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:
- 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.
Metformin
- Metformin is effective, safe and inexpensive. It may reduce risk of cardiovascular events and death. Patients should be advised to stop the medication in cases of nausea, vomiting or dehydration.
- Metformin is capable of decreasing the body weight but it's effect on muscle mass is unclear.
- A systemic review, observing 34,000 patients in total, concluded that Metformin is as safe as other anti-diabetic treatments in diabetic patients with heart failure.
- Some studies demonstrated lower risk of mortality in diabetic patients with concurrent COPD or Asthma who were taking Metformin compared to non-users.
- Metformin use in diabetic patients with sepsis, tuberculosis and Chronic obstructive pulmonary disease (COPD) were associated with lower mortality rate.
- One of the possible effects of Metformin is gut microbiota alteration, which results in Tauroursodeoxycholic acid (TUDCA) and Glycoursodeoxycholic Acid (GUDCA) elevation. Since both TUDCA and GUDCA act as intestinal farnesoid X receptor (FXR) antagonists, they can be effective in hyperglycemia treatment.
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
- Contraindications to metformin include, heart failure, liver failure, GFR ≤30 and metabolic acidosis.
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 and occurs for unusual reasons.
- The insulin analogues may not provide a meaningful advantage.
- Although Insulin increases the body weight, some data suggest that it is capable of increasing the muscle mass.
- 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[1] More recent randomized controlled trials have found no differences with glargine and have found that although long acting insulins were less effective, they were associated with less hypoglycemia.
- Premixed combinations of insulin, human or analogue, have similar reductions in HbA1c. A cohort study likewise found similar rates of hypoglycemia[2].
Bedtime insulin
- Initially, adding bedtime insulin to patients failed oral medications is more effective and with less weight gain than using multiple dose insulin. Nightly
- Insulin combines better with metformin that with sulfonylureas.
- The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L)[3]. If the fasting glucose is reported in mg/dl, multiple by 0.05551 (or divided by 18) to convert to mmol/L.
Combination therapy
- Any agent can be added as second drug based on patient condition. Although, 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 | 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 |
| ||||||
| ||||||
|
‡ Initial concerns regarding bladder cancer risk are decreasing after subsequent study.
§ Not licensed in Europe for type 2 diabetes.
† One study demonstrates factors like previous genital infection history, concurrent estrogen therapy and younger age as risk factors that augment the chance of this side effect. This study also reports chronic kidney disease and baseline DPP4 inhibitor therapy as factors that lower the risk of genital infection.
References
- ↑ Horvath K; et al. (2007). "Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus". Cochrane database of systematic reviews (Online): CD005613. PMID 17443605.
- ↑ 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.
- ↑
- ↑ Zelniker, Thomas A.; Wiviott, Stephen D.; Raz, Itamar; Im, KyungAh; Goodrich, Erica L.; Furtado, Remo H.M.; Bonaca, Marc P.; Mosenzon, Ofri; Kato, Eri T.; Cahn, Avivit; Bhatt, Deepak L.; Leiter, Lawrence A.; McGuire, Darren K.; Wilding, John P.H.; Sabatine, Marc S. (2019). "Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus". Circulation. 139 (17): 2022–2031. doi:10.1161/CIRCULATIONAHA.118.038868. ISSN 0009-7322.
- ↑ 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.