Prediabetes Management in Indian Adults: A Quasi- Experimental Study on Effectiveness of Integrated Intensive Lifestyle Intervention

M. Ganla

Prediabetes, a crucial metabolic state, significantly increases the risk of type 2 diabetes (T2D). India’s surging prediabetes cases outpace those of diabetes, highlighting the impending T2D crisis. Urgent attention and effective management strategies are crucial. M. Ganla aimed to assess the effectiveness of a one-year online lifestyle intervention program in prediabetes patients while exploring gender-specific and BMI-based differences in outcomes. The findings were presented at the 60th EASD Annual Meeting 2024, held in Madrid, Spain from 9th – 13th September 2024.
The study analysed data from 715 patients with prediabetes (HbA1c: 5.7%-6.4%; not on insulin or OHAs, aged >18 years) attending a one-year online lifestyle intervention program at a Diabetes Management Clinic in India. The intervention consisted of a personalised plant-based diet, physical activity, stress management, and medical management. The baseline and end-line assessments included anthropometric and biochemical parameters.

The study population comprised 60% females with a mean age of 50.6±10 years and a median HbA1c of 6.0% (5.8-6.2%). Forty-two percent of the individuals were on dyslipidaemia medication. Post-intervention, a substantial reduction in HbA1c (<5.7%) and BMI (<25 kg/m2) was observed in 56% and 16.1% of patients, respectively (p<0.05). Gender-based outcome: A significant higher % drop in HbA1c levels was observed in both genders, but women showed greater improvements in weight loss (kg), BMI (kg/m2), fasting insulin (U/ml), HOMA-IR, and QUICKI compared to men. Both genders showed similar improvement in lipid profile (p>0.1). BMI-based outcomes: Patients with a BMI > 25 kg/m2 showed greater weight loss (kgs) [-6.7 vs. -1.8; p<0.001] compared to those with a BMI < 25 kg/m2. A significant improvement in total cholesterol (8.9%), triglycerides (12.7%), and non-HDL-C (9.5%) was observed only in patients with a BMI > 25 kg/m(p<0.001). Improvement in HbA1c levels was comparable in both BMI categories (p>0.1). Moreover, binary logistic regression analysis showed that the absence of a family history of diabetes, age less than 50 years, and more than 10% weight loss were significant predictors of improvement in HbA1c (<5.7%) in prediabetes patients (Fig1).

The author concluded that women with prediabetes showed better outcomes in response to the lifestyle interventions than men. Weight loss relative to BMI improved the glycaemic profile of both obese and non-obese patients. Comprehensive lifestyle interventions may serve as effective strategies for managing diabetes.

 

Benefits of Early Glycemic Control in Type 2 Diabetes

Kamlesh Khunti

Major Adverse Cardiovascular Outcomes are more common in Type 2 Diabetes. In a study conducted in Sweden from 1998 through 2014, mortality and the incidence of cardiovascular outcomes declined substantially among persons with diabetes, although fatal outcomes declined less among those with type 2 diabetes than among controls. In a global study, both the prevalence and 3-year incidence of vascular complications were high in patients with relatively short T2D duration, highlighting the need for early risk-factor modification. Kamlesh Khunti discussed the benefits of early glycaemic control in type 2 diabetes at the 60th EASD Annual Meeting 2024, held in Madrid, Spain from 9th – 13th September 2024.

Glycaemic control deteriorates over time & majority of patients require polypharmacy to meet glycemic goals over time. Intensive glycaemic control leads to better outcomes. A meta-analysis of four CV trials showed a 15% reduction in Ml and 9% reduction in CV events inferring the benefits of tight glycaemic control. The UKPDS 44 Years (24 years post-trial) has shown consistent and persistent legacy effects. The findings emphasize the critical importance of detecting and treating T2D intensively at earliest possible opportunity. In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes. The ADA/EASD consensus on use of glucose-lowering medications in the management of type 2 diabetes was discussed.

Therapeutic inertia- a major issue in real world & is defined as “failure to advance therapy or to de-intensify therapy when appropriate to do so”. The global, prospective, observational DISCOVER trial investigated first- and second-line therapy in patients with T2D, across 37 countries and six regions. Therapeutic inertia is well documented in Western countries, but corresponding data are urgently needed in low- and middle-income countries, in view of their high prevalence of type 2 diabetes. Clinical inertia can cause persistently poor glycemic control and speed up the progression of diabetic retinopathy in T2D. Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes. Triple therapy with agents that improve insulin sensitivity and β-cell function in patients with new-onset T2DM produces greater, more durable HbA1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects.

The author concluded by saying that T2DM is a progressive disease. Early preventative interventions and tight glycaemic control (and risk factor control) is associated with longer term benefits. Therapy must be started early in the natural history of type 2 diabetes to prevent progressive ẞ-cell failure. Appropriate patients may require combination therapies with complimentary mechanisms of likely to achieve early tight glycaemic control. A number of interventions can help early glycaemic control.

 

CGM in Type 2 Diabetes Management

Tadej Battelino

Hyperglycemia is the primary cause of short- & long-term diabetes complications. A 1 mmol/mol increase in genetically proxied HbA1c was found to be associated with 11% higher CHD risk (HR 1.11, 95% CI 1.05, 1.18). In individuals without diabetes mellitus, lowering average blood glucose levels may reduce CHD risk in a dose-dependent way. Tadej Battelino discussed the importance of CGM in type 2 diabetes management. The findings were presented at the 60th EASD Annual Meeting 2024, held in Madrid, Spain from 9th – 13th September 2024.

Most CVD and kidney events occur in those below the threshold used to define T2D. It is possible to identify individuals with prediabetes who are at high risk for adverse outcomes, equivalent to those with overt T2D. Prospective identification and meticulous risk factor management in such high-risk prediabetic patients should be pursued. A study was conducted to investigate whether continuous HbA1c levels and HbA1c-polygenic risk scores (HbA1c-PRS) are significantly associated with worse brain health independent of type 2 diabetes (T2D) diagnosis (vs. not), by examining brain structure and cognitive test score phenotypes. The findings suggest that measured HbA1c is associated with poorer cognitive health, and that HbA1c-PRS do not add significant information to this. The association of type 2 diabetes with dementia differs by subtypes of dementia. The strongest detrimental association is observed for vascular dementia. Moreover, patients with type 2 diabetes with poor glycemic control have an increased risk of developing vascular and nonvascular dementia.

Elevated glucose is harmful. Among adults with poorly controlled type 2 diabetes treated with basal insulin without prandial insulin, continuous glucose monitoring, as compared with blood glucose meter monitoring, resulted in significantly lower HbA1c levels at 8 months. CGM should be adopted for the routine care of type diabetes mellitus. All people with T2DM (at diagnosis and early disease) should utilize CGM for 14 days after T2DM diagnosis. This will help to establish a baseline glucometric profile, provide education on the glycaemic response to diet and exercise in T2DM, decide on the initial treatment plan and therapy & evaluate the patient’s early (14-day) response to T2DM treatment.

Evidence generation will drive the paradigm shift to using continuous glucose monitoring in type 2 diabetes mellitus. US FDA definition of non-adjunctive CGM states, it is indicated to replace information obtained from standard BGM. It is intended to determine glucose levels and direction/rate of change of glucose levels & used to make diabetes-related treatment decisions (e.g., insulin dosing). It also provides historical glucose information, facilitating long-term therapy adjustments.

The author concluded by saying that hyperglycemia is the primary cause of short- & long-term diabetes complications. CGM helps all individuals with diabetes. TIR (Time in range) and TITR (time in tight range targets) – manage glycemia to target. TITR is a new target for “optimal control” and potentially remission of T2D.

 

Using Diabetes Technology in People on Dialysis or with Impaired Vision: What is Possible?

Tomas Griffin, presented a session at the 60th Annual Meeting of the European Association for the Study of Diabetes (EASD) 2024, held in Madrid, Spain from 9th September – 13th September that assessed the feasibility of using diabetes technology, in patients with dialysis or impaired vision, and to identify adaptations that improve access, glycaemic control, and quality of life.

The study was conducted to assess the glycemic control by continuous glucose monitoring (CGM), HbA1c measures, and glycated albumin and fructosamine measurements in patients with burnt-out diabetes (n = 20) and without a history of diabetes (n = 20). Patients with burnt-out diabetes had higher CGM-measured daily glucose levels, lower percent time in the range 70–180 mg/dL, higher percent time above range (>250 mg/dL), and longer duration of hyperglycemia >180 mg/dL (hours/day) compared with patients without diabetes (all P < 0.01). The use of CGM demonstrated that patients with burnt-out diabetes have significant undiagnosed hyperglycemia. CGM and glycated albumin provide better assessment of glycemic control than do values of HbA1c and fructosamine in patients with ESKD. The impact of CGM on glycaemia in people with T2DM on haemodialysis was assessed and CGM-adapted insulin regimen improves glycemic control without increasing hypoglycemic events in hemodialyzed diabetic patients. CGM could be a useful tool for the management of insulin therapy in these patients. The fully closed-loop insulin delivery improves glucose control of inpatients with T2DM receiving haemodilaysis. Time in hypoglycemia was reduced with closed-loop versus control. Fully closed-loop improved glucose control and reduced hypoglycemia compared with standard insulin therapy in adult outpatients with type 2 diabetes requiring dialysis.

The safety of CGM use in legally blind patients with diabetes was analyzed and it was found that There was a significant reduction in severe hypoglycemia requiring medical assistance for 12 months. Voice-enabled CGM use improved glycemic control and reduced severe hypoglycemia in legally blind patients with diabetes on intensive insulin therapy. The study was conducted whose objective was to assess the accuracy of two commercial CHO estimation applications, SNAQ and Calorie Mama, and compare their performance with the estimation accuracy of people with type 1 diabetes (T1D). SNAQ may provide effective CHO estimation support for people with T1D, particularly those with large or inconsistent CHO estimation errors. Its impact on glucose control remains to be evaluated. The Hybrid closed loop insulin pump therapy showed poor accessibility for people with low vision. Bionic pancreas was evaluated in T1DM patients. The use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. 

The author concluded saying trust your patients, use continuous glucose monitoring for management of diabetes. The hybrid closed loop needs improved accessibility and need clinical studies that involve people at design stage.

 

Predictors of Achieving and Sustaining Glycaemic Control and Weight Loss with Tirzepatide in People with Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)

Steven E Kahn, presented SURPASS-4 trial results at a 60th Annual Meeting of the European Association for the Study of Diabetes (EASD) 2024, held in Madrid, Spain from 9th September – 13th September. In this post-hoc analysis, predictors of achieving and sustaining HbA1c and weight loss targets at and beyond 52 weeks were identified. In SURPASS-4, people with type 2 diabetes and increased risk for cardiovascular events (mean baseline [BL] age 63.4 years, HbA1c 8.5%, weight 90.3 kg, BMI 32.6 kg/m2, 39% female) were randomised to tirzepatide (TZP) 5, 10 or 15 mg (N=329, 328, 338). The median duration of treatment was 85 weeks. At the primary endpoint (Week 52), the proportion of participants who achieved a HbA1c ≤6.5% was 67%, 73% and 81% with 5, 10 and 15 mg TZP, respectively. At Week 52, weight loss ≥10% was achieved by 35%, 52% and 65% of participants with 5, 10 and 15 mg TZP.

Of 619 participants treated with TZP who reached a HbA1c of ≤6.5% at Week 52, 75%, 80% and 83% (5, 10 and 15 mg) sustained their HbA1c until study end.  Tirzepatide once-weekly associated with a significant and sustained reduction in HbA1c. Tirzepatide once-weekly associated with a significant and sustained reduction in weight.

Factors that predicted sustained glycaemic control and weight loss with tirzepatide treatment in SURPASS-4

  • Glycaemic control: No sulfonylurea use, smaller decrease in fasting glucose and greater weight loss during the first 52 weeks, and higher HOMA-B at Week 52.
  • Weight loss: Greater decrease in low density lipoprotein cholesterol during the first 52 weeks.

A sustained response in glycaemic control and weight loss were maintained in approximately 80% of SURPASS-4 participants with type 2 diabetes and increased cardiovascular risk who reached HbA1c ≤6.5% or weight loss ≥10% at 52 weeks.Greater weight loss and better β-cell function achieved on initial tirzepatide therapy were the main predictors for sustained glycaemic control; greater reduction in LDL-C was the only predictor of sustained weight control, the clinical significance of this is unknown.

 

Is Semaglutide as Effective at Reducing Major Cardiovascular Events in the Presence of Impaired Kidney Function in People with Overweight or Obesity? A Prespecified Analysis from The SELECT Trial

In the SELECT trial, semaglutide (2.4 mg) reduced MACE by 20% vs placebo in overweight/obese participants (BMI ≥27) with prior CVD but no diabetes. This analysis assessed if the effect on MACE and MACE or all-cause death was maintained in participants with reduced eGFR or micro/macroalbuminuria.

Helen M. Colhoun, discussed SELECT trial results at the 60th Annual Meeting of the European Association for the Study of Diabetes (EASD) 2024, held in Madrid, Spain from 9th September – 13th September. SELECT trial was a multicentre, randomised, double-blind, placebo-controlled trial. Patients were randomised to once-weekly s.c. sema 2.4 mg or placebo

The primary endpoint was MACE composite. Time-to-first-occurrence of any component of Death from CV causes, Non-fatal MI, Non-fatal stroke

  • The outcomes were: 20% reduction in MACE with semaglutide 2.4 mg versus placebo
  • In patients with eGFR ≥60, MACE occurred in 6.0% of sema vs 7.3% of the pbo arm (HR=0.82 [95% CI 0.72-0.92]). In pts with eGFR <60, MACE occurred in 9.7% of sema vs 13.5% of the pbo arm (HR=0.69 [0.52-0.90]; p interaction=0.22). For MACE or death from any cause, HRs for sema vs pbo were 0.82 (0.74-0.92) for eGFR ≥60, vs 0.67 (0.53-0.84) for eGFR <60 (p interaction=0.12).
  • In patients with UACR <30, MACE occurred in 5.9% of sema vs 7.3% of the pbo arm (HR=0.80 [0.70-0.90]). In pts with UACR ≥30, MACE occurred in 9.9% of sema vs 12.3% of the pbo arm (HR=0.80 [0.62-1.02]

Semaglutide 2.4mg was at least as effective, in relative terms, at reducing MACE in participants with reduced eGFR and/or albuminuria as in those without. No additional safety concerns were identified among participants with reduced eGFR and/or albuminuria.

 

Disease-Modifying Treatment of Diabetic Neuropathy: Where We Are?

Triantafillos Didangelos, presented a session at the 60th Annual Meeting of the European Association for the Study of Diabetes (EASD) 2024, held in Madrid, Spain from 9th September – 13th September and discussed the need for disease modifying treatment for DN, the mechanisms of present drugs and what pointers to be taken into consideration for the treatment.

The speaker explained the other treatment for DN available other than tight glycaemic control are

  • ACE inhibitors
  • ARBs
  • A-Lipoic acid
  • Aldose reductase inhibitors
  • Vit B12 deficiency
  • Technology

The speaker discussed about the Vitamin B12 deficiency and its role in DPN: 

  • B12 has intrinsic antioxidant properties beyond its traditional cofactor role in cellular metabolism.
  • Oxidative stress plays a key role in the development of diabetic peripheral neuropathy (DPN).
  • B12 administration may be beneficial for treating overt DPN, early-stage DPN, or preventing DPN in the presence of oxidative stress

The pointers to be taken into consideration for new treatment cited were:

  • At present, pharmacological treatment for neuropathy is primarily palliative. They provide temporary relief from pain but do not address underlying mechanisms. This underscores the urgent need for pharmacological interventions that can simultaneously target pain and underlying mechanisms of neuropathy.
  • Such drugs provide comprehensive effective relief addressing both the symptoms and root cause of conditions
  • Most clinical studies investigate one part of neuropathy either peripheral or autonomic
  • Data about Vitamin B12 measurements have not been reported in most studies
  • The duration of investigation should be more thana year.

Despite drugs for DN, disease modifying treatments still need an approval from the main regulatory agencies (FDA and EMA). Strict glycaemic control is the recommended treatment. ACE-I could be an additional treatment. A combination treatment acting on two to three etiopathogenetic mechanisms could help manage DN in the future, in addition to the good glycaemic control.

 

Neuropathic Pain in Diabetes: New Mechanisms and Molecules

Giuseppe Lauria, presented a session at the 60th Annual Meeting of the European Association for the Study of Diabetes (EASD) 2024, held in Madrid, Spain from 9th September – 13th September and discussed about neuropathic pain in diabetes its mechanism and treatments.

 Some DN patients have neuropathic pain while other do not. The reasons are:

  • Contribution of the brain: Painful DPN was predicted from increased parietal GPC/cre and thalamic glu/cre
  • DRG molecule networks: 75% of DRG neurons express Nav1.8, including >90% of C-nociceptors
  • Genetics and epigenetics: Full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans.

The variants in gene encoding Nav and other channels are potential risk factors rather than causative. The effect of Nav inhibition was evaluated in a trial. Vixotrigine (BIIB074) is a broad-spectrum sodium channel blocker. The outcomes were:

  • VX-548 (suzetrigine) specifically targets Nav1.8 sodium channels, which play a key role in pain transmission, making it a promising treatment for neuropathic pain.
  • In clinical trials, over 30% of patients treated with VX-548 showed a 250% reduction in pain across all dose groups. This suggests substantial efficacy in reducing pain intensity.
  • More than 20% of patients in the mid- and high-dose groups experienced a ≥70% reduction in their weekly pain scores, indicating that higher doses may lead to more significant pain relief.
  • VX-548 was well tolerated at all dose levels, with no reports of severe adverse events, making it a potentially safe option for patients.
  • VX-548’s effective in pain reduction and has favourable safety profile.

Understanding the biological factors behind the painless phenotype could help address the causes of the painful phenotype in neuropathic conditions. Susceptibility to neuropathic pain is not solely determined by single-gene inheritance, and the effectiveness of targeting Nav channels remains to be confirmed. Identifying new therapeutic targets requires studying dorsal root ganglion (DRG) neuron clusters and controlling hyperexcitability. A biology-based approach to patient stratification, considering genetic, epigenetic, and central nervous system (CNS) metabolic factors, is essential. However, current randomized controlled trials (RCTs) still enroll patients based only on clinical features, assuming all have similar biological susceptibility.

 

Are Current Strategies Delivering the Holistic Treatment Approach for People Living with T2D?

Type 2 diabetes is a chronic complex disease, and management requires multifactorial behavioural and pharmacological treatments to prevent or delay complications and maintain quality of life. Melanie J. Davies discussed whether the current strategies are delivering the holistic treatment approach for people living with T2D? The findings were presented at the 60th EASD Annual Meeting 2024, held in Madrid, Spain from 9th – 13th September 2024.

Weight reduction has mostly been seen as a strategy to improve glycaemic management and reduce the risk for weight-related complications. It was recently suggested that weight loss of 5-15% should be a primary target in management for many people living with type 2 diabetes. A higher magnitude of weight loss confers better outcomes, and a 5-10% loss confers metabolic improvement, and a loss of 10-15% or more of body weight can have a disease-modifying effect, and lead to remission of diabetes. Weight loss may exert benefits that extend beyond glycaemic management to improve risk factors for cardiometabolic disease and quality of life.

SGLT2 inhibitors have come a long way: from glucose control to organ-protection. SGLT2 inhibitors have demonstrated, metabolic benefits in patients with T2D, CV and kidney benefits in patients with T2D and a high risk for CVD, or presence of CKD, CV benefits in patients with HF, independent of T2D & kidney benefits in patients with CKD, independent of T2D. Also, the GLP-1 class is highly heterogeneous offering weight reduction & reducing CV risk.

SELECT trial tested if Semaglutide 2.4 mg subcutaneously once weekly was superior to placebo when added to standard of care in preventing MACE in patients with established CVD and overweight or obesity but without diabetes. Semaglutide 2.4 mg significantly reduced MACE incidence, by 20%. Semaglutide 2.4 mg improves HF-related symptoms, physical limitations and exercise function, reduced inflammation, and resulted in greater weight loss as compared with placebo. The magnitude of these benefits were large, clinically meaningful and highly statistically significant. Semaglutide also resulted in lower NTproBNP (despite substantial observed weight loss), with a signal towards fewer HF events (although the number of events was small) – suggesting important disease-modifying effects. Semaglutide was well-tolerated, with significantly fewer SAEs than placebo. Trends in Diabetes Treatment and Control in U.S. Adults from 1999-2018 indicated that despite recent advances in treatment options, HbA1c and BMI are not improving in people with diabetes. 49.5% of individuals with diabetes did not achieve an HbA1c <7%. 89.7% of individuals with diabetes had overweight or obesity.

The author concluded by saying that the other issues coming in the way of successful management of diabetes are therapeutic inertia, current therapies being under-utilised, some sub-populations underrepresented in trials (age, sex, race). There is lack of therapeutic options for some co-morbidities – MASLD etc, tolerability of agents, complexity of some therapeutic options, titration etc & lack of precision medicine approach. However… future looks exciting.

 

Innovative Treatment Strategies: Will They Make a Difference, or More of The Same?

The epidemiological link of obesity, diabetes, and CVD is alarming. 86% of people with diabetes live with overweight or obesity. 31% of people living with obesity have diabetes. >32% of people with diabetes have CVD. 50% of deaths related to T2D are due to CV causes. >2/3 of deaths related to a high BMI are due to CV causes. Tina Vilsbøll discussed innovative treatment strategies: will they make a difference, or more of the same? The findings were presented at the 60th EASD Annual Meeting 2024, held in Madrid, Spain from 9th – 13th September 2024.

However, as excess adiposity is a stronger driver for heart failure (HF), and obesity levels have remained largely unchanged in high-income countries, HF risks have not declined as much and may even be rising in the increasing number of people developing type 2 diabetes at younger ages. Many Atherosclerotic cardiovascular disease (ASCVD) risk factors are often elevated well in advance of development of frank hyperglycemia and type 2 diabetes such that absolute ASCVD and indeed HF and kidney risk is already elevated in people with impaired glucose metabolism.

The author shared the overview of status and key observations from obesity CVOTs and registries. Body weight loss has shown to reverse T2D in RCTS, ~5% remission per 1% weight loss in early T2D short to medium term. GLP-1 RAs have multifactorial effects beyond glycaemic control, on heart, pancreas, bone, g.i. tract, kidney, brain, liver & muscle. Established and emerging evidence supporting use of GLP-1 medicines. The FLOW trial, evaluating kidney disease outcomes in T2D, concluded that Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease.

Multifactorial mechanisms potentially underpinning worse outcomes in obesity related HFpEF and T2D are Insulin resistance, excess and ectopic adiposity, inflammation, diffuse myocardial fibrosis, local and systemic lipotoxicity, accelerated frailty and sarcopenia, microvascular dysfunction, increased oxidative stress, reduced nitric oxide, increased atrial stiffness, altered myocardial substrate utilisation & left atrial myopathy. In the STEP 1 trial extension, one year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.

New appetite-regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight-loss maintenance beyond appetite regulation.

The author concluded by saying that the new paradigm is not just weight loss but better quality weight loss. The unmet need is preservation of muscle mass and increase or maintenance of resting energy expenditure.