The article covers the global impact of type 2 diabetes, focusing on its potential reversal through lifestyle changes, medication, & bariatric surgery. It provides insights from recent trials, offering a comprehensive look at strategies to manage & potentially overcome this prevalent health issue.

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According to the International diabetes federation (IDF), in 2021, 537 million adults will be living with diabetes mellitus in the world and by 2045, approximately 783 million people will be affected with diabetes mellitus.

A global appeal to the scientific and research community has been made to create strategies to reduce the prevalence of type 2 diabetes.

Previously thought type 2 diabetes was a chronic, progressive, and irreversible disease, but a series of trials and consensus documents in the past 15 years suggest that type 2 diabetes can be reversible.

Pathophysiology reveals insulin resistance plays a crucial role in the development of type 2 diabetes. Hence, improvement in insulin resistance by reduction of caloric intake and consequent weight loss led to a decrease in intrahepatic and intrapancreatic fat.

American diabetes association (ADA) defines diabetes remission as HbA1c <6.5% measured at least 3 months after cessation of glucose-lowering pharmacotherapy.

Three different interventions are now available for achieving diabetes remission:

1. Lifestyle intervention (caloric reduction and physical activity)
2. Pharmacotherapy
3. Bariatric surgery

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Lifestyle intervention & type 2 DM reversal

1. The twin cycle hypothesis states that the vicious cycle of fat accumulation in the liver and pancreas leads to the development of type 2 diabetes.

2. Weight loss can lead to a decrement of intrapancreatic fat and intrahepatic fat, resulting in an improvement in insulin secretion from the pancreas and hepatic glucose output, respectively.

3. For individuals with diabetes, the Look AHEAD (Action for Health in Diabetes) study showed that a loss of 5–10% of body weight could improve fitness, reduce HbA1c levels, improve cardiovascular disease risk factors, and decrease the use of diabetes, hypertension, and lipid-lowering medications.

4. A very low-calorie diet (VLCD) showed the most significant weight loss effect, containing 800 kcal or less per day with a relatively high protein-to-calorie ratio and with essential micronutrients. This diet is usually served in liquid form for 3 to 4 months. Researchers considered the VLCD protocol as a therapeutic approach for obese diabetic patients and also evaluated for diabetes remission.

5. The DiRECT trial used a structured approach with evidence-based (entirely non-surgical non-pharmaceutical) behaviour change interventions to deliver the initial weight loss, demonstrating that T2DM can be successfully reversed in the long term with a very low-energy diet.

1. At one-year follow-up, 46% of patients met the study criteria of diabetes remission (HbA1c <6.5% without antiglycemic medications) and at two years the remission rate was 36%.
2. 50% of the participants had a long-term reversal with a weight loss of 10kg and 90% with 15kg provided that this was achieved within 6 years of their diabetes diagnosis.

Different types of diets are available like low-fat diets, low-carbohydrate diets, Mediterranean diets etc. for weight loss but instead of macronutrient composition of diet, calorie amount is important. Calorie restriction plays a role.

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Pharmacotherapy for T2DM- from reversal to remission

The introduction of new anti-diabetic medications with weight loss as an extra benefit which can help in diabetes remission like: 

• GLP1anlogues
• Dual GLP1/GIP analogues
• SGLT2 inhibitors 

GLP-1 analogues: Since 2021, Phase 3 trials that contain high-dose GLP-1 analogues (like semaglutide) or GLP1/GIP dual analogues (like tirzepatide) can deliver stunning results and promise to be game-changers in the realm of T2DM reversal.

The SURPASS-1 study: In the SURPASS-1 study of tripeptide, 51.7% of participants assigned the highest dose (15mg) achieved an HbA1c of 5.7%. Average weight loss was 9.5 kg (11.0%) at 40 weeks. Tirzepatide resulted in a remission rate of diabetes of 66% to 81% depending on drug dose over 52 weeks.

STEP 2 trial: In the Semaglutide Treatment Effect in People with Obesity (STEP) 2 trial, the estimated change in mean body weight from baseline to week 68 was–9.6%. The proportion of patients who took semaglutide 2.4 mg achieved HbA1c levels of ≤6.5% was 67.5%. It causes significant weight loss and causes diabetes remission in a significant number of obese diabetes patients.

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Metabolic surgery and remission in type 2 diabetes

A. Metabolic surgery

Bariatric surgery represents the most effective measure to achieve and maintain long-term remission of diabetes.

According to the NIH (National Institutes of Health) standard, type 2 diabetes patients who have a BMI above 35 kg/m2 (Asians BMI >30 kg/m2) are eligible for bariatric surgery.

Different techniques to promote weight loss have been approved for weight loss and can cause diabetes remission like:

• Gastric banding
• Vertical banded gastroplasty
• Sleeve gastrectomy
• Roux-en-Y gastric bypass
• Biliopancreatic diversion with/without duodenal switching

Modern bariatric procedures can be classified into three types:

1. Restrictive procedures

It includes:

• The intragastric balloon
• Endoscopic sleeve gastroplasty
• Laparoscopic gastric banding
• Laparoscopic sleeve gastrectomy

2. Malabsorptive procedures

It includes:

• The jejunoileal bypass
• Ileal interposition
• Biliopancreatic diversion

3. The combined restrictive and malabsorptive type of intervention

It includes:

• The Roux-en-Y gastric bypass
• One anastomosis / mini gastric bypass (OA-MGB)
• The single anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S)

B. Remission in type 2 diabetes

Remission of diabetes usually occurs very early after surgery (2-3 days to 2-3 weeks) when weight loss has not yet occurred. It has been hypothesised that anatomical changes and the consequent hormonal changes brought about by surgery may play a role.

The probability of maintaining long-term remission depends on the type of surgery performed, the patient’s ability to make lifestyle changes, the presence of comorbidities and the ß-cell pancreatic reserve.

Diabetes remission depends on the type of surgery and most performed surgeries are Roux-en-y gastric bypass and sleeve gastrectomy. Laparoscopic and endoscopic procedures like endoscopic balloons, and laparoscopic banding were more commonly performed less invasive procedures.

The diabetes remission rate is more than twice as high with Roux-en-Y gastric bypass (RYGB) than with laparoscopic adjustable gastric banding, even when adjusted for weight loss.

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Case 1

Patient history

A 48-year-old woman, diagnosed with type 2 diabetes three years ago, had a BMI of 34 kg/m2 and was managing her diabetes with three oral hypoglycemic drugs. She initiated treatment with oral semaglutide at 3mg, later increased to 7mg, in combination with dapagliflozin at 10mg daily.

Results

Implementing a low-calorie diet and regular physical exercise, she successfully lost 15 kg, resulting in a current BMI of 23 kg/m2. Gradually reducing oral diabetic medications, she achieved an HbA1c of 6 and is now maintaining her health without any medication, relying on consistent physical activity and a low-calorie diet.

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Case 2

Patient history

A 35-year-old man, with a BMI of 36 kg/m2 and a waist circumference of 110cm, was diagnosed with new-onset diabetes mellitus (HbA1c 7). He initiated a very low-calorie diet of 800 kcal/d along with daily walking.

Results

After three months, he successfully attained an HbA1c level of approximately 6 and experienced a weight loss of 9 kgs.

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Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Ganesh Patti MBBS, MD, DM Consultant Endocrinologist, MRCP SCE Endocrinology (UK).