It’s important to treat obesity and prediabetes before diabetes can develop because obesity is the leading indicator in developing diabetes. Data from the National Health and Nutrition Examination Survey reveals that only 12.2 percent of American adults are metabolically healthy. Eighty-six million adults in the U.S. have prediabetes (HbA1c ranging from 5.7–6.4%), and up to 70 percent of these individuals will eventually develop diabetes. Obesity is the main factor in the progression of prediabetes to diabetes.
Almost all patients who present to our clinics have significant issues associated with pain, which is one of the hallmarks of metabolic inflammation. The vast majority of patients who present to our clinics are also overweight, and when we evaluate their biochemical markers, they have prediabetes and metabolic inflammation. Pre-diabetes is known to be a condition that precedes type 2 diabetes (T2D). The changes in immune cells’ concentration and function can cause an increased migration of these inflammatory cells to already inflamed tissue. There is also upregulation of cytokines. This immune activation begins during the pre-diabetic state.
The HbA1c has a significant tendency to miss cases of diabetes. When compared to the oral glucose-tolerance test (OGTT), HbA1c will under-diagnose diabetes in 73 percent of adults. HbA1c has a sensitivity of 26.93 percent and specificity of 99.39 percent.
The 2019 American Diabetes Association Standards of Medical Care in Diabetes recommends at least yearly screening for those with high risk of prediabetes, stating that patients with “A1C 5.7−6.4% (39−47 mmol/mol)…are ideal candidates for diabetes prevention efforts” as well as that “lifestyle/behavioral therapy featuring an individualized reduced calorie meal plan is highly effective in preventing type 2 diabetes and improving other cardiometabolic markers (such as blood pressure, lipids, and inflammation). ”
- Weight loss utilizing coaching, dietary change, self-efficacy, and increased physical activity can help as well. The recommendation is to “achieve and maintain 7% loss of initial body weight and increase moderate-intensity physical activity (such as brisk walking) to at least 150 min/week.” Additionally, “Metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially for those with BMI ≥35 kg/m2, those aged <60 years, and women with prior gestational diabetes mellitus.”
They further state that “Prediabetes is associated with heightened cardiovascular risk; therefore, screening for and treatment of modifiable risk factors for cardiovascular disease is suggested.”
Type 2 diabetes is characterized by both peripheral insulin resistance and inadequate insulin production. Insulin resistance has been associated with elevated levels of free fatty acids and proinflammatory cytokines in plasma and leads to decreased glucose transport into muscle cells.
For Type 2 Diabetes to occur, both insulin resistance and inadequate insulin secretion must co-exist. For example, overweight individuals may have insulin resistance, but diabetes only develops in those who cannot increase insulin secretion sufficiently to compensate for their insulin resistance. Unfortunately, this period of prediabetes permits significant tissue damage.
Increased cardiovascular risk begins prior to the development of persistent hyperglycemia, due to insulin resistance (Stern, 1996; Haffner and D’Agostino, 1999). Macrovascular damage has already occurred with the onset of insulin resistance, while microvascular damage increases with the onset of hyperglycemia. The United Kingdom Prospective Diabetes Study (UKPDS) analyzed more than 4,000 type 2 diabetes patients who were aggressively treated and followed for up to 15 years. Those in the intensely treated group had a significantly lower rate of progression of microvascular complications than patients receiving standard care. Rates of macrovascular disease were only reduced in the metformin-monotherapy arm, where the risk of myocardial infarction was significantly decreased.
In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, there was a 66 percent increase in mortality per 1 percent increase in HbA1c, with the best outcome for patients maintaining HbA1c below 6.0.
Early intervention in the atherogenic prediabetic state, while HbA1c remains in the prediabetic range (5.7-6.4%), reduces the 200-400 percentage of increased risk of cardiovascular events and plaque formation. This intervention is cost-effective, low-risk, and disease-modifying if using both lifestyle modification and metformin. Delaying early intervention (when HbA1c > 6.5) increases the glycocalyx and endothelial damage and irreversible diabetes-specific microvascular complications. We readily acknowledge that overly rigorous blood glucose control may have a negative outcome if multiple hypoglycemic agents are used in addition to metformin. However, the ability to tolerate metformin is excellent if dose escalation is done slowly.
Our early intervention is geared towards lifestyle modification and metformin monotherapy, using the following lifestyle modifications: reducing gastrointestinal permeability from gluten and gliadin, thus reducing inflammatory load
reducing carbohydrate loading to reduce insulin resistance and fat deposition in the liver, specifically fructose
restoring an appropriate Omega 6:3 ratio by removing industrial seed oils and supplementing with omega-3 fish oil
improving insulin sensitivity by reducing insulin release, using time-restricted feeding and reducing the overall glycemic load
- Metformin has historically been considered a pharmaceutical first line agent in the treatment of type 2 diabetes, with a very low side effect profile, except for individuals with renal compromise. Despite the extensive use of metformin, its mechanism of action remains unclear. The following are possibilities when considering how metformin works:
- antibiotic, changing the gut microbiome ratio to a lower proinflammatory load
- effect on the mTOR pathway, which may independently reduce neuropathic pain and is associated with cancer suppression as well as life-lengthening
- change in vagal tone, reducing sympathetic tone and cortisol secretion
- enhances insulin sensitivity at the receptor and lower blood level of insulin
- reduces the formation of advanced glycation end-products
- inhibits the liver’s ability to release glucose into the bloodstream
- inhibits the mitochondrial respiratory chain in the liver, leading to activation of AMPK, enhancing insulin sensitivity (via effects on fat metabolism) and lowering AMP, thus reducing the expression of gluconeogenic enzymes
- inhibition of fructose-1,6-bisphosphatase by AMP in the liver
The longer we can delay progression to Type 2 Diabetes, even if using oral hypoglycemics, the more cost effective it is. The following is a cost analysis of early intervention with metformin, compared to delay in treatment until insulin supplementation is required due to B-cell fatigue, assuming similar lifestyle management:
- The average wholesale cost of generic Metformin is less than $0.05/tablet 1,000 mg, making a 30-day supply $6.00 per month. https://www.goodrx.com/metformin?dosage=1000mg&form=tablet&label_override=metformin&quantity=60
- For an average wholesale insulin cost, a combination of both long-acting and short-acting insulin is prescribed.
Long-acting insulin, Lantus, costs $431/month, and the short-acting insulin, Humalog, costs $533/month, for a combined cost of $964/month excluding injection supplies.
Someone could pay for 160 months of metformin therapy for the same cost as 1 month of insulin therapy.
Metformin continues to reduce the likelihood of developing type 2 diabetes among those at high risk for it over 15 years, particularly among those with higher baseline glycemia. Metformin prevents diabetes, which is important because diabetes leads to vision loss, renal failure, amputations, and heart disease.
Preventing or delaying or reducing the risk for diabetes is, is in and of itself, important. Metformin is cheap and well-tolerated with a powerful effect.
Diabetes prevention seen at 15 Years, regardless of analytic method.
Long-term Effects of Metformin on Diabetes Prevention: Identification of Subgroups That Benefited Most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Diabetes Prevention Program Research Group. Diabetes Care Apr 2019, 42 (4) 601-608; DOI: 10.2337/dc18-1970
Reversion to normal glucose regulation with reversal of insulin resistance, using early intervention prevents progression of prediabetes to diabetes. Normalized glucose regulation is an indicator of disease modification, with measurable reduced all-cause mortality. Our goal is to reduce metabolic inflammation and avoid the preventable complications of insulin resistance.
References for additional reading:
Prevalence of optimal metabolic health is remarkably low among U.S. adults, with one in eight Americans achieving optimal levels of the five traditional cardiometabolic risk factors without medication.
Joana Araújo, Jianwen Cai, and June Stevens. Metabolic Syndrome and Related Disorders. Feb 2019. http://doi.org/10.1089/met.2018.0105
ENDO 2019: The Endocrine Society Annual Meeting.
Prescrire Int. 2014 Nov;23(154):269-72. https://www.ncbi.nlm.nih.gov/pubmed/25954799
N Engl J Med 2008; 358:2545-2559 https://www.nejm.org/doi/full/10.1056/nejmoa0802743
“Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63, p=0.017), and 36% for all-cause mortality (9-55, p=0.011).”
Lancet. 1998 Sep 12;352(9131):854-65. https://www.ncbi.nlm.nih.gov/pubmed/9742977
“The increased risk of adverse cardiovascular outcomes associated with type 2 diabetes does not begin at the diagnostic cutoff for plasma glucose (or HbA1c) at which the condition is diagnosed. Rather, there appears to be a continuum of increased microvascular and macrovascular risk that extends to levels of glycaemia well below these cutoffs. While it seems reasonable to hypothesize that correction of prediabetic dysglycemia might also reduce the future risk of adverse cardiovascular outcomes, further evidence from clinical trials is needed to demonstrate improved long-term outcomes in this setting.”
Hopper I, Billah B, Skiba M, Krum H. Prevention of diabetes and reduction in major cardiovascular events in studies of subjects with prediabetes: meta-analysis of randomized controlled clinical trials. Eur J Cardiovasc Prev Rehabil. 2011;18:813–823. [PubMed]
Metformin to be considered in IGT, IFG, HbA1c of 5.7–6.4 %, especially in BMI >35 kg/m2, age <60 years or prior GDM
“As most individuals with prediabetes will eventually go on to develop type 2 diabetes, the large number of people with prediabetes worldwide implies a reservoir of new type 2 diabetes cases to come. Optimizing the management of prediabetes, with the aim of delaying diabetes onset for as long as possible, is therefore an urgent global clinical priority.”
“In the Diabetes Prevention Study (DPS), for example, no patient who achieved at least four of the five lifestyle goals (weight reduction, total fat intake, saturated fat intake, fibre intake, exercise) went on to develop diabetes during the period of follow-up.”
Diabetes Prevention Program Research Group. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care 2012;35:723–730
“The Diabetes Prevention Program (DPP), a randomized controlled clinical trial, demonstrated that compared with the placebo intervention (placebo), the intensive lifestyle intervention (lifestyle) reduced the incidence of type 2 diabetes by 58%, and the metformin intervention (metformin) reduced the incidence of type 2 diabetes by 31% over 2.8 years”
Balk EM, Earley A, Raman G, Avendano EA, Pittas AG, Remington PL. Combined diet and physical activity promotion programs to prevent type 2 diabetes among persons at increased risk: a systematic review for the Community Preventive Services Task Force. Ann Intern Med 2015;163:437–451
Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403