Diabetes and CVD Drug Developments: Opportunities to Improve Outcomes

In reviewing key trial findings, the Food and Drug Administration has granted approval to drugs that promise better glucose control or lipid-lowering efficacy.

with John Buse, MD, PhD, and Eliot A. Brinton, MD

First non-insulin drug to gain FDA approval to improve type 1 diabetes management.

Expanded CVD Indication Granted to Dulaglutide for Diabetes

GLP- receptor agonist, dulaglutide (Trulicity), gains Food and Drug Administration approval for a dual indication of both primary and secondary cardiovascular (CV) prevention in response to demonstrated efficacy in reducing of major adverse cardiovascular events (MACE) in adults with type 2 diabetes who have either multiple CV risk factors or established disease,1 according to Eli Lilly and Company.

The new indication was given consideration after reviewing results from the REWIND Trial—a randomized, double-blind, placebo-controlled REWIND CV outcomes trial conducted at 371 centers internationally—for patients of at least 50 years with type 2 diabetes who received a once-weekly injection of dulaglutide or placebo experienced a reduction in nonfatal myocardial infarctions, stroke and cardiovascular mortality by 12% in adults with T2D.2

This trial,2 is the longest-running cardiovascular-related study of the GLP-1 receptor agonist class (with a median follow-up time of 5.4 years) achieved one of the lowest baseline hemoglobin A1c levels of any CV outcome trial in a diabetic population.

"For the first time, health care providers can prescribe a diabetes medicine proven to significantly reduce the risk of experiencing a cardiovascular event for people with type 2 diabetes with and without established cardiovascular disease," said Sherry Martin, MD, vice president of medical affairs at Eli Lilly and Company. "Trulicity can help people achieve their A1C goals and protect them from experiencing a cardiovascular event with a once-weekly, easy-to-use treatment option."1

Eli Lilly underwrote the REWIND study. 

Daily Oral Formulation Enhances Blood Glucose Control in Type 1 Diabetes

In reviewing results of an investigational oral glucose therapeutic—a liver selective glucokinase activator, known as TTP399—from the Simplici-T1 study,3 researchers reported that daily oral administration of this pharmacotherapy showed improved insulin control based on hemoglobin A1c (HbA1c) levels in adults with type 1 diabetes.

Results of a 12-week, phase 2 (part 2) trial was conducted to demonstrate achievement of optimal insulin management by achieving a greater reduction in HbA1c among adults (n=85) with type 1 diabetes when compared with placebo plus insulin,presented at the 55th annual meet of the European Association for the Study of Diabetes. In announcing these findings,4  the efficacy of this novel antidiabetes medication as adjustive therapy for type 1 diabetes was touted for achieving a placebo-adjusted reduction in HbA1c of 0.32% at the end of the three-month study.

“In the type 1 diabetes space, this offers the best prospect for enhancing treatment since insulin was introduced,” John Buse, MD, PhD, director of the Diabetes Center and executive associate dean for clinical research at the University of North Carolina School of Medicine at Chapel Hill, told EndocrineWeb.

Dr. Buse, a principal investigator, and colleagues used two statistical approaches in evaluating the effects of TTP399. The primary analysis evaluated the effect of HbA1c regardless of treatment adherence or changes in insulin delivery showing that the primary endpoint was met:   improvement in HbA1c levels with TTP399 compared with placebo at week 12 (P = 0.03).3,4

To rule out the chance that the HbA1c reduction was achieved due to increased delivery of insulin (3 units per day), a second analysis was conducted to assess for participants treated with TTP399 who achieved a placebo-subtracted reduction in HbA1c of 0.32% (P = 0.001).3,4

Participants who received TTP399 experienced a mean 0.21% reduction in their HbA1c as compared to the placebo group which had a  0.11% increase in their glucose level. The mean baseline HbA1c was 7.6% after the insulin optimization period.3,4

The researchers reported that the drug was well tolerated, with no between-group differences in treatment-related adverse events, including no reports of diabetic ketoacidosis. Among patients receiving TTP399, there were fewer reports of symptomatic hypoglycemic versus placebo (2 and 8, respectively).3,4

There was a two-hour improvement in daily time-in-range in the treatment group in comparison to placebo (P = 0.03), and a reduction in total mealtime bolus insulin dose of 11% relative to baseline (P = 0.02) while the placebo group had a mean 3% decrease.4

“This drug has a unique mechanism of action that promises to fulfill a tremendous unmet need in type 1 diabetes,” Dr. Buse told EndocrineWeb. “The majority of patients type 1 diabetes are inadequately controlled and have a need to achieve a greater reduction in their HbA1c, so I am encouraged by the results of this study and of the prospect that it might have a meaningful clinical impact.”

“To have innovation in the type 2 diabetes space, we would now need a very effective drug to break into what is already a crowded [therapeutic] space given the need for a large investment to gain FDA approval, whereas for type 1 diabetes, there is essentially no competition so the benefits seen with [TTP399} are on par for those seen with continuous glucose monitoring, GLP-1RAs, and SGLT-2 inhibitors,” said Dr. Buse, “with no serious adverse effects albeit with arguably small numbers.”

“That said, further studies are required to define the role of TTP399 in the management of type 1 diabetes,” he said. Whether it will deliver moderate benefits in all patients or convey greater benefits to specific patient subgroups remains to be seen.

First-in-class Non-Statin Lipid-Lowering Agent Approved to Fill Unmet Need

Nexletol (bempedoic acid), the first oral, daily, non-statin lipid-lowering agent— a small molecule ATP citrate lyase inhibitor—was granted approval by the Food and Drug Administration to augment LDL-cholesterol lowering in adults when used as an adjunct to diet and maximally tolerated statin therapy in patients with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease (CVD),5 according to Esperion Therapeutics.

The new drug application was granted after data representing the clinical trial treatment experience of more than 3,000 patients was reviewed in data submitted from several clinical studies, indicating an 18% increase in efficacy in reducing LDL-C as compared with placebo.6

“Bempedoic acid alone provides only modest LDL-C lowering; however, [there are some distinct advantages], Eliot A. Brinton, MD, FAHA, FNLA, FACE, president of the Utah Lipid Center in Salt Lake City, and past president of the American Board of Clinical Lipidology, told EndocrineWeb:

  • It has a benign safety and tolerability profile.
  • It is roughly twice as effective when added to ezetimibe, and fewer than 10% of ezetimibe-eligible patients are currently taking that drug. Bempedoic acid then becomes a vehicle to facilitate the correction of the serious under-use of ezetimibe, which is an important CV prevention drug.
  • When bempedoic acid is given in combination with ezetimibe, it will be priced and accessible identically to bempedoic acid alone, so the ezetimibe will be free and will not require a separate prescription.

“Bempedoic acid is roughly one-third more effective when given without a statin, and many patients who need further LDL-C lowering have refused or have stopped taking statin therapy,” said Dr. Brinton.

Overview of Clinical Data Used to Support this New Drug Application

The review included three major clinical trials:

  • CLEAR Harmony—Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients with Hyperlipidemia and High CV Risk trial was an interventional, randomized study of individuals (n=2,230) whose LDL were not sufficiently controlled on statin therapy from 98 sites were received treatment for 52 weeks.6 The findings,6 published in the New England Journal of Medicine, were favorable. However, the incidence of adverse events led to a higher withdrawal rate in the bempedoic acid group than placebo (10.9% vs. 7.1%, respectively), and similarly for gout (1.2% vs. 0.3%). 
  • CLEAR Serenity—A phase 3, randomized double‐blind, placebo‐controlled CLEAR (Cholesterol Lowering via bEmpedoic acid, an ACL‐inhibiting Regimen) Serenity 2:1 study for patients (n= 345) with hyperlipidemia and a history of intolerance to at least two statins (1 at the lowest available dose) due to muscle-related side effects was conducted to evaluate the safety and efficacy of bempedoic acid (180 mg) over placebo for 24 weeks.7 These results appeared in the Journal of the American Heart Association.
  • CLEAR Wisdom—Phase 3, clinical trial of patients (n=779) enrolled in 91 sites in the US and Europe who were taking background, maximally tolerated statin therapy for LDL-C levels of 70 mg/dL or higher who were randomized (2:1) to bempedoic acid (19=80 m placebo over 12 weeks.9  The results, published in JAMA, supported the efficacy of bempedoic acid which achieved a significant reduction in LDL-C levels versus placebo at study completion (–15.1% vs 2.4%, respectively; difference:  –17.4% [95% CI, –21.0% to –13.9%]; P < 0.001).8

Overall, reported side effects were comparable in the treatment and placebo group; label warnings and precautions include hyperuricemia, with the development of gout in a small percentage of patients, as well as a slight increase in risk of tendon rupture or injury. For more information about indications and side effect, here’s the label.

Combination Therapy of Bempedoic Acid and Ezetimibe—Nexlizet— Approved

A second LDL-C lowering medicine—a fixed dose bempedoic acid (180 mg)/ezetimibe (10 mg) combination pill—was also granted FDA approval, within the same week as bempedoic acid alone, also to be prescribed in addition to diet and maximally tolerated statin therapy.9,10

The CLEAR Tranquility Cardiovascular Outcomes Trial, is a phase 3, randomized, event-driven, double-blind, placebo-controlled study of 14,032 patients who have hyperlipidemia and an elevated CV risk enrolled in 1,400 sites across 32 countries.10 This CLEAR trial—to evaluate the efficacy and safety of bempedoic acid as add-on to ezetimibe therapy in patients with elevated LDL-C)—examined the change in LDL-C in CV at-risk individuals unable to tolerate statin therapy at doses greater than those defined as low dose.

Results of this single center, four-arm clinical trial in which patients (n=301) taking a maximally tolerated statin received the fixed dose combination treatment resulting in a 38% reduction in LDL-C compared to placebo therapy.10 (See clinical studies). The data also indicated that this combination treatment was able to decrease high sensitivity C-reactive protein by 35% from baseline levels as compared with placebo. 

The FDA advises clinicians to inform patients that bempedoic acid/ezetimibe therapy:11

  • May be taken with or without food
  • Avoidance of concomitant use with simvastatin dosed greater than 20 mg or pravastatin at dose greater than 40 mg.
  • For patients also on a bile acid sequestrant, this lipid-lowering agent should be taken at least two hours before or four hours after taking the bile acid sequestrant.

“One key point in favor of the fixed dose, non-statin lipid-lowering combination is that both medications are only available in a single dose so there is no need to worry about dosing, which is a frequent concern with other fixed-dose combinations,” said Dr. Brinton.

“In my opinion, Esperion would do well do make clear to all providers that the fixed dose combination therapy is essentially always the best idea [for high risk patients],” he said.

Which Patients Should be Considered for Combination Therapy? “Those not yet taking ezetimibe—the vast majority of patients are seen by PCPs, cardiologists, [and endocrinologists]—whereas the few lipidologists in the US are already using ezetimibe in everyone patient but we writer fewer than 5% of all lipid prescriptions,” said Dr. Brinton.

He added: “And, those already taking ezetimibe who would like to save on out-of-pocket costs, and/or reduce their pill count. Basically, this applies to all patients needing additional LDL-lowering management‑which accounts for two-thirds or more of all high-risk patients. In effect, all patients except the rare ezetimibe intolerant patient” would gain cardiovascular disease risk lowering benefit from this add-on treatment.

Awaiting CLEAR Cardiovascular Outcomes Trial Results for Bempedoic Acid

The CLEAR Cardiovascular Outcomes Trial, is a phase 3, randomized, event-driven, double-blind, placebo-controlled study of 14,032 patients who have hyperlipidemia and an elevated CV risk enrolled in 1,400 sites across 32 countries.

Data on the efficacy of bempedoic acid on cardiovascular morbidity and mortality is currently being analyzed from a global CLEAR cardiovascular outcomes trial (CVOT) initiated to assess the effects of bempedoic acid on the occurrence of MACE in patients with, or at high risk for, CV disease who were taking the maximum dosage of at least a moderate statin and deemed insufficiently responsive.

“Although the CVOT data with bempedioic acid will be helpful, it is not necessary at this point,” said Dr. Briton. “The LDL-lowering hypothesis has been proven, especially for medications that lower LDL by upregulating the LDL-receptor; this means that we can use bempedoic acid with confidence that it will reduce CVD roughly proportional to the LDL-C reduction and underlying risk of the patient.”

He added: “Bempedoic acid alone may well outperform expectations in the CVOT because these subjects are not taking statins. This will increase the CV rates and risk in the trial, placing [patients] on a steeper rate slope (related to but perhaps somewhat independent of their baseline LDL-C), thereby increasing the LDL-C lowering effect achieved by bempedoic acid.”

Nexetol will be commercially available prescription in the US, on March 30, 2020, and the company expects that with insurance coverage consumers may pay as little as $10 per script for up to a three-month supply,5 according to the company. Nexlizet will be available later in the year.

CLINICAL GUIDANCE ON LIPID MANAGEMENT IN HIGH-RISK, POOR LDL RESPONDING PATIENTS

Dr. Brinton offers the following recommendations for lipid-lowering in patients whose LDL-C remains high while on statin monotherapy; rather, they could be handled by following the next three steps (in sequence):

  1. Have a frank conversation about resuming statin adherence—assess whether they ever filled the first prescription? Are they actually taking it? Can they be persuaded to take it consistently, on a daily basis, instead of occasionally or to restart if they’ve stopped?
  2. Try a different statin—most patients who have failed statin therapy have tried only ONE, at only ONE dose—and most of these patients are most likely to be successful on a different statin or lower dose on the first statin. "Despite our best efforts, many patients are truly statin-intolerant, or at least cannot be persuaded out of their statin phobia, and at best, primary care providers rarely have time to perform optimal fine-tuning of statin treatment.”
  3. Add ezetimibe monotherapy—cheap and somewhat effective, but not tried often enough. For patients who have never tried ezetimibe despite a need for enhanced LDL-lowering should do so, but ezetimibe is too seldom prescribed. “This combination [BA/ezetimibe] therapy doubles the LDL lowering seen with ezetimibe alone, making LDL goal achievement likely in most patients. Those who remain above the LDL-C threshold on maximally tolerated statin therapy plus ezetimibe and bempedoic acid will be the ones who still require the injectable PCSK9 inhibitor monoclonal antibodies.”

"Although I predict that many clinicians may simply opt to add bempedoic acid without first attempting these 3 steps, I recommend that bempedoic acid be added only after the patient has done their best with statins, followed by ezetimibe and then bempedoic acid (if needed) in sequence," said Dr. Brinton.

"Alternatively, if the patient is still roughly 30% or more above goal on maximally-tolerated statin therapy, adding ezetimibe and bempedoic acid at the same time (as a fixed-dose combination) would be simpler and likely better. Hopefully, both commercial and government insurance will readily cover bempedoic acid monotherapy now, and the fixed-dose combination once it becomes available,” he said.

Dr. Buse was a primary investigator on the TTP399, which was funded by vTv Therapeutics Inc.; Dr. Brinton is a consultant and speaker for Esperion.  

Continue Reading:
Managing Complex Lipid Disorders: Choosing the Right Pharmacotherapy
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