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The content contained in this presentation was developed by Sanofi. Statements regarding specific patient cases reflect the views of the speaker. Patient care depends on the physician’s professional judgment in consideration of all available information for the individual case. The healthcare professional was compensated by Sanofi in connection with this presentation.

SOLIQUA 100/33 is a combination of a long-acting human insulin analog with a glucagon-like peptide-1 (GLP-1) receptor agonist (RA) indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use:

• Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
• Not recommended for use in combination with any other product containing a GLP-1 receptor agonist.
• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
• Not recommended for use in patients with gastroparesis.
• Has not been studied in combination with prandial insulin.

Important Safety Information for SOLIQUA 100/33 (insulin glargine and lixisenatide) injection 100 Units/mL and 33 mcg/mL

Contraindications

• During episodes of hypoglycemia.
• In patients with known serious hypersensitivity to insulin glargine, lixisenatide, or to any of the product components.

Please see full Important Safety Information at the end of the video.

Please see full Prescribing Information available at the link above the video.

Hi everybody. I'm Dr. Jeremy Pettus. I am an endocrinologist at the University of California San Diego.

In my experience, SOLIQUA 100/33 is the combination injectable therapy that helps my adult patients with type 2 diabetes and a high A1C uncontrolled on metformin, plus or minus one additional oral agent, or GLP-1 receptor agonist, achieve their A1C goals.

[Intro Music]

In order to examine the safety and efficacy of SOLIQUA 100/33, compared with both of its components, Lantus, which is insulin glargine, 100 Units per mL, and lixisenatide, a GLP-1 RA, insulin-naive type 2 adult patients inadequately controlled on OADs were evaluated in a randomized 30-week, open-label, multi-center study.

To be eligible for inclusion in the study, patients were screened and had to meet the following key criteria. They had to be diagnosed at least one year before screening, to show inadequate glycemic control, despite being treated for greater than or equal to three months with metformin, with or without a second oral glucose-lowering therapy. Now inadequate glycemic control was defined as an A1C between 7.5 percent and 10 percent for patients treated with metformin alone, and between 7 percent and 9 percent for patients treated with metformin and a second oral glucose-lowering therapy, including a sulfonylurea, glinide, SGLT2 inhibitor, or DPP4 inhibitor.

So of 2,457, a total of 1,170 patients were randomized to the study. The mean age was approximately 58.4 years, 50.6 percent of patients were male. The mean A1C at screening was 8.2 percent. The mean BMI was 32. The mean duration of diabetes was about nine years. And at screening, 57.9 percent of patients used a second OAD in addition to metformin.

The clinical study had two distinct phases, a four-week run-in period, followed by randomization. And then, a 30-week treatment period.

During the four-week run-in period, metformin treatment was optimized and all other OADs were discontinued. At the end of the run-in period, patients who had an A1C between 7 and 10 percent, and a fasting plasma glucose that was less than or equal to 250 milligrams per deciliter, were randomized to either SOLIQUA 100/33, Lantus, or lixisenatide.

Randomized patients then entered the 30-week treatment phase. The doses of SOLIQUA 100/33 and Lantus were titrated weekly to achieve a fasting plasma glucose target of less than 100 milligrams per deciliter. The Lantus dose was capped at a maximum of 60 Units. The trial was designed to show the contribution of the GLP-1 component to glycemic-lowering. And the insulin glargine dose, and the dosing algorithm, was selected to isolate the effect of the GLP-1 component. The primary endpoint was a mean change in A1C from baseline to week 30.

Study results from the LixiLan-O pivotal trial showed that SOLIQUA 100/33 significantly reduced A1C over 30 weeks.

The A1C decreased over time from a baseline level of 8.1 percent at randomization to 6.5 percent in the SOLIQUA 100/33 arm, 6.8 percent in the Lantus arm, and 7.3 percent in the lixisenatide arm at week 30.

Moreover, 74 percent of patients receiving SOLIQUA 100/33 reached an A1C of less than 7 percent by week 30, versus 59 percent in the Lantus arm, and 33 percent in the lixisenatide arm.

The final mean basal insulin daily dose was similar between SOLIQUA 100/33, which was 39.8 Units, and Lantus dose, which was 40.5 Units, determined by the FPG titration.

Now keep in mind, results observed in this trial may not reflect the effect that will be observed in the care setting.

What I find interesting are the results of a post-hoc subgroup analysis of patients with a baseline A1C that was greater than or equal to 9 percent. Now in this subgroup of patients with a high A1C, SOLIQUA 100/33 reduced A1C by 2.9 percent versus 1.7 percent with the GLP-1 RA lixisenatide, and 2.5 percent with Lantus.

The post-hoc subgroup analysis of the LixiLan-O clinical trial evaluated patients with a baseline A1C that was greater than or equal to 9 percent, up to 10.4 percent, after the four-week metformin run-in period. The doses were similar between SOLIQUA 100/33, which was 45 Units, and Lantus, of 44 Units.

Study limitations included the study was not designed or powered to detect differences between treatments within this subgroup. There was a limited sample size of 134 patients. And the p values are for descriptive purposes only, without multiplicity adjustments. Difference in effect observed may not necessarily reflect the effect that will be observed in the care setting, where alternative insulin glargine dosage can be used.

In this same post-hoc analysis of patients with an A1C of greater than or equal to 9 percent, SOLIQUA 100/33 helped 73.5 percent get to goal, versus 47.3 percent of those taking Lantus, and zero percent of patients taking the GLP-1 RA lixisenatide.

That's nearly three out of four patients. Please note the analysis limitations that I just mentioned. Now these figures support the use of the injectable combination therapy SOLIQUA 100/33 in patients with high A1C, uncontrolled, on two or more OADs.

In another post-hoc analysis of the LixiLan-O trial, glycemic variability data with SOLIQUA 100/33 was compared with data from its individual components, lixisenatide and Lantus. SOLIQUA 100/33 demonstrated greater reduction in mean SMPG concentrations across all time points, compared with its individual components alone. Now study limitations include that this data was obtained from SMPG rather than CGM. And the only patients with measurements at both baseline and week 30 were included. And glycemic variability was not the primary endpoint of these trials.

Time to glycemic control with SOLIQUA 100/33 versus Lantus was also evaluated in the post-hoc analysis. The median time for 50 percent of the patients to achieve glycemic control was 85 days for SOLIQUA 100/33 versus 166 days for Lantus. Half of the patients on SOLIQUA 100/33 achieved an A1C less than 7 percent in half the time versus Lantus.

The limitations included the present analysis was performed post-hoc. Therefore, the sample size and power calculations performed to address the study's primary endpoints may not apply to this analysis. And the present study examined patients enrolled in clinical trials, and follow-up of trial populations tends to be different from that performed in routine clinical practice.

In the pivotal study, SOLIQUA 100/33 demonstrated safety and tolerability in patients uncontrolled on OADs.

The incidence of severe hypoglycemia was zero percent with SOLIQUA 100/33. And the incidence of symptomatic hypoglycemia, which was defined as a plasma glucose less than 54 milligrams per deciliter, was 8.1 percent.

Hypoglycemia is the most common AE with insulin-containing therapy. Treatment-emergent AEs, with a frequency greater than or equal to five percent, included nausea, diarrhea, upper respiratory tract infection, nasopharyngitis, and headache.

We know that with the GLP-1 RAs in particular, GI AEs can be problematic. So let's take a closer look at the GI numbers and see how SOLIQUA 100/33, compared with the GLP-1 RA lixisenatide. Patients were five times less likely to discontinue SOLIQUA 100/33 due to GI side effects versus lixisenatide.

0.9 percent of patients discontinued SOLIQUA 100/33 due to GI side effects versus 5.2 percent for lixisenatide. The incidence of nausea was less than 10 percent with SOLIQUA 100/33, versus 24 percent with lixisenatide. The incidence of diarrhea was the same, and the incidence of vomiting was 3.2 percent with SOLIQUA 100/33 versus 6.4 percent with lixisenatide. These data suggest that SOLIQUA 100/33 has demonstrated safety and tolerability.

In my practice, most patients, at some point, will either need to go onto injectable therapy, or are already on injectable therapy. So I think they're very in favor of this idea of combining injections, because who wants to take, you know, more injections? And if you have a patient that, you know, you're deciding between, do I need basal insulin or GLP-1? Being able to combine these into one therapy, one injection, where you get, as we saw, you know, significant reductions in A1C, you can do this safely, it becomes a great option for patients to really kind of limit the burden of diabetes, you know, the number of—of injections or medications they're taking, and get them to a healthy, safe place with their—where they want their A1C to be, and where you want it to be.

Thank you for watching. To learn more about how the combination injectable SOLIQUA 100/33 can help your adult type 2 patients achieve their A1C goals, please visit the links below, or ask your Sanofi sales representative for more information or additional videos.

Important Safety Information for SOLIQUA 100/33 (insulin glargine and lixisenatide) injection 100 Units/mL and 33 mcg/mL

Contraindications

• During episodes of hypoglycemia.
• In patients with known serious hypersensitivity to insulin glargine, lixisenatide, or to any of the product components.

Warnings and Precautions

• Anaphylaxis and Serious Hypersensitivity Reactions: In clinical trials of lixisenatide, there have been cases of anaphylaxis and other serious hypersensitivity reactions including angioedema. Severe, life- threatening, generalized allergic reactions, including anaphylaxis and angioedema, can occur with insulins, including insulin glargine. There have been reports of serious hypersensitivity reactions, including anaphylactic reactions and angioedema, in patients treated with SOLIQUA 100/33. If hypersensitivity reactions occur, discontinue SOLIQUA 100/33. Use caution in patients with a history of anaphylaxis or angioedema with another GLP-1 RA because it is unknown whether such patients will be predisposed to anaphylaxis.
• Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 RAs. Cases of pancreatitis were reported in clinical trials of lixisenatide. After initiation of SOLIQUA 100/33, observe patients for signs and symptoms of pancreatitis (e.g., persistent severe abdominal pain, sometimes radiating to the back and which may be accompanied by vomiting). If pancreatitis is suspected, SOLIQUA 100/33 should promptly be discontinued. If pancreatitis is confirmed, restarting SOLIQUA 100/33 is not recommended and other antidiabetic therapies should be considered.
• Never Share a SOLIQUA 100/33 SoloStar^® Pen between Patients: Pen-sharing poses a risk for transmission of blood-borne pathogens, even if the needle is changed.
• Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Changes in insulin regimen including, strength, manufacturer, type, injection site or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Changes should be made cautiously, and the frequency of blood glucose monitoring should be increased. Adjustments in concomitant oral antidiabetic treatment may be needed.
  Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis may result in hyperglycemia; sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia. Advise patients to rotate injection site to unaffected areas and closely monitor for hypoglycemia.
• Medication Errors: SOLIQUA 100/33 contains two drugs. Do not administer more than 60 units of SOLIQUA 100/33, which may result in overdose of the lixisenatide component. Do not use other GLP-1 RAs. Accidental mix-ups between insulin products have been reported. Instruct patients to always check the label before administration. Do not withdraw SOLIQUA 100/33 from the pen with a syringe.
• Hypoglycemia: Hypoglycemia is the most common adverse reaction associated with insulin-containing therapy, which may be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity, and in patients with renal or hepatic impairment and hypoglycemia unawareness.
• Acute Kidney Injury: There have been reports of acute renal failure and worsening of chronic failure, which may sometimes require hemodialysis in patients treated with SOLIQUA 100/33. Some of these events were reported in patients without known underlying renal disease. Most reports occurred in patients who experienced nausea, vomiting, diarrhea, or dehydration; advise patients to take precautions to avoid fluid depletion. Monitor blood glucose and renal function in patients with renal impairment. SOLIQUA 100/33 is not recommended in patients with end-stage renal disease.
• Immunogenicity: Patients may develop antibodies to insulin and lixisenatide. If there is worsening glycemic control or failure to achieve targeted glycemic control, significant injection site reactions or allergic reactions, then other antidiabetic therapy should be considered.
• Hypokalemia: All insulin containing products can cause hypokalemia, which may be life-threatening. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated.
• Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Fluid retention, which may lead to or exacerbate heart failure, can occur with concomitant use of thiazolidinediones (TZDs) and insulin. These patients should be observed for signs and symptoms of heart failure. If heart failure occurs, dosage reduction or discontinuation of TZD must be considered.
• Acute Gallbladder Disease: Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and post-marketing. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

Most Common Adverse Reactions

The most common adverse reactions reported in ≥ 5% of patients treated with SOLIQUA 100/33 include hypoglycemia, nausea, nasopharyngitis, diarrhea, upper respiratory tract infection, headache

Drug Interactions

• Certain drugs may affect glucose metabolism, requiring dose adjustment of SOLIQUA 100/33 and close monitoring of blood glucose.
• The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs (eg, beta-blockers, clonidine, guanethidine, and reserpine).
• The lixisenatide in SOLIQUA 100/33 delays gastric emptying, which may reduce the rate of absorption of orally administered medication with a narrow therapeutic ratio or that require careful clinical monitoring. If such medications are to be administered with food, do not co-administer with SOLIQUA 100/33.
• Antibiotics, acetaminophen, or other medications that are dependent on threshold concentrations for efficacy, or where a delay in effect is undesirable, should be administered at least 1 hour before SOLIQUA 100/33 injection.
• Oral contraceptives should be taken at least 1 hour before SOLIQUA 100/33 administration or 11 hours after.

Please see full Prescribing Information available at the link above the video.