 65. You have to convince people that the extra alerts are worth it to you.

A lot of people said they put their lower alert at 65 and they don’t realize this situation called the “lag time.” So, when your blood sugar is dropping, even if you have a diagonal arrow down compared to, even worse, one arrow down or two arrows down, looking at the Dexcom arrows, they don’t realize that the glucose in your circulation is probably much lower than it appears on the Dexcom monitor or your phone. Because the Dexcom sensor and other sensors too, they measure the glucose in the subcutaneous tissue, and there’s a lag between the subcutaneous tissue and the circulation.

When your Dexcom goes off or when your CGM goes off at 65, and if your trend arrow’s going down, you could be 45 or 40. So that’s really an important issue, especially for people that their symptoms aren’t as obvious anymore. You could be caught off guard. And I had multiple patients that has occurred with. And then unfortunately, as you know, the majority of T1Ds in this country do not wear a CGM and that’s the topic of a whole other story.

Does this lag time issue apply to a regular glucometer as well?

Yes. If your blood sugar is dropping, your meter or CGM may be perfectly accurate of the subcutaneous tissue at 65. If you checked your blood sugar with a meter, it’s still going to say 65, but your circulation that’s going to your brain might be 45. So, the lag time is key. You could have the most accurate meter or CGM in the world, it doesn’t affect the lag time.


Click for my five-year-old article on drugs that can cause diabetes.

Click for my brief article on hypoglycemia unawareness.

Click for my general article on recognition and treatment of hypoglycemia.

Steve Parker, M.D.

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Finerenon: New Hope for Prevention of Kidney Disease and Cardiac Death in Type 2 Diabetes

Your friendly neighborhood drug supplier

Verbatim from the FDA press release:

FDA has approved Kerendia (finerenone) tablets to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidney disease associated with type 2 diabetes.

Diabetes is the leading cause of chronic kidney disease and kidney failure in the United States. Chronic kidney disease occurs when the kidneys are damaged and cannot filter blood normally. Because of defective filtering, patients can have complications related to fluid, electrolytes (minerals required for many bodily processes), and waste build-up in the body. Chronic kidney disease sometimes can progress to kidney failure. Patients also are at high risk of heart disease.

The ultimate role of finerenone in our armamentarium against disease and suffering will probably depend on cost and the number needed to treat.

The efficacy of Kerendia to improve kidney and heart outcomes was evaluated in a randomized, multicenter, double-blind, placebo-controlled study in adults with chronic kidney disease associated with type 2 diabetes. In this study, 5,674 patients were randomly assigned to receive either Kerendia or a placebo.

The study compared the two groups for the number of patients whose disease progressed to a composite (or combined) endpoint that included at least a 40% reduction in kidney function, progression to kidney failure, or kidney death. Results showed that 504 of the 2,833 patients who received Kerendia had at least one of the events in the composite endpoint compared to 600 of the 2,841 patients who received a placebo.

The study also compared the two groups for the number of patients who experienced cardiovascular death, a non-fatal heart attack, non-fatal stroke, or hospitalization for heart failure. Results showed that 367 of the 2,833 patients receiving Kerendia had at least one of the events in the composite endpoint compared to 420 of the 2,841 patients who received a placebo, with the treatment showing a reduction in the risk of cardiovascular death, non-fatal heart attack, and hospitalization for heart failure.

Side effects of Kerendia include hyperkalemia (high levels of potassium), hypotension (low blood pressure), and hyponatremia (low levels of sodium). Patients with adrenal insufficiency (when the body does not produce enough of certain hormones) and those receiving simultaneous treatment with strong CYP3A4 inhibitors should not take Kerendia.

Kerendia received priority review and fast track designations for this application.

FDA granted the approval of Kerendia to Bayer Healthcare.


Click for prescribing information.


Parker here.

Just offhand, finerenone doesn’t look like a great drug. Helpful, maybe. Chronic kidney disease can end up at ESRD (end stage renal disease), which requires thrice weekly hemodialysis if the patient wants to stay alive. (Yes, peritoneal dialysis is an alternative.) Preventing ESRD is an incredible benefit for an individual.

Finerenone seems to be a well-tolerated daily pill. The main adverse effect is elevated blood potassium level, which can cause palpitations, and death infrequently. Less commonly, the drug can cause low blood pressure.

Steve Parker, M.D.

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Filed under Drugs for Diabetes, Heart Disease, kidney disease, Longevity, Stroke

Diabetes Drug Semaglutide Promotes Weight Loss

“Should I wait for FDA approval?”

I met a patient at the hospital recently who was taking semaglutide. I asked how long he had diabetes and he told me he didn’t have diabetes: his PCP (primary care physician) was prescribing it for weight loss.

A recent study enrolled 1,961 obese non-diabetics and found a very significant weight loss difference compared to the placebo group. I expect Novo Nordisc will be asking for FDA approval to market semaglutide, originally for diabetes, as a weight-loss drug. But what happens after you quit taking the drug? I bet you know.

In participants with overweight or obesity, 2.4 mg of semaglutide [injected] once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight.

Source: Once-Weekly Semaglutide in Adults with Overweight or Obesity | NEJM

Steve Parker, M.D.

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Are Insulin Prices Higher Under the Biden Administration?

Roasted Radishes and Brussels Sprouts

Newsweek looks at the issue.

In any case, why not reduce your need for insulin with low-carb eating?

Steve Parker, M.D.

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Proton Pump Inhibitors Linked to Type 2 Diabetes

prilosec, proton pump inhibitor
Neither the cited study nor I implicate Prilosec in particular

Regular use of proton-pump inhibitors (PPIs) increases patients’ risk of developing type 2 diabetes mellitus (T2DM) by 24%, an observational study published in Gut has suggested.

Source: Regular use of PPIs linked with increased risk of type 2 diabetes, study suggests | News | Pharmaceutical Journal

Proton pump inhibitors are widely used in the U.S. to treat esophageal reflux, ulcers, and dyspepsia. They are among the most widely prescribed drugs. You can also get them over-the-counter. Brand names include Protonix, Prilosec, and Nexium.

The study at hand defined “regular use” as at least twice per week. The study was an epidemiological one observing participants for 10-12 years. The more years of regular use, the greater risk of diabetes developing. Nearly all participants were White, so results may not apply to other ethnicities.

Note that this study doesn’t prove that PPIs cause diabetes. They just found a statistical linkage. As you know, correlation does not equal causation. We don’t know how PPIs could cause T2 diabetes. From the article:

According to the study, the possible mechanism for the association could be related to gut microbiota, as previous studies have shown that PPI use is associated with reduced diversity of gut microbiome and consistent changes in the microbiota phenotype.

Steve Parker, M.D.

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Cut Your Diabetes Drug Costs

Caprese salad: mozzarella cheese, tomatoes, basil, extra virgin olive oil≠≠≠≠

Christine Fallabel has and article at Diabetes Daily that may save you beaucoup bucks on your diabetes care, whether or not you have insurance coverage.

If you live in a country like the United States, where the majority of health insurance is privatized and there is no strong social safety net, it can feel as though managing a chronic disease like diabetes requires nothing but lots of money. And it does. As of 2017, diabetes cost the United States a staggering $327 billion dollars per year on direct health care costs, and people with diabetes average 2.3x higher health care costs per year than people living without the disease.

Diabetes is also devastatingly expensive personally: the cost of insulin has risen over 1200% in the past few decades, with no change to the chemical formula. In 1996, when Eli Lilly’s Humalog was first released, the price for a vial of insulin was $21. In 2019, that same vial costs around $275. Studies show that 1 in 4 people ration insulin simply due to cost. Diabetes Daily recently conducted a survey study, with almost 2,000 participants, of which an overwhelming 44% reported  struggling to afford their insulin.

So where does this leave patients who don’t have tons of money to spend on insulin and supplies, or who don’t have adequate health insurance coverage for the technology to help prevent complications? Can you manage diabetes well without lots of money? The short answer is yes. The long answer is a bit more complicated.

Source: Can You Manage Diabetes Well Without Lots of Money? – Diabetes Daily

Steve Parker, M.D.

PS: What else can cut your diabetes drug bill? Low-carb eating!

low-carb mediterranean diet

Click the pic to purchase at Amazon.com. E-book versions also available at Smashwords.com.

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Are Your Drugs So Expensive Due to PBMs?

Compared to Europe and Canada, drugs are about 10 times more expensive in the U.S.

The American Prospect has an eye-opening article from 2017 that sheds light on pharmacy benefits managers (PBMs). Ever heard of them?

Author David Dayen starts with comments from pharmacy owner Frankil talking about how he determines how much money he makes on retail sale of a drug:

Like any retail outlet, Frankil purchases inventory from a wholesale distributor and sells it to customers at a small markup. But unlike butchers or hardware store owners, pharmacists have no idea how much money they’ll make on a sale until the moment they sell it. That’s because the customer’s co-pay doesn’t cover the cost of the drug. Instead, a byzantine reimbursement process determines Frankil’s fee.

“I get a prescription, type in the data, click send, and I’m told I’m getting a dollar or two,” Frankil says. The system resembles the pull of a slot machine: Sometimes you win and sometimes you lose. “Pharmacies sell prescriptions at significant losses,” he adds. “So what do I do? Fill the prescription and lose money, or don’t fill it and lose customers? These decisions happen every single day.”

Frankil’s troubles cannot be traced back to insurers or drug companies, the usual suspects that most people deem responsible for raising costs in the health-care system. He blames a collection of powerful corporations known as pharmacy benefit managers, or PBMs. If you have drug coverage as part of your health plan, you are likely to carry a card with the name of a PBM on it. These middlemen manage prescription drug benefits for health plans, contracting with drug manufacturers and pharmacies in a multi-sided market. Over the past 30 years, PBMs have evolved from paper-pushers to significant controllers of the drug pricing system, a black box understood by almost no one. Lack of transparency, unjustifiable fees, and massive market consolidations have made PBMs among the most profitable corporations you’ve never heard about.

***

In the case of PBMs, their desire for larger patient networks created incentives for their own consolidation, promoting their market dominance as a means to attract customers. Today’s “big three” PBMs—Express Scripts, CVS Caremark, and OptumRx, a division of large insurer UnitedHealth Group—control between 75 percent and 80 percent of the market, which translates into 180 million prescription drug customers. All three companies are listed in the top 22 of the Fortune 500, and as of 2013, a JPMorgan analyst estimated total PBM revenues at more than $250 billion.

***

PMBs initially came about as a means of saving costs. Why hasn’t that panned out?

The biggest reason experts cite is an information advantage in the complex pharmaceutical supply chain.

***

This lack of transparency enables PBMs to enjoy multiple hidden revenue streams from every other player. “It’s OK to have intermediaries, we have Visa,” says David Balto, an antitrust litigator and former top official with the Federal Trade Commission. “But these companies make a fabulous amount of money, even though they’re not buying the drug, not producing the drug, not putting themselves at risk.”

The PBM industry is rife with conflicts of interest and kickbacks. For example, PBMs secure rebates from drug companies as a condition of putting their products on the formulary, the list of reimbursable drugs for their network. However, they are under no obligation to disclose those rebates to health plans, or pass them along. Sometimes PBMs call them something other than rebates, using semantics to hold onto the cash. Health plans have no way to obtain drug-by-drug cost information to know if they’re getting the full discount.

***

It’s a long article and I confess I haven’t read the whole thing yet. I’ve read enough to rile up my sense of indignation! Pharmaceutical companies and health insurers don’t seem too upset. Because costs associated with these third-party shenanigans is simply passed on to the consumer—that’s you—in higher insurance premiums, deductibles, and co-pays.

Steve Parker, M.D.

PS: Reduce your needs for drugs with a healthy diet and lifestyle. I can help.

low-carb mediterranean diet

Click the pic to purchase at Amazon.com. E-book versions also available at Smashwords.com.

 

 

 

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Metformin: New Uses for an Old Drug

Metformin? A shirt from 1967?

Medical Xpress has an article about the possible future uses of metformin for weight loss, prostate cancer treatment, and tuberculosis treatment. It didn’t mention metformin as an anti-aging drug.

From the article:

Among medications, metformin has a long and storied past. The compound destined to become metformin was first isolated during the Middle Ages from the French lilac, a plant scientifically known as Galega officinalis. Ground flowers and leaves were administered by healers to patients suffering from constant urination, a hallmark of a disorder that later would become known as diabetes. The active ingredient in French lilac, a plant also called goat’s rue, was identified hundreds of years later as galegine, which triggered a striking reduction in blood glucose.

By the 1950s, scientists were able to exploit folk medicine uses and develop the drug that became metformin.

Source: Wonder drug? Exploring the molecular mechanisms of metformin, a diabetes drug with Medieval roots

Don’t believe everything you read. The article claims metformin’s effectiveness in type 2 diabetes is primarily due to weight loss. Conventional thinking is that it’s mostly due to decreased production and release of glucose by the liver. I guess time will tell which theory wins out. In either case, it’s a good initial drug for T2 diabetes if diet and exercise prove inadequate.

Steve Parker, M.D.

low-carb mediterranean diet

Click the pic to purchase at Amazon.com. E-book versions also available at Smashwords.com.

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Do Certain Diabetes Drugs Protect the Heart and Kidneys?

 

Blood pressure control is also extremely important for protection of heart and kidneys

I’ve been reticent to tout the putative heart-protective effects of diabetes drugs in the classes called SGLT2 inhibitors and GLP-1 receptor agonists. Frankly, their supposed kidney-protective effects haven’t even been on my radar. My hesitation to report on these matters stems from:

Maybe if Big Pharma sent me a nice check….

The GLP-1 receptor agonists seem to have beneficial effects on both heart and kidney. With SGLT2 inhibitors, renal benefits may be more prominent than cardiac. Also note that any beneficial heart or renal effects may be attributable only to certain drug within the class, and not a class effect.

For what it’s worth, the American Diabetes Association recently hosted a conference on these issues. I assume the ADA endorses the report written by three experts, two of whom have received some sort of compensation from pharmaceutical companies. This doesn’t necessarily mean they are biased. Some excerpts:

Since patients with diabetes are at increased risk for CV [cardiovascular] and renal events, reducing the risk of these events is of primary interest to improve outcomes in the long-term. [Cardiovascular events usually refers to heart attacks, strokes, and death from those. Renal events would be high loss of protein through the kidneys, impaired kidney function or chronic kidney disease, or the need for dialysis.]

SGLT2 inhibitors and GLP-1 RAs have dramatically changed the treatment landscape of type 2 diabetes due to their established CV benefits, and the observed improvements in renal function seen with these classes of agents are currently undergoing intense investigation.

***

It is now apparent that both SGLT2 inhibitors and GLP-1 RAs show consistent reductions in major adverse cardiovascular events for patients with established cardiovascular (CV) disease, and both appear to have renal benefits as well.

***

The nephron is the microscopic structural and functional unit of the kidney.

Renal effects of GLP-1 receptor agonists

These drugs may exert their beneficial actions on the kidneys through their effects on lowering blood glucose and blood pressure and by reducing the levels of insulin.

For GLP-1RAs, these [studies] include ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN-6 with semaglutide, EXCSEL with exenatide once-weekly, HARMONY with albiglutide, and REWIND with dulaglutide.

All these studies indicate that albuminuria [protein loss through urine] is reduced during treatment with GLP-1 RAs, and eGFR [estimated glomerular filtration rate, a measure of kidney function] appears to be stabilized.

These benefits are seen independently of HbA1c, weight, and blood pressure variations.

***

Heart attack is only one type of cardiovascular event

Cardiovascular effects of GLP-1 receptor agonists

Large CV outcomes trials with GLP-1 RAs have shown that these agents can reduce the risk of major adverse CV events, CV mortality, and all-cause mortality.

These CV benefits appear to be related to four distinct mechanisms:

    • Improve myocardial [heart muscle] performance in ischemic heart failure [caused by poor blood flow to heart]
    • Improve myocardial survival in ischemic heart disease
    • Ameliorate endothelial dysfunction [endothelium is the lining of arteries]
    • Decrease markers of CV risk.

***

Renal effects of SGLT2 inhibitors

  • However, many potential mechanisms have been linked to the renoprotective effects of SGLT2 inhibitors.
  • These include reduction of blood pressure, improved metabolic parameters, reduced volume overload, reduction in albuminuria, and glomerular pressure.
  • For the latter, SGLT2 inhibition appears to reduce hyperfiltration via a tubuloglomerular feedback mechanism.
  • Clinical data from CV outcomes trials have shown consistent variations in eGFR and reduction in death from renal causes with empagliflozin, canagliflozin, and dapagliflozin.
  • However, to gain more information about the renal effects of these agents, dedicated renal outcomes trials are needed to study reductions in albuminuria, changes in eGFR, number of patients reaching end-stage renal disease, need for dialysis, and deaths due to kidney failure.

***

Key Messages from the authors

Large CV outcomes trials have shown that both SGLT2 inhibitors and GLP-1 RAs are associated with significant reductions in CV events in patients with elevated CV risk.

From CV outcomes trials both classes of agents also appear to have renal benefits, although large dedicated studies are needed to establish the magnitude of this potential benefit

The mechanism of action at the basis of CV and renal benefits of SGLT2 inhibitors and GLP-1 RAs is complex, multifactorial, and still not completely understood.

 

I’m still skeptical but will keep an open mind.

Steve Parker, M.D.

PS: Bold emphasis above is mine.

low-carb mediterranean diet

Click the pic to purchase at Amazon.com. E-book versions also available at Smashwords.com.

 

 

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Filed under coronary heart disease, Drugs for Diabetes, Heart Disease, kidney disease, Stroke