Metformin is the world’s most-prescribed diabetes drug. For a generation, most Americans with newly diagnosed type 2 diabetes have been prescribed metformin as their first medication.
But now metformin’s reign as the universally acknowledged “first-line” treatment for type 2 diabetes has come to an end. Updated guidance from the American Diabetes Association (ADA), released on December 12, 2022, has substantially minimized the importance of the popular drug. The ADA’s committee of experts removed metformin from key recommendations and now ranks the drug as inferior to other options for blood sugar control, weight loss, and long-term heart and kidney protection
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The new ADA recommendation can be seen as a major endorsement for the stars of the newest generation of diabetes drugs: SGLT-2 inhibitors and GLP-1 and GIP/GLP-1 receptor agonists. These options combat hyperglycemia effectively but add other important benefits that metformin cannot claim: enhanced weight loss and more robust protection against cardiovascular and kidney disease.
In November, 2022, the FDA approved the first drug that can delay onset of type 1 diabetes. The FDA press release won’t make much sense unless you know that type 1 diabetes has several stages. From Diabetes Care:
Stage 2, like stage 1, includes individuals with two or more islet autoantibodies but whose disease has now progressed to the development of glucose intolerance, or dysglycemia, from loss of functional β-cell mass. The 5-year risk of symptomatic disease at this stage is approximately 75%, and the lifetime risk approaches 100%.
Stage 3 represents manifestations of the typical clinical symptoms and signs of diabetes, which may include polyuria, polydipsia, weight loss, fatigue, diabetic ketoacidosis (DKA), and others.
What follows is the verbatim FDA press release:
Today, the U.S. Food and Drug Administration approved Tzield (teplizumab-mzwv) injection to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes.
“Today’s approval of a first-in-class therapy adds an important new treatment option for certain at-risk patients,” said John Sharretts, M.D., director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research. “The drug’s potential to delay clinical diagnosis of type 1 diabetes may provide patients with months to years without the burdens of disease.”
Type 1 diabetes is a disease that occurs when the immune system attacks and destroys the cells that make insulin. People with a type 1 diabetes diagnosis have increased glucose that requires insulin shots (or wearing an insulin pump) to survive and must check their blood sugar levels regularly throughout the day. Although it can appear at any age, type 1 diabetes is usually diagnosed in children and young adults. A person is at higher risk for type 1 diabetes if they have a parent, brother or sister with type 1 diabetes, although most patients with type 1 diabetes do not have a family history.
Tzield binds to certain immune system cells and delays progression to stage 3 type 1 diabetes. Tzield may deactivate the immune cells that attack insulin-producing cells, while increasing the proportion of cells that help moderate the immune response. Tzield is administered by intravenous infusion once daily for 14 consecutive days.
Tzield’s safety and efficacy were evaluated in a randomized, double-blind, event-driven, placebo-controlled trial with 76 patients with stage 2 type 1 diabetes. In the trial, patients randomly received Tzield or a placebo once daily via intravenous infusion for 14 days. The primary measure of efficacy was the time from randomization to development of stage 3 type 1 diabetes diagnosis. The trial results showed that over a median follow-up of 51 months, 45% of the 44 patients who received Tzield were later diagnosed with stage 3 type 1 diabetes, compared to 72% of the 32 patients who received a placebo. The mid-range time from randomization to stage 3 type 1 diabetes diagnosis was 50 months for the patients who received Tzield and 25 months for those who received a placebo. This represents a statistically significant delay in the development of stage 3 type 1 diabetes.
The most common side effects of Tzield include decreased levels of certain white blood cells, rash and headache. The use of Tzield comes with warnings and precautions, including premedicating and monitoring for symptoms of Cytokine Release Syndrome; risk of serious infections; decreased levels of a type of white blood cell called lymphocytes; risk of hypersensitivity reactions; the need to administer all age-appropriate vaccinations prior to starting Tzield; as well as avoiding concurrent use of live, inactivated and mRNA vaccines with Tzield.
From the U.S. Food and Drug Administration May 13, 2022:
Today, the U.S. Food and Drug Administration approved Mounjaro (tirzepatide) injection to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise. Mounjaro was effective at improving blood sugar and was more effective than the other diabetes therapies with which it was compared in clinical studies.
“Given the challenges many patients experience in achieving their target blood sugar goals, today’s approval of Mounjaro is an important advance in the treatment of type 2 diabetes,” said Patrick Archdeacon, M.D., associate director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research.
Type 2 diabetes, the most common form of diabetes, is a chronic and progressive condition in which the body does not make or use insulin normally, leading to high levels of glucose (sugar) in the blood. More than 30 million Americans have type 2 diabetes. Despite the availability of many medications to treat diabetes, many patients do not achieve the recommended blood sugar goals.
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in blood sugar control. Mounjaro is a first-in-class medicine that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control. Mounjaro is administered by injection under the skin once weekly, with the dose adjusted as tolerated to meet blood sugar goals.
Three different doses of Mounjaro (5 milligrams, 10 milligrams and 15 milligrams) were evaluated in five clinical trials as either a stand-alone therapy or as an add-on to other diabetes medicines. The efficacy of Mounjaro was compared to placebo, a GLP-1 receptor agonist (semaglutide) and two long-acting insulin analogs.
On average, patients randomized to receive the maximum recommended dose of Mounjaro (15 milligrams) had lowering of their hemoglobin A1c (HbA1c) level (a measure of blood sugar control) by 1.6% more than placebo when used as stand-alone therapy, and 1.5% more than placebo when used in combination with a long-acting insulin. In trials comparing Mounjaro to other diabetes medications, patients who received the maximum recommended dose of Mounjaro had lowering of their HbA1c by 0.5% more than semaglutide, 0.9% more than insulin degludec and 1.0% more than insulin glargine.
Obesity was common among study participants, with an average body mass index of 32 to 34 kilograms/height in meters squared reported at the time of enrollment. Among patients randomized to the maximum recommended dose, the average weight loss with Mounjaro was 15 pounds more than placebo when neither were used with insulin and 23 pounds more than placebo when both were used with insulin. The average weight loss with the maximum recommended dose of Mounjaro was 12 pounds more than semaglutide, 29 pounds more than insulin degludec and 27 pounds more than insulin glargine. Those patients receiving insulin without Mounjaro tended to gain weight during the study.
Mounjaro can cause nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort and abdominal pain.
Mounjaro causes thyroid C-cell tumors in rats. It is unknown whether Mounjaro causes such tumors, including medullary thyroid cancer, in humans. Mounjaro should not be used in patients with a personal or family history of medullary thyroid cancer or in patients with Multiple Endocrine Neoplasia syndrome type 2.
Mounjaro has not been studied in patients with a history of pancreas inflammation (pancreatitis), and it is not indicated for use in patients with type 1 diabetes.
Mounjaro received priority review designation for this indication. A priority review designation directs overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions.
The starting dose is 2.5 mg subcutaneously once weekly. After four weeks dose can be increased to 5 mg once weekly. Dose can be increased every four weeks to a maximum of 15 mg once weekly.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Diabetic Mediterranean Diet 