Understanding Diabetes Mellitus

Diabetes mellitus (commonly referred to as diabetes) is a chronic (long-term) medical condition characterized by high blood glucose (sugar). This may be because the pancreas (an organ in the belly) does not make enough insulin (a hormone), or because the body is not responding to insulin the way it should. Insulin helps glucose get into cells in the body, giving it energy. With diabetes, sugar builds up in the blood because the body stops responding to insulin, or because there is not enough of it.

Types of Diabetes

• Type 1 diabetes - the pancreas makes no insulin, or a very small amount
• Type 2 diabetes - cells in the body do not respond to insulin the way it should; sometimes, the pancreas also does not make enough insulin

Diabetes is usually managed by eating healthy foods, getting plenty of exercise, and sometimes medicines. Medicines are used to either control blood sugar, or to lower the chance of problems that can happen in the future because of diabetes. These medications can be insulin itself, or medications that help the body make more insulin or help insulin do its job.

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs used primarily in the management of type 2 diabetes mellitus. DPP-4 inhibitors work by blocking the action of the DPP-4 enzyme, which is responsible for the degradation of incretin hormones, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones are secreted from the gut in response to meals and stimulate insulin secretion in a glucose-dependent manner. By inhibiting DPP-4, the levels of these active incretins increase, enhancing the secretion of insulin and suppressing glucagon release, thereby lowering blood glucose levels.

DPP-4 inhibitors are generally used as second-line therapy for type 2 diabetes when lifestyle modifications and metformin have failed to achieve glycemic control. They can be used as monotherapy or in combination with other antidiabetic drugs including metformin, sulfonylureas, thiazolidinediones, and insulin.

Key Points Regarding DPP-4 Inhibitors:

• The efficacy of DPP-4 inhibitors in reducing glycosylated hemoglobin (HbA1c) levels is modest, with a reduction of approximately 0.5 to 1.0 percent, but they are well tolerated and have a neutral effect on body weight.
• In terms of cardiovascular safety, large randomized trials have demonstrated that DPP-4 inhibitors do not increase the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes who have established cardiovascular disease or are at high risk.

Note:

1. The Plan requires that members either be unable to use, or have tried and failed preferred medication(s) first. Requests for non-formulary medications are subject to Medical Necessity Criteria for Non-Formulary Products (PG069).
2. Coverage for prescription medications intended for obesity treatment, weight loss, weight reduction, or dietary control is determined by each member's specific benefit policy. Please refer to the member’s benefit plan document for information on benefit eligibility and terms of coverage. In cases where the plan includes coverage for drugs prescribed for obesity treatment or weight management, the Oscar Clinical Guideline: Weight Loss Agents (PG070) may also apply.

Dipeptidyl Peptidase-4 (DDP-4) Inhibitor and Thiazolidinedione (Glitazone) Antidiabetic Combinations

Oseni (Alogliptin; Pioglitazone)

• Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

include both brand and generic and all dosage forms and strengths unless otherwise stated

DPP-4 and Sodium Glucose Co-transporter 2 (SGLT2) Inhibitor Antidiabetic Combinations are part of Antidiabetic Agents - Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors & SGLT2 Antidiabetic Combinations (PG154). Please refer to Oscar Clinical Guideline PG154 for coverage criteria.

Definitions

"Insulin" is a hormone made by the beta cells of the pancreas. Insulin allows glucose to enter the cells in the body for use in energy production, and when it is inadequate, the sugar remains in the blood leading to diabetes. There are a variety of oral and parenteral medications that can increase insulin production, increase the body’s sensitivity to existing insulin and reduce blood sugar. Insulin can also be injected or infused when lifestyle changes and non-insulin medications are inadequate.
"Type 1 Diabetes" is an autoimmune condition that occurs when the beta cells of the pancreas are unable to produce enough insulin and therefore blood glucose cannot enter cells to be used for energy. Type 1 diabetes is often referred to as “insulin-dependent” because these patients require insulin daily to maintain their blood glucose at acceptable levels.
"Type 2 Diabetes" is a condition that occurs when either the pancreas doesn't produce enough insulin or the body cells become resistant to insulin. Type 2 diabetes is much more common than Type 1, and is often treated with combinations of lifestyle changes and non-insulin medications, although insulin can be required later in the disease course. Many individuals with Type 2 Diabetes are “insulin-requiring”.
"Blood Glucose" is the main sugar found in the blood and the body's main source of energy. It is also called glucose or blood sugar. The blood level of glucose is noted in milligrams per deciliter (mg/dL). When blood sugar is too high for long periods of time, complications can occur as a result of blood vessel damage.
"Hemoglobin A1c (HbA1c)" is a test that measures a person's average blood glucose level over the past 2 to 3 months. It is also known as “A1C” or “glycosylated hemoglobin”. A1C should be measured at least twice annually for stable glycemic control and at least quarterly for unstable glycemic control. A1C test results may be affected by age, certain conditions, ethnicity, genetic traits, and pregnancy; the ADA recommends that treating providers review for discrepancies between A1c results and blood glucose results.
"Hyperglycemia" is excessive blood glucose. Fasting hyperglycemia is blood glucose above a desirable level after a person has fasted for at least 8 hours. Postprandial hyperglycemia is blood glucose above a desirable level 1 to 2 hours after a person has eaten.
"Hypoglycemia" is a condition that occurs when one's blood glucose is lower than normal, usually less than 70 mg/dL. Signs include hunger, nervousness, shakiness, perspiration, dizziness or lightheadedness, sleepiness, and confusion. If left untreated, hypoglycemia may lead to unconsciousness. Hypoglycemia is treated by consuming a carbohydrate-rich food such as a glucose tablet or juice. It may also be treated with an injection of glucagon if the person is unconscious or unable to swallow.

Medical Necessity Criteria for Authorization

The Plan considers Dipeptidyl Peptidase-4 (DPP-4) Inhibitors & DPP-4 Antidiabetic Combinations medically necessary when ALL the following criteria are met:

1. The medication is age-appropriate for the member as per the FDA-approved indication; AND
2. The member has a diagnosis of type 2 diabetes mellitus based on at least ONE of the following diagnostic criteria:
   • A fasting glucose level of greater than 126 mg/dL; and/or
   • A 2-hour glucose tolerance test result of greater than 200 mg/dL.; and/or
   • Hemoglobin A1c ≥6.5%; and/or
   • Symptoms of hyperglycemia plus a random plasma glucose ≥200 mg/dL;
   NOTE: Abnormal results must be confirmed on a second occasion unless they are unequivocal.
3. The member has ONE of the following:
   • is unable to use, or has adequately tried and failed metformin at a minimum dose of 1500 milligrams daily for 90 days; or
   • requires combination therapy AND has an A1c (hemoglobin A1c) of 7.5 percent or greater; or

has been receiving the requested drug for at least 3 months, AND has demonstrated a reduction in A1c (hemoglobin A1c) since starting this therapy.

If the above prior authorization criteria are met, the requested drug will be approved for 12 months.

Experimental or Investigational / Not Medically Necessary

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors & DPP-4 Antidiabetic Combinations for any other indication is considered not medically necessary by the Plan, as it is deemed to be experimental, investigational, or unproven.

Appendix

Metformin in Type 2 Diabetes

The recommendation for a minimum effective dose of 1500 milligrams daily of metformin is derived from clinical findings which show that this dosage effectively regulates both fasting blood glucose and glycosylated hemoglobin levels - crucial markers of long-term glucose control.

Metformin functions by decreasing glucose production in the liver and enhancing insulin sensitivity in both the liver and peripheral tissues. This enhancement in turn improves the uptake and usage of glucose. The efficacy of metformin is dose-dependent, with the most clinically meaningful responses usually not seen at doses below 1500 milligrams per day.

The strategy of starting metformin treatment at a lower dose and gradually stepping up the dose over time (typically over a period of weeks) is useful in reducing the occurrence and intensity of gastrointestinal side effects. These side effects are the most common adverse reactions linked with metformin therapy and can include symptoms such as nausea, vomiting, diarrhea, abdominal cramping, and bloating. Commencing therapy at a lower dose (for instance, 500 mg twice daily or 850 mg once daily) and progressively increasing the dosage over time allows patients to better tolerate metformin. This results in improved medication adherence and ultimately, superior glycemic control.

• For patients who need further glycemic control beyond what can be achieved with a total daily dose of 2000 mg, the dosage of metformin can be boosted up to a maximum of 2550 mg per day, given in divided doses. This upper limit is based on clinical trials that show doses above this level do not provide an additional glycemic control benefit but may increase the risk of adverse effects.
• For pediatric patients, the same principle of beginning at a lower dose and incrementally increasing applies, with a maximum limit of 2000 mg per day given in divided doses.

Table 2: Metformin in Diabetes Treatment

References

1. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 190: Gestational diabetes mellitus. Obstet Gynecol. 2018;131(2):e49-e64.
2. American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin No. 201: Pregestational diabetes mellitus. Obstet Gynecol. 2018;132(6):e228-e248. doi:10.1097/AOG.0000000000002960
3. American Diabetes Association (ADA). Standards of medical care in diabetes–2021. Diabetes Care. 2021;44(suppl 1):S1-S232.
4. American Diabetes Association (ADA). Standards of medical care in diabetes–2021. Diabetes Care. 2021;44(suppl 1):S1-S232. Accessed January 13, 2021.
5. American Diabetes Association Professional Practice Committee, Draznin, B., Aroda, V. R., Bakris, G., Benson, G., Brown, F. M., Freeman, R., Green, J., Huang, E., Isaacs, D., Kahan, S., Leon, J., Lyons, S. K., Peters, A. L., Prahalad, P., Reusch, J., & Young-Hyman, D. (2022). 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes- 2022. Diabetes care, 45(Suppl 1), S125–S143. https://doi.org/10.2337/dc22-S009
6. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227-4249.
7. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701. doi:10.2337/dci18-0033
8. ElSayed NA, Aleppo G, Aroda VR, et al. 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes-2023. Diabetes Care 2023; 46:S19.
9. Garber AJ, Handelsman Y, Grunberger G et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2020 executive summary. Endocr Pract. 2020; 26:107-139. [PubMed 32022600]
10. Janumet (sitagliptin/metformin) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; November 2021.
11. Janumet XR (sitagliptin/metformin) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; November 2021.
12. Januvia (sitagliptin) [prescribing information]. Whitehouse Station, NJ: Merck and Co Inc; December 2021.
13. Jentadueto (linagliptin and metformin) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; March 2020.
14. Jentadueto XR (linagliptin and metformin) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; October 2021.
15. Kazano (alogliptin and metformin) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals America Inc; March 2022.
16. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2020;98(supp 4):S1-S115. doi:10.1016/j.kint.2020.06.019
17. Kombiglyze XR (saxagliptin/metformin) [prescribing information]. Wilmington, DE: AstraZenecaPharmaceuticals LP; October 2019.
18. LeRoith D, Biessels GJ, Braithwaite SS, et al. Treatment of diabetes in older adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1520-1574. doi:10.1210/jc.2019-00198
19. Nesina (alogliptin) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals America Inc; March 2022.
20. Onglyza (saxagliptin) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; June 2019.
21. Oseni (alogliptin and pioglitazone) [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America Inc; March 2022.
22. Tradjenta (linagliptin) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals and Indianapolis, IN: Eli Lilly and Company; March 2020.

Clinical Guideline Revision / History Information

Original Date: 06/29/2023
Reviewed/Revised: 7/31/2023

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