Diabetes mellitus type 2 medical therapy
Diabetes mellitus type 2 Microchapters |
Differentiating Diabetes Mellitus Type 2 from other Diseases |
Diagnosis |
Treatment |
Medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
Overview
The main goals of treatment are to eliminate hyperglycemic symptoms, control the long term complications and improve the patient's quality of life.
Diabetes mellitus type 2 is initially treated by life style modification and weight loss, especially in obese patients. Metformin is the first line pharmacologic therapy that is usually started once the diagnosis is confirmed unless contraindications exist. If glycemic goals are not achieved, a second agent must be added to metformin. A wide range of options are available to add as combination therapy based on the patient's condition and comorbidities.
Pharmacologic therapy
Inpatients
Outpatients
Medical therapy starts with metformin monotherapy unless there is a contraindication for it. In the following conditions, treatment starts with dual therapy:[1][2][3][4][5][6]
- If HbA1C is greater than 9, start with dual oral blood glucose lowering agent.
- If HbA1C is greater than 10 or blood glucose is more than 300 mg/dl or patient is markedly symptomatic, consider combination therapy with insulin.
The most effective class of drugs for reducing death are probably sodium glucose transporter 2 (SGLT2) inhibitors or GLP-1 receptor agonists.[7]
Metformin
Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death. Patients should be advised to stop the medication in cases of nausea, vomiting or dehydration. Contraindications to metformin include, heart failure, liver failure, GFR ≤30 and metabolic acidosis.
Contraindications
- As of June 2020, The US Food and Drug Administration (FDA) recalls extended-release metformin which is made by few pharma companies due to detection of high levels of N-nitrosodimethylamine (NDMA).
- N-nitrosodimethylamine (NDMA) is a carcinogenic agent when exposed in higher levels leads to cancer.
- The following are the pharma companies that the FDA recalls the extended-release metformin:
- Lupin
- Apotex Corp
- Actavis
- Time-Cap Labs, Inc
- Amneal
Total duration was 14 weeks with at least 8 weeks on final dose. | Placebo | 500 mg once daily | 1000 mg
(500 mg twice daily) |
1500 mg
(500 mg thrice daily) |
2000 mg
(1000 mg twice daily) |
2500 mg
(1000 am, 500 lunch, 1000 at supper daily |
---|---|---|---|---|---|---|
Any GI ADR | 13% | 16% | 29% | 24% | 23% | 29% |
Diarrhea | 5% | 8% | 21% | 12% | 19% | 14% |
HbA1c change | + 1.2 | + 0.3 | + 0.1 | - 0.5 | - 0.8 | - 0.04 |
Source: Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL (1997). "Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial". Am J Med. 103 (6): 491–7. doi:10.1016/s0002-9343(97)00254-4. PMID 9428832. |
Insulin
The lack of inexpensive, generic insulin may lead to underuse of insulin[9] and occurs for unusual reasons[10].
The insulin analogues may not provide a meaningful advantage[11][12][13].
A meta-analysis of randomized controlled trials by the Cochrane Collaboration found "only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2" compared to human insulin[13] More recent randomized controlled trials have found no differences with glargine[14] and have found that although long acting insulins were less effective, they were associated with less hypoglycemia.[15]
Premixed combinations of insulin, human or analogue, have similar reductions in HbA1c[16]. A cohort study likewise found similar rates of hypoglycemia[12].
Bedtime insulin
Initially, adding bedtime insulin to patients failing oral medications is more effective and with less weight gain than using multiple dose insulin.[17] Nightly insulin combines better with metformin that with sulfonylureas.[18] The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L)[17]. If the fasting glucose is reported in mg/dl, multiple by 0.05551 (or divided by 18) to convert to mmol/L.[19]
Combination therapy
Any agent can be added as second drug based on patient condition but the American Association of Clinical Endocrinologists recommends either incretin based therapy or sodium glucose transporter 2 (SGLT2) inhibition agents.
The following table summarize the available FDA approved glucose lowering agents that may help to individualize treatment for each patient.
Class | Drug | Mechanism of action | Primary physiologic action | Advantages | Disadvantages | Cost |
---|---|---|---|---|---|---|
Biguanides | Metformin | Activates AMP-kinase | ↓ Hepatic glucose
production |
|
|
Low |
Sulfonylureas | 2nd generation | Closes K-ATP channels on beta cell plasma membranes | ↑ Insulin secretion |
|
|
Low |
Meglitinides | Closes K-ATP channels on beta cell plasma membranes | ↑ Insulin secretion |
|
|
Moderate | |
Thiazolidinedione
(TZDs) |
Activates the nuclear transcription factor PPAR-gama | ↑ Insulin sensitivity |
|
|
Low | |
α-Glucosidase
inhibitors |
Inhibits intestinal
α-glucosidase |
Slows intestinal carbohydrate
digestion/absorption |
|
|
Low to
moderate | |
DPP-4 | Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations |
|
|
|
High | |
Bile acid sequestrants | Colesevelam | Binds bile acids in intestinal tract,
increasing hepatic bile acid production |
|
|
|
High |
Dopamine-2 | Bromocriptine
(quick release)§ |
Activates dopaminergic receptors |
|
|
|
High |
SGLT2
inhibitors |
Inhibits SGLT2 in the proximal nephron |
|
|
|
High | |
GLP-1 receptor agonists |
|
Activates GLP-1 receptors |
|
|
|
High |
Amylin mimetics | Pramlintide§ | Activates amylin receptors |
|
|
|
High |
Insulins |
|
Activates insulin receptors |
|
|
|
High |
| ||||||
| ||||||
| ||||||
|
‡ lnitial concerns regarding bladder cancer risk are decreasing after subsequent study.
§ Not licensed in Europe for type 2 diabetes.
References
- ↑ Qaseem A, Hopkins RH, Sweet DE, Starkey M, Shekelle P (2013). "Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians". Ann. Intern. Med. 159 (12): 835–47. doi:10.7326/0003-4819-159-12-201312170-00726. PMID 24145991.
- ↑ "Standards of Medical Care in Diabetes-2017: Summary of Revisions". Diabetes Care. 40 (Suppl 1): S4–S5. 2017. doi:10.2337/dc17-S003. PMID 27979887.
- ↑ Colagiuri S, Cull CA, Holman RR (2002). "Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes associated with improved outcomes?: U.K. prospective diabetes study 61". Diabetes Care. 25 (8): 1410–7. PMID 12145243.
- ↑ Davidson MB (1992). "Successful treatment of markedly symptomatic patients with type II diabetes mellitus using high doses of sulfonylurea agents". West. J. Med. 157 (2): 199–200. PMC 1011263. PMID 1441492.
- ↑ Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S (2016). "Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis". Ann. Intern. Med. 164 (11): 740–51. doi:10.7326/M15-2650. PMID 27088241.
- ↑ Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, Maggo J, Gray V, De Berardis G, Ruospo M, Natale P, Saglimbene V, Badve SV, Cho Y, Nadeau-Fredette AC, Burke M, Faruque L, Lloyd A, Ahmad N, Liu Y, Tiv S, Wiebe N, Strippoli GF (2016). "Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis". JAMA. 316 (3): 313–24. doi:10.1001/jama.2016.9400. PMID 27434443.
- ↑ GitHub Contributors. Hypertonic Saline for Bronchiolitis: a living systematic review. GitHub. Available at http://openmetaanalysis.github.io/Diabetes-mellitus-type-2-mortality-prevention-with-pharmacotherapy/. Accessed June 11, 2018.
- ↑ Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL (1997). "Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial". Am J Med. 103 (6): 491–7. doi:10.1016/s0002-9343(97)00254-4. PMID 9428832.
- ↑ Herkert D, Vijayakumar P, Luo J, Schwartz JI, Rabin TL, DeFilippo E; et al. (2018). "Cost-Related Insulin Underuse Among Patients With Diabetes". JAMA Intern Med. doi:10.1001/jamainternmed.2018.5008. PMID 30508012.
- ↑ Greene JA, Riggs KR (2015). "Why is there no generic insulin? Historical origins of a modern problem". N Engl J Med. 372 (12): 1171–5. doi:10.1056/NEJMms1411398. PMID 25785977.
- ↑ Luo J, Khan NF, Manetti T, Rose J, Kaloghlian A, Gadhe B; et al. (2019). "Implementation of a Health Plan Program for Switching From Analogue to Human Insulin and Glycemic Control Among Medicare Beneficiaries With Type 2 Diabetes". JAMA. 321 (4): 374–384. doi:10.1001/jama.2018.21364. PMID 30694321.
- ↑ 12.0 12.1 Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ (2018). "Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With Glycemic Control in Patients With Type 2 Diabetes". JAMA. 320 (1): 53–62. doi:10.1001/jama.2018.7993. PMC 6134432. PMID 29936529.
- ↑ 13.0 13.1 Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J; et al. (2007). "Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus". Cochrane Database Syst Rev (2): CD005613. doi:10.1002/14651858.CD005613.pub3. PMID 17443605. Review in: ACP J Club. 2007 Sep-Oct;147(2):46
- ↑ Esposito K; et al. (2008). "Addition of neutral protamine lispro insulin or insulin glargine to oral type 2 diabetes regimens for patients with suboptimal glycemic control: a randomized trial". Ann Intern Med. 149: 531–9. PMID 18936501.
- ↑ Holman RR; et al. (2007). "Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes". N Engl J Med. 357: 1716–30. doi:10.1056/NEJMoa075392. PMID 17890232.
- ↑ Qayyum R, Bolen S, Maruthur N, Feldman L, Wilson LM, Marinopoulos SS; et al. (2008). "Systematic review: comparative effectiveness and safety of premixed insulin analogues in type 2 diabetes". Ann Intern Med. 149 (8): 549–59. PMC 4762020. PMID 18794553.
- ↑ 17.0 17.1 Yki-Järvinen H, Kauppila M, Kujansuu E; et al. (1992). "Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus". N. Engl. J. Med. 327 (20): 1426–33. PMID 1406860.
- ↑ Yki-Järvinen H, Ryysy L, Nikkilä K, Tulokas T, Vanamo R, Heikkilä M (1999). "Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial". Ann. Intern. Med. 130 (5): 389–96. PMID 10068412.
- ↑ Kratz A, Lewandrowski KB (1998). "Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Normal reference laboratory values". N. Engl. J. Med. 339 (15): 1063–72. PMID 9761809.
- ↑ 20.0 20.1 Paneni F, Lüscher TF (2017). "Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes". Am J Cardiol. 120 (1S): S17–S27. doi:10.1016/j.amjcard.2017.05.015. PMID 28606340.